ESSENTIALS OF DIAGNOSIS
Risk factors include age, delayed childbearing, positive family history of breast cancer or genetic mutations (BRCA1, BRCA2), and personal history of breast cancer or some types of proliferative conditions.
Early findings: Single, nontender, firm to hard mass with ill-defined margins; mammographic abnormalities and no palpable mass.
Later findings: Skin or nipple retraction; axillary lymphadenopathy; breast enlargement, erythema, edema, pain; fixation of mass to skin or chest wall.
Breast cancer will develop in one of eight American women. Next to skin cancer, breast cancer is the most common cancer in women; it is second only to lung cancer as a cause of death. In 2016, there were approximately 246,660 new cases and 40,450 deaths from breast cancer in the United States. Worldwide, breast cancer is diagnosed in approximately 1.7 million women, and about 521,900 die of breast cancer each year, with the highest rates of diagnosis in Western Europe and North America and lowest rates in Africa and Asia. The highest rates of death are in black women in the United States and the lowest rates are in Korean women. These regional differences in incidence are likely due to the variable availability of screening mammography as well as differences in reproductive and hormonal factors. In western countries, incidence rates decreased with a reduced use of postmenopausal hormone therapy and mortality declined with increased use of screening and improved treatments. In contrast, incidence and mortality from breast cancer in many African and Asian countries have increased as reproductive factors have changed (such as delayed childbearing) and as the incidence of obesity has risen.
The most significant risk factor for the development of breast cancer is age. A woman’s risk of breast cancer rises rapidly until her early 60s, peaks in her 70s, and then declines. A significant family history of breast or ovarian cancer may also indicate a high risk of developing breast cancer. Germline mutations in the BRCA family of tumor suppressor genes accounts for approximately 5–10% of breast cancer diagnoses and tend to cluster in certain ethnic groups, including women of Ashkenazi Jewish descent. Women with a mutation in the BRCA1 gene, located on chromosome 17, have an estimated 85% chance of developing breast cancer in their lifetime. Other genes associated with an increased risk of breast and other cancers include BRCA2 (associated with a gene on chromosome 13); ataxia-telangiectasia mutation; and mutation of the tumor suppressor gene p53. If a woman has a compelling family history (such as breast cancer diagnosed in two first-degree relatives, especially if diagnosed younger than age 50; ovarian cancer; male breast cancer; or a first-degree relative with bilateral breast cancer), genetic testing may be appropriate. In general, it is best for a woman who has a strong family history to meet with a genetics counselor to undergo a risk assessment and decide whether genetic testing is indicated.
Even when genetic testing fails to reveal a predisposing genetic mutation, women with a strong family history of breast cancer are at higher risk for development of breast cancer. Compared with a woman with no affected family members, a woman who has one first-degree relative with breast cancer has double the risk of developing breast cancer and a woman with two first-degree relatives with breast cancer has triple the risk of developing breast cancer. The risk is further increased for a woman whose affected family member was premenopausal at the time of diagnosis or had bilateral breast cancer. Lifestyle and reproductive factors also contribute to risk of breast cancer. Nulliparous women and women whose first full-term pregnancy occurred after the age of 30 have an elevated risk. Early menarche (under age 12) and late natural menopause (after age 55) are associated with an increase in risk, especially for hormone receptor–positive breast cancer. Combined oral contraceptive pills may increase the risk of breast cancer. Several studies show that concomitant administration of progesterone and estrogen to postmenopausal women may markedly increase the incidence of breast cancer, compared with the use of estrogen alone or with no hormone replacement treatment. The Women's Health Initiative prospective randomized study of hormone replacement therapy stopped treatment with estrogen and progesterone early because of an increased risk of breast cancer compared with untreated women or women treated with estrogen alone. Alcohol consumption, high dietary intake of fat, and lack of exercise may also increase the risk of breast cancer. Fibrocystic breast condition, when accompanied by proliferative changes, papillomatosis, or atypical epithelial hyperplasia, and increased breast density on mammogram are also associated with an increased incidence. A woman who had cancer in one breast is at increased risk for cancer developing in the other breast. In these women, a contralateral cancer develops at rate of 1% or 2% per year. Women with cancer of the uterine corpus have a risk of breast cancer significantly higher than that of the general population, and women with breast cancer have a comparably increased risk of endometrial cancer. Socioeconomic and racial factors have also been associated with breast cancer risk. Breast cancer tends to be diagnosed more frequently in women of higher socioeconomic status.
Women at greater than average risk for developing breast cancer (Table 17–2) should be identified by their clinicians and monitored carefully. Several risk assessment models have been validated (most extensively the Gail 2 model) to evaluate a woman’s risk of developing cancer. Those with an exceptional family history should be counseled about the option of genetic testing. Some of these high-risk women may consider prophylactic mastectomy, oophorectomy, tamoxifen, or an aromatase inhibitor. The Prevention and Observation of Surgical Endpoints (PROSE) consortium monitored women with deleterious BRCA1/2 mutations from 1974 to 2008 and reported that 15% of women with a known BRCA mutation underwent bilateral prophylactic mastectomy, and none of them developed breast cancer during the 3 years of follow-up. In contrast, subsequent breast cancer developed in 98 (7%) of the 1372 women who did not have surgery. Moreover, women who underwent prophylactic salpingo-oophorectomy had a lower risk of ovarian cancer, all-cause mortality, as well as breast cancer- and ovarian cancer-specific mortality.
Table 17–2.Factors associated with increased risk of breast cancer. |Favorite Table|Download (.pdf) Table 17–2. Factors associated with increased risk of breast cancer.
|Race ||White |
|Age ||Older |
|Family history ||Breast cancer in parent, sibling, or child (especially bilateral or premenopausal) |
|Genetics ||BRCA1, BRCA2, or other unknown mutations |
|Previous medical history || |
Proliferative forms of fibrocystic disease
Cancer in other breast
|Menstrual history || |
Early menarche (under age 12)
Late menopause (after age 50)
|Reproductive history ||Nulliparous or late first pregnancy |
Women with genetic mutations in whom breast cancer develops may be treated in the same way as women who do not have mutations (ie, lumpectomy), though there is an increased risk of ipsilateral and contralateral breast cancer after lumpectomy for these women. One study showed that of patients with a diagnosis of breast cancer who were found to be carriers of a BRCA mutation, approximately 50% chose to undergo bilateral mastectomy.
et al. Reproductive risk factors and breast cancer subtypes: a review of the literature. Breast Cancer Res Treat. 2014 Feb;144(1):1–10.
et al. Breast cancer statistics, 2015: convergence of incidence rates between black and white women. CA Cancer J Clin. 2016 Jan;66(1):31–42.
et al. Increased rate of phenocopies in all age groups in BRCA1/BRCA2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2013 Dec;22(12):2269–76.
et al. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res (Phila). 2014 Feb;7(2):211–7.
VA; U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Feb 18;160(4):271–81.
et al. Long-term outcomes of BRCA1/BRCA2
testing: risk reduction and surveillance. Cancer. 2012 Jan 15;118(2):510–7.
et al. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):16–27.
et al. Breast density and breast cancer risk: a practical review. Mayo Clin Proc. 2014 Apr;89(4):548–57.
Several clinical trials have evaluated the use of selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, for prevention of breast cancer in women with no personal history of breast cancer but at high risk for developing the disease. A meta-analysis of nine of these studies including 83,399 women with a median follow-up of 65 months demonstrated a 38% reduction in breast cancer incidence (hazard ratio [HR], 0.62; 95% CI, 0.56, 0.69) with a 10-year cumulative incidence of 6.3% in control groups and 4.2% in SERM-treated groups. An increased risk of endometrial cancer, cataracts and venous thromboembolic events but a reduced risk of vertebral fractures was seen in SERM groups. While SERMs have been shown to be effective at reducing the risk of breast cancer, the use of this intervention by women has been relatively low, possibly due to the perceived risks and side effects of therapy. A cost-effectiveness study based on a meta-analysis of four randomized prevention trials showed that tamoxifen saves costs and improves life expectancy when higher risk (Gail 5-year risk at least 1.66%) women under the age of 55 years were treated.
Similar to SERMs, aromatase inhibitors (AIs), such as exemestane and anastrozole, have shown success in preventing breast cancer with a lower risk of uterine cancer and thromboembolic events, although bone loss is a significant side effect of this treatment. In one study, 4560 postmenopausal women at high risk for breast cancer were randomly assigned to receive exemestane or placebo for 5 years. With a median follow up of 35 months, there was a 65% relative risk reduction in the annual risk of invasive breast cancer (0.19% vs 0.55%; HR, 0.35; 95% CI, 0.18, 0.70; P = 0.002) for patients who received exemestane. While exemestane use was associated with a higher rate of adverse events (88% vs 85%; P = 0.003), there were no significant differences between the groups in terms of skeletal fractures or cardiovascular events, though longer follow up is needed to accurately assess these outcomes. The IBIS-II study randomized 3864 postmenopausal women at high risk for breast cancer to receive placebo or anastrozole for 5 years and demonstrated a 53% risk reduction in the anastrozole group (HR, 0.47; 95% CI, 0.32–0.68; P < 0.0001). Based on these data, exemestane and anastrozole are reasonable risk-reducing options for postmenopausal women at higher risk for breast cancer.
et al. Priorities for the primary prevention of breast cancer. CA Cancer J Clin. 2014 May–Jun;64(3):186–94.
et al; IBIS-II investigators. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014 Mar 22;383(9922):1041–8.
et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013 May 25;381(9880):1827–34.
et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015 Jan;16(1):67–75.
et al; CTG MAP
. 3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23;364(25):2381–91.
et al. A systematic review of breast cancer incidence risk prediction models with meta-analysis of their performance. Breast Cancer Res Treat. 2012 Apr;132(2):365–77.
et al. Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013 Apr 16;158(8):604–14.
Early Detection of Breast Cancer
A number of large screening programs, consisting of physical and mammographic examination of asymptomatic women, have been conducted over the years. On average, these programs identify 10 cancers per 1000 women over the age of 50 and 2 cancers per 1000 women under the age of 50. Screening detects breast cancer before it has spread to the lymph nodes in about 80% of the women evaluated. This increases the chance of survival to about 85% at 5 years.
Substantial evidence supports the use of routine screening mammography; however, recommendations relating to timing and frequency vary by different agencies and countries. About one-third of the abnormalities detected on screening mammograms will be found to be malignant when biopsy is performed. The probability of cancer on a screening mammogram is directly related to the Breast Imaging Reporting and Data System (BIRADS) assessment, and workup should be performed based on this classification. The sensitivity of mammography varies from approximately 60% to 90%. This sensitivity depends on several factors, including patient age, breast density, tumor size, tumor histology (lobular versus ductal), location, and mammographic appearance. In young women with dense breasts (eFigure 17–1), mammography is less sensitive than in older women with fatty breasts, in whom mammography can detect at least 90% of malignancies (eFigure 17–2). Smaller tumors, particularly those without calcifications, are more difficult to detect, especially in dense breasts. The lack of sensitivity and the low incidence of breast cancer in young women have led to questions concerning the value of mammography for screening in women 40–50 years of age. The specificity of mammography in women under 50 years varies from about 30% to 40% for nonpalpable mammographic abnormalities to 85% to 90% for clinically evident malignancies. In 2009, the US Preventive Services Task Force recommended against routine screening mammography in this age range, and also recommended mammography be performed every 2 years for women between the ages of 50 and 74. The change in recommendation for screening women aged 40–50 was particularly controversial in light of several meta-analyses that included women in this age group and showed a 15–20% reduction in the relative risk of death from breast cancer with screening mammography. To add to the controversy, an analysis of the Surveillance, Epidemiology and End Results (SEER) database from 1976 to 2008 suggests that screening mammography has led to substantial increases in the number of breast cancer cases diagnosed but has only had a minor impact on the rate of women presenting with advanced disease. Currently, the American College of Radiology recommends annual mammography screening for women aged 40 and older and the American Cancer Society recommends screening average-risk women annually starting at the age of 45 and offering mammography to women who choose to do so starting at the age of 40. Thus, clinicians should have an informed discussion with patients about screening mammography regarding its potential risks (eg, false positives, overdiagnosis) and benefits (eg, early diagnosis), taking into consideration a patient’s individual risk factors.
Extremely dense breast. (Used, with permission, from Karla Kerlikowske, MD.)
Fatty breast. (Used, with permission, from Karla Kerlikowske, MD.)
Mammography is the most reliable means of detecting breast cancer before a mass can be palpated. Most slowly growing cancers can be identified by mammography at least 2 years before reaching a size detectable by palpation.
Indications for mammography are as follows: (1) screening at regular intervals asymptomatic women at risk for developing breast cancer; (2) evaluating each breast when a diagnosis of potentially curable breast cancer has been made, and at regular intervals thereafter; (3) evaluating a questionable or ill-defined breast mass or other suspicious change in the breast; (4) searching for an occult breast cancer in women with metastatic disease in axillary nodes or elsewhere from an unknown primary; (5) screening women prior to cosmetic operations or prior to biopsy of a mass, to examine for an unsuspected cancer; (6) monitoring women with breast cancer who have been treated with breast-conserving surgery and radiation; and (7) monitoring the contralateral breast in women with breast cancer treated with mastectomy.
Film screen mammography delivers less than 0.4 cGy to the mid breast per view. Although full-field digital mammography provides an easier method to maintain and review mammograms and may improve image quality, it has not been proven to improve overall cancer detection and is less economical. It may offer screening benefits to women younger than age 50 years and to women with dense breasts. While computer-assisted detection may increase the sensitivity of mammography, it has not been shown to improve mortality rates. Tomosynthesis creates tomographic “slices” of the breast volume with a single acquisition. This technique may improve the sensitivity of mammogram especially in patients with dense breast tissue but has not yet been shown in prospective studies to improve patient outcomes.
Calcifications are the most easily recognized mammographic abnormality. The most common findings associated with carcinoma of the breast are clustered pleomorphic microcalcifications. Such calcifications are usually at least five to eight in number, aggregated in one part of the breast and differing from each other in size and shape, often including branched or V- or Y-shaped configurations. There may be an associated mammographic mass density or, at times, only a mass density with no calcifications. Such a density usually has irregular or ill-defined borders and may lead to architectural distortion within the breast (eFigure 17–3) but may be subtle and difficult to detect.
Cancer in a fatty breast. (Used, with permission, from Karla Kerlikowske, MD.)
Patients with a dominant or suspicious mass on examination must undergo biopsy despite mammographic findings. The mammogram should be obtained prior to biopsy so that other suspicious areas can be noted and the contralateral breast can be evaluated. Mammography is never a substitute for biopsy because it may not reveal clinical cancer, especially in a very dense breast (eFigure 17–4).
Heterogeneously dense tissue. (Used, with permission, from Karla Kerlikowske, MD.)
Communication and documentation among the patient, the referring clinician, and the interpreting physician are critical for high-quality screening and diagnostic mammography. The patient should be told about how she will receive timely results of her mammogram; that mammography does not “rule out” cancer; and that she may receive a correlative examination such as ultrasound at the mammography facility if referred for a suspicious lesion. She should also be aware of the technique and need for breast compression and that this may be uncomfortable. The mammography facility should be informed in writing by the clinician of abnormal physical examination findings. The Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines strongly recommend that all mammography reports be communicated in writing to the patient and referring clinician. Legislation has been passed in a number of US states that requires imaging facilities to report to patients the density of their breasts. This may prompt women with dense breasts to discuss with their clinician whether or not additional screening options would be appropriate in addition to mammogram.
MRI and ultrasound may be useful screening modalities in women who are at high risk for breast cancer but not for the general population. The sensitivity of MRI is much higher than mammography; however, the specificity is significantly lower and this results in multiple unnecessary biopsies. The increased sensitivity despite decreased specificity may be considered a reasonable trade-off for those at increased risk for developing breast cancer but not for normal-risk population. The National Comprehensive Cancer Network guidelines recommend MRI in addition to screening mammography for high-risk women, including those with BRCA1/2 mutations, those who have a lifetime risk of breast cancer of greater than 20%, and those with a personal history of LCIS. Women who received radiation therapy to the chest in their teens or twenties are also known to be at high risk for developing breast cancer and screening MRI may be considered in addition to mammography. MRI is useful in women with breast implants to determine the character of a lesion present in the breast and to search for implant rupture and at times is helpful in patients with prior lumpectomy and radiation.
C. Clinical Breast Examination and Self-Examination
Breast self-examination has not been shown to improve survival. Because of the lack of strong evidence demonstrating value, the American Cancer Society no longer recommends monthly breast self-examination. While breast self-examination is not a recommended practice, patients should recognize and report any breast changes to their clinicians as it remains an important facet of proactive care.
et al. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012 Nov 22;367(21):1998–2005.
et al. Beyond mammography: new frontiers in breast cancer screening. Am J Med. 2013 Jun;126(6):472–9.
et al. Breast cancer screening: an evidence-based update. Med Clin North Am. 2015 May;99(3):451–68.
et al. The cost of breast cancer screening in the Medicare population. JAMA Intern Med. 2013 Feb 11;173(3):220–6.
et al. United States Preventive Services Task Force screening mammography recommendations: science ignored. AJR Am J Roentgenol. 2011 Feb;196(2):W112–6.
Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012 Nov 17;380(9855):1778–86.
et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ. 2014 Feb 11;348:g366.
et al. MRI for breast cancer screening, diagnosis, and treatment. Lancet. 2011 Nov 19;378(9805):1804–11.
et al. Benefits and harms of breast cancer screening: a systematic review. JAMA. 2015 Oct 20;314(15):1615–34.
et al. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015 Oct 20;314(15):1599–614.
et al. Breast cancer screening in an era of personalized regimens: a conceptual model and National Cancer Institute initiative for risk-based and preference-based approaches at a population level. Cancer. 2014 Oct 1;120(19):2955–64.
et al. A systematic assessment of benefits and risks to guide breast cancer screening decisions. JAMA. 2014 Apr 2;311(13):1327–35.
et al. The National Prevention Strategy and breast cancer screening: scientific evidence for public health action. Am J Public Health. 2013 Sep;103(9):1545–8.
et al. Impact of the addition of digital breast tomosynthesis (dbt) to standard 2d digital screening mammography on the rates of patient recall, cancer detection, and recommendations for short-term follow-up. Acad Radiol. 2017 Mar;24(3):302–7.
et al. Breast-cancer tumor size, overdiagnosis, and mammography screening effectiveness. N Engl J Med. 2016 Oct 13;375(15):1438–47.
Clinical Findings Associated With Early Detection of Breast Cancer
The presenting complaint in about 70% of patients with breast cancer is a lump (usually painless) in the breast. About 90% of these breast masses are discovered by the patient. Less frequent symptoms are breast pain; nipple discharge; erosion, retraction, enlargement, or itching of the nipple; and redness, generalized hardness, enlargement, or shrinking of the breast. Rarely, an axillary mass or swelling of the arm may be the first symptom. Back or bone pain, jaundice, or weight loss may be the result of systemic metastases, but these symptoms are rarely seen on initial presentation.
The relative frequency of carcinoma in various anatomic sites in the breast is shown in Figure 17–2.
Frequency of breast carcinoma at various anatomic sites.
Inspection of the breast is the first step in physical examination and should be carried out with the patient sitting, arms at her sides and then overhead. Abnormal variations in breast size and contour, minimal nipple retraction, and slight edema, redness, or retraction of the skin can be identified (Figure 17–3). Asymmetry of the breasts and retraction or dimpling of the skin can often be accentuated by having the patient raise her arms overhead or press her hands on her hips to contract the pectoralis muscles. Axillary and supraclavicular areas should be thoroughly palpated for enlarged nodes with the patient sitting (Figure 17–4). Palpation of the breast for masses or other changes should be performed with the patient both seated and supine with the arm abducted (eFigure 17–5). Palpation with a rotary motion of the examiner’s fingers as well as a horizontal stripping motion has been recommended.
Peau d’orange sign (resemblance to the skin of an orange due to lymphedema) in advanced breast cancer. (Reproduced, with permission, from Richard P. Usatine, MD.)
Palpation of axillary region for enlarged lymph nodes.
Palpation of breasts. Palpation is performed with the patient supine and arm abducted.
Breast cancer usually consists of a nontender, firm or hard mass with poorly delineated margins (caused by local infiltration). Very small (1–2 mm) erosions of the nipple epithelium may be the only manifestation of Paget disease of the breast. Watery, serous, or bloody discharge from the nipple is an occasional early sign but is more often associated with benign disease.
A lesion smaller than 1 cm in diameter may be difficult or impossible for the examiner to feel but may be discovered by the patient. She should always be asked to demonstrate the location of the mass; if the clinician fails to confirm the patient’s suspicions and imaging studies are normal, the examination should be repeated in 2–3 months, preferably 1–2 weeks after the onset of menses. During the premenstrual phase of the cycle, increased innocuous nodularity may suggest neoplasm or may obscure an underlying lesion (eFigure 17–6). If there is any question regarding the nature of an abnormality under these circumstances, the patient should be asked to return after her menses.
Scattered fibroglandular tissue. (Used, with permission, from Karla Kerlikowske, MD.)
Metastases tend to involve regional lymph nodes, which may be palpable. One or two movable, nontender, not particularly firm axillary lymph nodes 5 mm or less in diameter are frequently present and are generally of no significance. Firm or hard nodes larger than 1 cm are typical of metastases. Axillary nodes that are matted or fixed to skin or deep structures indicate advanced disease (at least stage III). On the other hand, if the examiner thinks that the axillary nodes are involved, that impression will be borne out by histologic section in about 85% of cases. The incidence of positive axillary nodes increases with the size of the primary tumor. Noninvasive cancers (in situ) do not metastasize. Metastases are present in about 30% of patients with clinically negative nodes.
In most cases, no nodes are palpable in the supraclavicular fossa. Firm or hard nodes of any size in this location or just beneath the clavicle should be biopsied. Ipsilateral supraclavicular or infraclavicular nodes containing cancer indicate that the tumor is in an advanced stage (stage III or IV). Edema of the ipsilateral arm, commonly caused by metastatic infiltration of regional lymphatics, is also a sign of advanced cancer.
Liver or bone metastases may be associated with elevation of serum alkaline phosphatase. Hypercalcemia is an occasional important finding in advanced cancer of the breast. Serum tumor markers such as carcinoembryonic antigen (CEA) and CA 15-3 or CA 27-29 are not recommended for diagnosis of early lesions or for routine surveillance for recurrence after a breast cancer diagnosis.
1. For lesions felt only by the patient
Ultrasound is often valuable and mammography essential when an area is felt by the patient to be abnormal but the clinician feels no mass. MRI may be considered, but the lack of specificity should be discussed by the clinician and the patient. MRI should not be used to rule out cancer because MRI has a false-negative rate of about 3–5%. Although lower than mammography, this false-negative rate cannot permit safe elimination of the possibility of cancer. False-negative results are more likely seen in infiltrating lobular carcinomas and DCIS than invasive ductal carcinoma.
2. For metastatic lesions
For patients with suspicious symptoms or signs (bone pain, abdominal symptoms, elevated liver biochemical tests) or locally advanced disease (clinically abnormal lymph nodes or large primary tumors), staging scans are indicated prior to surgery or systemic therapy. Chest imaging with CT or radiographs may be done to evaluate for pulmonary metastases. Abdominal imaging with CT or ultrasound may be obtained to evaluate for liver metastases. Bone scans using 99mTc-labeled phosphates or phosphonates are more sensitive than skeletal radiographs in detecting metastatic breast cancer. Bone scanning has not proved to be of clinical value as a routine preoperative test in the absence of symptoms, physical findings, or abnormal alkaline phosphatase or calcium levels. The frequency of abnormal findings on bone scan parallels the status of the axillary lymph nodes on pathologic examination. Positron emission tomography (PET) scanning alone or combined with CT (PET-CT) may also be used for detecting soft tissue or visceral metastases in patients with symptoms or signs of metastatic disease.
The diagnosis of breast cancer depends ultimately on examination of tissue or cells removed by biopsy. Treatment should never be undertaken without an unequivocal histologic or cytologic diagnosis of cancer. The safest course is biopsy examination of all suspicious lesions found on physical examination or mammography, or both. About 60% of lesions clinically thought to be cancer prove on biopsy to be benign, while about 30% of clinically benign lesions are found to be malignant. These findings demonstrate the fallibility of clinical judgment and the necessity for biopsy.
All breast masses require a histologic diagnosis with one probable exception: a nonsuspicious, presumably fibrocystic mass, in a premenopausal woman. Rather, these masses can be observed through one or two menstrual cycles. However, if the mass is not cystic and does not completely resolve during this time, it must be biopsied. Figures 17–5 and 17–6 present algorithms for management of breast masses in premenopausal and postmenopausal patients.
Evaluation of breast masses in premenopausal women. (Adapted, with permission, from Chang S, Haigh PI, Giuliano AE. Breast disease. In: Berek JS, Hacker NF [editors], Practical Gynecologic Oncology, 4th ed, Philadelphia: Lippincott Williams & Wilkins, 2004.)
Evaluation of breast masses in postmenopausal women. (Adapted, with permission, from Chang S, Haigh PI, Giuliano AE. Breast disease. In: Berek JS, Hacker NF [editors], Practical Gynecologic Oncology, 4th ed, Philadelphia: Lippincott Williams & Wilkins, 2004.)
The simplest biopsy method is needle biopsy, either by aspiration of tumor cells (FNA cytology) or by obtaining a small core of tissue with a hollow needle (core biopsy).
Large-needle (core needle) biopsy removes a core of tissue with a large cutting needle and is the diagnostic procedure of choice for both palpable and image-detected abnormalities. Handheld biopsy devices make large-core needle biopsy of a palpable mass easy and cost effective in the office with local anesthesia. As in the case of any needle biopsy, the main problem is sampling error due to improper positioning of the needle, giving rise to a false-negative test result. This is extremely unusual with image-guided biopsies. Core biopsy allows the tumor to be tested for the expression of biological markers, such as estrogen receptor (ER), progesterone receptor (PR) and HER2.
FNA cytology is a technique whereby cells are aspirated with a small needle and examined cytologically. This technique can be performed easily with virtually no morbidity and is much less expensive than excisional or open biopsy. The main disadvantages are that it requires a pathologist skilled in the cytologic diagnosis of breast cancer and it is subject to sampling problems, particularly because deep lesions may be missed. Furthermore, noninvasive cancers usually cannot be distinguished from invasive cancers and immunohistochemical tests to determine expression of hormone receptors and the amplification of the HER2 oncogene cannot be reliably performed on FNA biopsies. The incidence of false-positive diagnoses is extremely low, perhaps 1–2%. The false-negative rate is as high as 10%. Most experienced clinicians would not leave a suspicious dominant mass in the breast even when FNA cytology is negative unless the clinical diagnosis, breast imaging studies, and cytologic studies were all in agreement, such as a fibrocystic lesion or fibroadenoma. Given the stated limitations, FNA is not the modality of choice for sampling an abnormal breast mass.
Open biopsy under local anesthesia as a separate procedure prior to deciding upon definitive treatment has become less common with the increased use of core needle biopsy. Needle biopsy, when positive, offers a more rapid approach with less expense and morbidity, but when nondiagnostic it must be followed by open biopsy. It generally consists of an excisional biopsy, which is done through an incision with the intent to remove the entire abnormality, not simply a sample. As an alternative in highly suspicious circumstances, the diagnosis may be made on a frozen section of tissue obtained by open biopsy under general anesthesia. If the frozen section is positive, the surgeon can proceed immediately with the definitive operation. This one-step method is rarely used today except when a cytologic study has suggested cancer but is not diagnostic and there is a high clinical suspicion of malignancy in a patient well prepared for the diagnosis of cancer and its treatment options.
In general, the two-step approach—outpatient large-needle biopsy followed by definitive operation at a later date—is preferred in the diagnosis and treatment of breast cancer because patients can be given time to adjust to the diagnosis of cancer, can consider alternative forms of therapy, and can seek a second opinion if they wish. There is no adverse effect from the few weeks’ delay of the two-step procedure.
2. Biopsy with ultrasound guidance
Ultrasonography is performed primarily to differentiate cystic from solid lesions but may show signs suggestive of carcinoma. Ultrasonography may show an irregular mass within a cyst in the rare case of intracystic carcinoma. If a tumor is palpable and feels like a cyst, an 18-gauge needle can be used to aspirate the fluid and make the diagnosis of cyst. If a cyst is aspirated and the fluid is nonbloody, it does not have to be examined cytologically. If the mass does not recur, no further diagnostic test is necessary. Nonpalpable mammographic densities that appear benign should be investigated with ultrasound to determine whether the lesion is cystic or solid. These may even be needle biopsied with ultrasound guidance.
3. Biopsy with mammographic guidance (“stereotactic biopsy”)
When a suspicious abnormality is identified by mammography alone and cannot be palpated by the clinician, the lesion should be biopsied under mammographic guidance. In the computerized stereotactic guided core needle technique, a biopsy needle is inserted into the lesion with mammographic guidance, and a core of tissue for histologic examination can then be examined. Vacuum assistance increases the amount of tissue obtained and improves diagnosis.
Mammographic localization biopsy is performed by obtaining a mammogram in two perpendicular views and placing a needle or hook-wire near the abnormality so that the surgeon can use the metal needle or wire as a guide during operation to locate the lesion. After mammography confirms the position of the needle in relation to the lesion, an incision is made and the subcutaneous tissue is dissected until the needle is identified. Often, the abnormality cannot even be palpated through the incision—as is the case with microcalcifications—and thus it is essential to obtain a mammogram of the specimen to document that the lesion was excised. At that time, a second marker needle can further localize the lesion for the pathologist. Stereotactic core needle biopsies have proved equivalent to mammographic localization biopsies. Core biopsy is preferable to mammographic localization for accessible lesions since an operation can be avoided. A metal clip should be placed after any image-guided core biopsy to facilitate finding the site of the lesion if subsequent treatment is necessary.
4. Other imaging modalities
Other modalities of breast imaging have been investigated for diagnostic purposes. Automated breast ultrasonography is useful in distinguishing cystic from solid lesions but should be used only as a supplement to physical examination and mammography. Ductography may be useful to define the site of a lesion causing a bloody discharge, but since biopsy is almost always indicated, ductography may be omitted and the blood-filled nipple system excised. Ductoscopy has shown some promise in identifying intraductal lesions, especially in the case of pathologic nipple discharge, but in practice, this technique is rarely used. MRI is highly sensitive but not specific and should not be used for screening except in highly selective cases. For example, MRI is useful in differentiating scar from recurrence postlumpectomy and may be valuable to screen high-risk women (eg, women with BRCA mutations). It may also be of value to examine for multicentricity when there is a known primary cancer; to examine the contralateral breast in women with cancer; to examine the extent of cancer, especially lobular carcinomas; or to determine the response to neoadjuvant chemotherapy. Moreover, MRI-detected suspicious findings that are not seen on mammogram or ultrasound may be biopsied under MRI-guidance. PET scanning does not appear useful in evaluating the breast itself but is useful to examine for distant metastases.
Cytologic examination of nipple discharge or cyst fluid may be helpful on rare occasions. As a rule, mammography (or ductography) and breast biopsy are required when nipple discharge or cyst fluid is bloody or cytologically questionable.
The lesions to be considered most often in the differential diagnosis of breast cancer are the following, in descending order of frequency: fibrocystic condition of the breast, fibroadenoma, intraductal papilloma, lipoma, and fat necrosis.
The American Joint Committee on Cancer and the International Union Against Cancer have agreed on a TNM (tumor, regional lymph nodes, distant metastases) staging system for breast cancer. Using the TNM staging system (https://cancerstaging.org/references-tools/quickreferences/Documents/BreastLarge.pdf) enhances communication between researchers and clinicians. eTable 17–1 outlines the TNM classification.
eTable 17–1.TNM staging for breast cancer. |Favorite Table|Download (.pdf) eTable 17–1. TNM staging for breast cancer.
|Primary Tumor (T) |
|Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3). If other measurements, such as mammographic or pathologic measurements, are used, the subsets of T1 can be used. Tumors should be measured to the nearest 0.1 cm increment. |
|TX||Primary tumor cannot be assessed |
|T0||No evidence of primary tumor |
|Tis||Carcinoma in situ |
|Tis (DCIS)||Ductal carcinoma in situ |
|Tis (LCIS)||Lobular carcinoma in situ |
|Tis (Paget)||Paget disease of the nipple with no tumor |
|Note: Paget disease associated with a tumor is classified according to the size of the tumor. |
|T1||Tumor 2 cm or less in greatest dimension |
|T1mic||Microinvasion 0.1 cm or less in greatest dimension |
|T1a||Tumor more than 0.1 cm but not more than 0.5 cm in greatest dimension |
|T1b||Tumor more than 0.5 cm but not more than 1 cm in greatest dimension |
|T1c||Tumor more than 1 cm but not more than 2 cm in greatest dimension |
|T2||Tumor more than 2 cm but not more than 5 cm in greatest dimension |
|T3||Tumor more than 5 cm in greatest dimension |
|T4||Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below |
|T4a||Extension to chest wall, not including pectoralis muscle |
|T4b||Edema (including peau d'orange [see Figure 17–3]) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast |
|T4c||Both T4a and T4b |
|T4d||Inflammatory carcinoma |
|Regional Lymph Nodes (N) |
|NX||Regional lymph nodes cannot be assessed (eg, previously removed) |
|N0||No regional lymph node metastasis |
|N1||Metastasis in movable ipsilateral axillary lymph node(s) |
|N2||Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent1 ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis |
|N2a||Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures |
|N2b||Metastasis only in clinically apparent1 ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis |
|N3||Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparent1 ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement |
|N3a||Metastasis in ipsilateral infraclavicular lymph node(s) |
|N3b||Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) |
|N3c||Metastasis in ipsilateral supraclavicular lymph node(s) |
|Regional Lymph Nodes (pN)2 |
|pNX||Regional lymph nodes cannot be assessed (eg, previously removed, or not removed for pathologic study) |
|pN0||No regional lymph node metastasis histologically, no additional examination for isolated tumor cells |
|Note: Isolated tumor cells (ITC) are defined as single tumor cells or small cell clusters not > 0.2 mm, usually detected only by immunohistochemical (IHC) or molecular methods but which may be verified on hematoxylin and eosin stains. ITCs do not usually show evidence of malignant activity, eg, proliferation or stromal reaction. |
|pN0(i–)||No regional lymph node metastasis histologically, negative IHC |
|pN0(i+)||No regional lymph node metastasis histologically, positive IHC, no IHC cluster > 0.2 mm |
|pN0(mol–)||No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)3 |
|pN0(mol+)||No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)3 |
|pN1||Metastasis in one to three axillary lymph nodes, and/or in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent4 |
|pN1mi||Micrometastasis (> 0.2 mm, none > 2.0 mm) |
|pN1a||Metastasis in one to three axillary lymph nodes |
|pN1b||Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent 4 |
|pN1c||Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent.4 (If associated with greater than three positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden) |
|pN2||Metastasis in four to nine axillary lymph nodes, or in clinically apparent1 internal mammary lymph nodes in the absence of axillary lymph node metastasis |
|pN2a||Metastasis in four to nine axillary lymph nodes (at least one tumor deposit > 2.0 mm) |
|pN2b||Metastasis in clinically apparent1 internal mammary lymph nodes in the absence of axillary lymph node metastasis |
|pN3||Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparent1 ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes |
|pN3a||Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit > 2.0 mm), or metastasis to the infraclavicular lymph nodes |
|pN3b||Metastasis in clinically apparent1 ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent4 |
|pN3c||Metastasis in ipsilateral supraclavicular lymph nodes |
|Distant Metastasis (M) |
|MX||Distant metastasis cannot be assessed |
|M0||No distant metastasis |
|M1||Distant metastasis |
|Stage Grouping |
|Stage 0 ||Tis ||N0 ||M0 |
|Stage 1 ||T15 ||N0 ||M0 |
|Stage IIA || |
|Stage IIB || |
|Stage IIIA || |
|Stage IIIB || |
|Stage IIIC ||Any T ||N3 ||M0 |
|Stage IV ||Any T ||Any N ||M1 |
Numerous pathologic subtypes of breast cancer can be identified histologically (Table 17–3).
Table 17–3.Histologic types of breast cancer. |Favorite Table|Download (.pdf) Table 17–3. Histologic types of breast cancer.
|Type ||Frequency of Occurrence |
|Infiltrating ductal (not otherwise specified) ||80–90% |
| Medullary ||5–8% |
| Colloid (mucinous) ||2–4% |
| Tubular ||1–2% |
| Papillary ||1–2% |
|Invasive lobular ||6–8% |
|Noninvasive ||4–6% |
| Intraductal ||2–3% |
| Lobular in situ ||2–3% |
|Rare cancers ||< 1% |
| Juvenile (secretory) || |
| Adenoid cystic || |
| Epidermoid || |
| Sudoriferous || |
Except for the in situ cancers, the histologic subtypes have only a slight bearing on prognosis when outcomes are compared after accurate staging. The noninvasive cancers by definition are confined by the basement membrane of the ducts and lack the ability to spread. Histologic parameters for invasive cancers, including lymphovascular invasion and tumor grade, have been shown to be of prognostic value. Immunohistochemical analysis for expression of hormone receptors and for overexpression of HER2 in the primary tumor offers prognostic and therapeutic information.
Special Clinical Forms of Breast Cancer
Paget carcinoma is not common (about 1% of all breast cancers). Over 85% of cases are associated with an underlying invasive or noninvasive cancer, usually a well differentiated infiltrating ductal carcinoma or a DCIS. The ducts of the nipple epithelium are infiltrated, but gross nipple changes are often minimal, and a tumor mass may not be palpable.
Because the nipple changes appear innocuous, the diagnosis is frequently missed. The first symptom is often itching or burning of the nipple, with superficial erosion or ulceration. These are often diagnosed and treated as dermatitis or bacterial infection, leading to delay or failure in detection. The diagnosis is established by biopsy of the area of erosion. When the lesion consists of nipple changes only, the incidence of axillary metastases is less than 5%, and the prognosis is excellent. When a breast mass is also present, the incidence of axillary metastases rises, with an associated marked decrease in prospects for cure by surgical or other treatment.
B. Inflammatory Carcinoma
This is the most malignant form of breast cancer and constitutes less than 3% of all cases. The clinical findings consist of a rapidly growing, sometimes painful mass that enlarges the breast. The overlying skin becomes erythematous, edematous, and warm. Often there is no distinct mass, since the tumor infiltrates the involved breast diffusely. The inflammatory changes, often mistaken for an infection, are caused by carcinomatous invasion of the subdermal lymphatics (eFigure 17–7), with resulting edema and hyperemia (eFigure 17–8). If the clinician suspects infection but the lesion does not respond rapidly (1–2 weeks) to antibiotics, biopsy should be performed. The diagnosis should be made when the redness involves more than one-third of the skin over the breast and biopsy shows infiltrating carcinoma with invasion of the subdermal lymphatics. Metastases tend to occur early and widely, and for this reason inflammatory carcinoma is rarely curable. Radiation, hormone therapy (if hormone receptor positive), anti-HER2 therapy (if HER2 overexpressing or amplified), and chemotherapy are the measures most likely to be of value initially rather than operation. Mastectomy is indicated when chemotherapy and radiation have resulted in clinical remission with no evidence of distant metastases. In these cases, residual disease in the breast may be eradicated.
Acute mastitis, which can look clinically identical to inflammatory carcinoma. (Used, with permission, from Armando E. Giuliano, MD.)
Inflammatory breast carcinoma, showing dermal lymphatic containing carcinoma cells (arrows). (Reproduced, with permission, from Chandrasoma P, Taylor CR. Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)
Breast Cancer Occurring During Pregnancy or Lactation
Breast cancer complicates up to one in 3000 pregnancies. The diagnosis is frequently delayed, because physiologic changes in the breast may obscure the lesion and screening mammography is not done in young or pregnant women. Data are insufficient to determine whether interruption of pregnancy improves the prognosis of patients who are identified to have potentially curable breast cancer and who receive definitive treatment during pregnancy. Theoretically, the high levels of estrogen produced by the placenta as the pregnancy progresses could be detrimental to the patient with occult metastases of hormone-sensitive breast cancer. The decision whether or not to terminate the pregnancy must be made on an individual basis, taking into account the patient’s clinical stage of the cancer and overall prognosis, the gestational age of the fetus, the potential for premature ovarian failure in the future with systemic therapy, and the patient’s wishes.
It is important for primary care and reproductive specialists to aggressively work up any breast abnormality discovered in a pregnant woman. Pregnancy (or lactation) is not a contraindication to operation or treatment, and therapy should be based on the stage of the disease as in the nonpregnant (or nonlactating) woman. Women with early-stage gestational breast cancer who choose to continue their pregnancy should undergo surgery to remove the tumor and systemic therapy if indicated. Retrospective reviews of patients treated with anthracycline-containing regimens for gestational cancers (including leukemia and lymphomas) have established the relative safety of these regimens during pregnancy for both the patient and the fetus. Taxane-based and trastuzumab-based regimens have not been evaluated extensively, however. Radiation therapy should be delayed until after delivery. Overall survival rates have improved, since cancers are now diagnosed in pregnant women earlier than in the past and treatment has improved.
Bilateral breast cancer occurs in less than 5% of cases, but there is as high as a 20–25% incidence of later occurrence of cancer in the second breast. Bilaterality occurs more often in familial breast cancer, in women under age 50 years, and when the tumor in the primary breast is lobular. The incidence of second breast cancers increases directly with the length of time the patient is alive after her first cancer—about 1–2% per year.
In patients with breast cancer, mammography should be performed before primary treatment and at regular intervals thereafter, to search for occult cancer in the opposite breast or conserved ipsilateral breast.
Noninvasive cancer can occur within the ducts (DCIS) or lobules (LCIS). DCIS tends to be unilateral and most often progresses to invasive cancer if untreated. In approximately 40–60% of women who have DCIS treated with biopsy alone, invasive cancer develops within the same breast. LCIS is generally agreed to be a marker of an increased risk of breast cancer rather than a direct precursor of breast cancer itself. The probability of breast cancer (DCIS or invasive in either breast) in a woman in whom LCIS has been diagnosed is estimated to be 1% per year. If LCIS is detected on core needle biopsy, an excisional biopsy without lymph node sampling should be performed to rule out DCIS or invasive cancer since these are found in 10–20% of patients. The incidence of LCIS is rising, likely due to increased use of screening mammography. In addition, the rate of mastectomy after the diagnosis of LCIS is increasing in spite of the fact that mastectomy is only recommended in those patients who otherwise have an increased risk of breast cancer through family history, genetic mutation, or past exposure to thoracic radiation. Pleomorphic LCIS may behave more like DCIS and may be associated with invasive carcinoma. For this reason, pleomorphic LCIS should be surgically removed with clear margins.
The treatment of intraductal lesions is controversial. DCIS can be treated by wide excision with or without radiation therapy or with total mastectomy. Conservative management is advised in patients with small lesions amenable to lumpectomy. Patients in whom LCIS is diagnosed or who have received lumpectomy for DCIS may discuss chemoprevention (with hormonal therapy) with their clinician, which is effective in preventing invasive breast cancer in both LCIS and DCIS that has been completely excised by breast-conserving surgery. Axillary metastases from in situ cancers should not occur unless there is an occult invasive cancer. Because one cannot perform a sentinel lymph node biopsy after mastectomy, one might consider performing a sentinel node biopsy in a patient undergoing mastectomy for DCIS in case an invasive component is discovered.
et al. The evaluation of national time trends, quality of care, and factors affecting the use of minimally invasive breast biopsy and open biopsy for diagnosis of breast lesions. Am J Surg. 2014 Sep;208(3):382–90.
AJ 3rd. Miscellaneous syndromes and their management: occult breast cancer, breast cancer in pregnancy, male breast cancer, surgery in stage IV disease. Surg Clin North Am. 2013 Apr;93(2):519–31.
et al. Association with pregnancy increases the risk of local recurrence but does not impact overall survival in breast cancer: a case-control study of 87 cases. Breast. 2016 Dec;30:222–7.
et al. The prognosis of women diagnosed with breast cancer before, during and after pregnancy: a meta-analysis. Breast Cancer Res Treat. 2016 Nov;160(2):347–60.
et al. Trends in incidence and management of lobular carcinoma in situ: a population-based analysis. Ann Surg Oncol. 2013 Oct;20(10):3240–6.
et al. Inflammatory breast cancer: the disease, the biology, the treatment. CA Cancer J Clin. 2010 Nov–Dec;60(6):351–75.
et al. No impact of breast magnetic resonance imaging on 15-year outcomes in patients with ductal carcinoma in situ or early-stage invasive breast cancer managed with breast conservation therapy. Cancer. 2017 Apr 15;123(8):1324-32.
Biomarkers & Gene Expression Profiling
Determining the ER, PR, and HER2 status of the tumor at the time of diagnosis of early breast cancer and, if possible, at the time of recurrence is critical, both to gauge a patient’s prognosis and to determine the best treatment regimen. In addition to ER status and PR status, the rate at which tumor divides (assessed by an immunohistochemical stain for Ki-67) and the grade and differentiation of the cells are also important prognostic factors. These markers may be obtained on core biopsy or surgical specimens, but not reliably on FNA cytology. Patients whose tumors are hormone receptor-positive tend to have a more indolent disease course than those whose tumors are receptor-negative. Moreover, treatment with an anti-hormonal agent is an essential component of therapy for hormone-receptor positive breast cancer at any stage. While up to 60% of patients with metastatic breast cancer will respond to hormonal manipulation if their tumors are ER-positive, less than 5% of patients with metastatic, ER-negative tumors will respond.
Another key element in determining treatment and prognosis is the amount of the HER2 oncogene present in the cancer. HER2 overexpression is measured by an immunohistochemical assay that is scored using a numerical system: 0 and 1+ are considered negative for overexpression, 2+ is borderline/indeterminate, and 3+ is overexpression. In the case of 2+ expression, fluorescence in situ hybridization (FISH) is recommended to more accurately assess HER2 amplification. Guidelines for the interpretation of HER2 results by IHC and FISH have been published by the College of American Pathologists. According to these guidelines, a tumor is positive for HER2 amplification if one of the two criteria is met: (1) dual-probe HER2/CEP17 ratio is 2.0 or more or (2) dual-probe HER2/CEP17 ratio is less than 2.0 with an average HER2 copy number 6.0 signals per cell or greater. If the dual-probe HER2/CEP17 ratio is less than 2.0 with an average HER2 copy number of 4.0 to 5.9 signals per cell, this is equivocal. The presence of HER2 amplification and overexpression is of prognostic significance and predicts the response to trastuzumab. Occasionally, a tumor has an indeterminate HER2 result by both immunohistochemistry and FISH testing. The College of American Pathologists guidelines provide direction for further analysis in this situation.
Individually these biomarkers are predictive and thus provide insight to guide appropriate therapy. Moreover, when combined they provide useful information regarding risk of recurrence and prognosis. In general, tumors that lack expression of HER2, ER, and PR (“triple negative”) have a higher risk of recurrence and metastases and are associated with a worse survival compared with other types. Neither endocrine therapy nor HER2-targeted agents are useful for this type of breast cancer, leaving chemotherapy as the only treatment option. In contrast, patients with early stage, hormone receptor–positive breast cancer may not benefit from the addition of chemotherapy to hormonally targeted treatments. Several molecular tests have been developed to assess risk of recurrence and to predict which patients are most likely to benefit from chemotherapy. Oncotype DX (Genomic Health) evaluates the expression of 21 genes relating to ER, PR, HER2, and proliferation in a tumor specimen and categorizes a patient's risk of recurrence (recurrence score) as high, intermediate, or low risk. In addition to providing prognostic information, the test also has predictive value since studies have shown that patients in the high-risk category are most likely to respond to chemotherapy. This test is primarily indicated for ER-positive, lymph node-negative tumors but at least one study has shown that it may also have value in node-positive tumors. Centralized testing for ER, PR, HER2 and Ki67 by standard immunohistochemical techniques is able to provide as much prognostic information as Oncotype DX. Mammaprint (Agendia) is an FDA-approved 70-gene signature assay that is available for evaluating prognosis. This test classifies patients into good and poor prognostic groups to predict clinical outcome and may be used on patients with hormone receptor positive or negative breast cancer. Several other assays are in development to better stratify patients based on risk assessment.
et al; The Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010 Jan;11(1):55–65.
et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4273–8.
et al. Molecular predictors of response to therapy for breast cancer. Cancer J. 2011 Mar–Apr;17(2):96–103.
et al. Breast-conserving therapy for triple-negative breast cancer. JAMA Surg. 2014 Mar;149(3):252–8.
et al. Molecular markers for breast cancer diagnosis, prognosis and targeted therapy. J Surg Oncol. 2015 Jan;111(1):81–90.
et al. HER2 gene amplification testing by Fluorescent In Situ Hybridization (FISH): comparison of the ASCO-College of American Pathologists Guidelines with FISH Scores used for enrollment in Breast Cancer International Research Group clinical trials. J Clin Oncol. 2016 Aug 29. [Epub ahead of print]
et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC 4 in the TransATAC study population. Lancet Oncol. 2013 Oct;14(11):1067–76.
et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015 Nov 19;373(21):2005–14.
et al. Epigenetic modifications in breast cancer and their role in personalized medicine. Am J Pathol. 2013 Oct;183(4):1052–63.
et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013 Nov 1;31(31):3997–4013.
Not all breast cancer is systemic at the time of diagnosis and a pessimistic attitude concerning the management of breast cancer is unwarranted. Most patients with early breast cancer can be cured. Treatment with a curative intent is advised for clinical stage I, II, and III disease (see Table 39–4). Patients with locally advanced (T3, T4) and even inflammatory tumors may be cured with multimodality therapy, but metastatic disease will be diagnosed in most patients and at that point, palliation becomes the goal of therapy. Treatment with palliative intent is appropriate for all patients with stage IV disease and for patients with unresectable local cancers.
A. Choice and Timing of Primary Therapy
The extent of disease and its biologic aggressiveness are the principal determinants of the outcome of primary therapy. Clinical and pathologic staging help in assessing extent of disease (see eTable 17–1), but each is to some extent imprecise. Other factors such as tumor grade, hormone receptor assays, and HER2 oncogene amplification are of prognostic value and are key to determining systemic therapy, but are not as relevant in determining the type of local therapy.
Controversy has surrounded the choice of primary therapy of stage I, II, and III breast carcinoma. Currently, the standard of care for stage I, stage II, and most stage III cancer is surgical resection followed by adjuvant radiation or systemic therapy, or both, when indicated. Neoadjuvant therapy has become popular since large tumors may be shrunk by chemotherapy prior to surgery, making some patients who require mastectomy candidates for lumpectomy. It is important for patients to understand all of the surgical options, including reconstructive options, prior to having surgery. Patients with large primary tumors, inflammatory cancer, or palpably enlarged lymph nodes should have staging scans performed to rule out distant metastatic disease prior to definitive surgery. In general, adjuvant systemic therapy is started when the breast has adequately healed, usually within 4–8 weeks after surgery. While no prospective studies have defined the appropriate timing of adjuvant chemotherapy, a single institution study of over 6800 patients suggests that systemic therapy should be started within 60 days of surgery, especially in women with stage II or III breast cancer, triple-negative breast cancer or HER2-positive disease.
1. Breast-conserving therapy
Multiple, large, randomized studies including the Milan and NSABP trials show that disease-free and overall survival rates are similar for patients with stage I and stage II breast cancer treated with partial mastectomy (breast-conserving lumpectomy or “breast conservation”) plus axillary dissection followed by radiation therapy and for those treated by modified radical mastectomy (total mastectomy plus axillary dissection).
Tumor size is a major consideration in determining the feasibility of breast conservation. The NSABP lumpectomy trial randomized patients with tumors as large as 4 cm. To achieve an acceptable cosmetic result, the patient must have a breast of sufficient size to enable excision of a 4-cm tumor without considerable deformity. Therefore, large tumor size is only a relative contraindication. Subareolar tumors, also difficult to excise without deformity, are not contraindications to breast conservation. Clinically detectable multifocality is a relative contraindication to breast-conserving surgery, as is fixation to the chest wall or skin or involvement of the nipple or overlying skin. The patient—not the surgeon—should be the judge of what is cosmetically acceptable. Given the relatively high risk of poor outcome after radiation, concomitant scleroderma is a contraindication to breast-conserving surgery. A history of prior therapeutic radiation to the ipsilateral breast or chest wall (or both) is also generally a contraindication for breast conservation.
Axillary dissection is primarily used to properly stage cancer and plan radiation and systemic therapy. Intraoperative lymphatic mapping and sentinel node biopsy identify lymph nodes most likely to harbor metastases if present (Figure 17–7). Sentinel node biopsy is a reasonable alternative to axillary dissection in patients without clinical evidence of axillary lymph node metastases. If sentinel node biopsy reveals no evidence of axillary metastases, it is highly likely that the remaining lymph nodes are free of disease and axillary dissection may be omitted. An important study from the American College of Surgeons Oncology Group randomized women with sentinel node metastases to undergo completion of axillary dissection or to receive no further axillary treatment after lumpectomy; no difference in survival was found, showing that axillary dissection is not necessary for selected patients with node involvement who are treated with lumpectomy, whole breast irradiation, and adjuvant systemic therapy. Omission of axillary dissection is accepted at many major cancer institutions.
Sentinel node. (Used, with permission, from Armando E. Giuliano, MD.)
Breast-conserving surgery with radiation is the preferred form of treatment for patients with early-stage breast cancer. Despite the numerous randomized trials showing no survival benefit of mastectomy over breast-conserving partial mastectomy and irradiation, breast-conserving surgery still appears to be underutilized.
Modified radical mastectomy was the standard therapy for most patients with early-stage breast cancer. This operation removes the entire breast, overlying skin, nipple, and areolar complex usually with underlying pectoralis fascia with the axillary lymph nodes in continuity (eFigure 17–9). The major advantage of modified radical mastectomy is that radiation therapy may not be necessary, although radiation may be used when lymph nodes are involved with cancer or when the primary tumor is 5 cm or larger. The disadvantage of mastectomy is the cosmetic and psychological impact associated with breast loss. Radical mastectomy, which removes the underlying pectoralis muscle, should be performed rarely, if at all. Axillary node dissection is not indicated for noninvasive cancers because nodal metastases are rarely present. Skin-sparing and nipple-sparing mastectomy is currently gaining favor but is not appropriate for all patients. Breast reconstruction, immediate or delayed, should be discussed with patients who choose or require mastectomy. Patients should have an interview with a reconstructive plastic surgeon to discuss options prior to making a decision regarding reconstruction. Time is well spent preoperatively in educating the patient and family about these matters.
Modified radical mastectomy defect. (Used, with permission, from Armando E. Giuliano, MD.)
Radiotherapy after partial mastectomy consists of 5–7 weeks of five daily fractions to a total dose of 5000–6000 cGy. Most radiation oncologists use a boost dose to the cancer location. Shorter fractionation schedules may be reasonable for women over the age of 50 with early stage, lymph node–negative breast cancer. Accelerated partial breast irradiation, in which only the portion of the breast from which the tumor was resected is irradiated for 1–2 weeks, appears effective in achieving local control for selected patients; however, the results of prospective randomized trials, such as the NSABP B-39/RTOG 0413, are awaited. In women over the age of 70 with small (less than 2 cm), lymph node–negative, hormone receptor–positive cancers, radiation therapy may be avoided. The recurrence rates after intraoperative radiation, while low, appear significantly higher than postoperative whole breast radiation therapy. However, in all of these situations, a balanced discussion with a radiation oncologist to weigh the risks and benefits of each approach is warranted.
Current studies suggest that radiotherapy after mastectomy may improve recurrence rates and survival in younger patients and those with tumors 5 cm or larger or positive lymph nodes. The AMAROS study randomized women with sentinel node metastases to ALND or nodal irradiation and found no significant difference in survival but lower lymphedema rates after radiation. An ACOSOG study (Z0010) and large NSABP trial (B-32) showed no adverse impact of micrometastases on survival and support no alteration in treatment when found. A Canadian trial (MA20) of postoperative nodal irradiation after lumpectomy and axillary dissection showed improved disease-free survival but not overall survival with nodal irradiation.
D. Adjuvant Systemic Therapy
The goal of systemic therapy, including hormone-modulating drugs (endocrine therapy), cytotoxic chemotherapy, and HER2-targeted agents such as trastuzumab, is to kill cancer cells that have escaped the breast and axillary lymph nodes as micrometastases before they become macrometastases (ie, stage IV cancer). Systemic therapy improves survival and is advocated for most patients with curable breast cancer. In practice, most medical oncologists are currently using adjuvant chemotherapy for patients with either node-positive or higher-risk (eg, hormone receptor-negative or HER2-positive) node-negative breast cancer and using endocrine therapy for all hormone receptor–positive invasive breast cancer unless contraindicated. Prognostic factors other than nodal status that are used to determine the patient’s risks of recurrence are tumor size, ER and PR status, nuclear grade, histologic type, proliferative rate, oncogene expression (Table 17–4), and patient’s age and menopausal status. In general, systemic chemotherapy decreases the chance of recurrence by about 30%, hormonal modulation decreases the relative risk of recurrence by 40–50% (for hormone receptor–positive cancer), and HER2-targeted therapy decreases the relative risk of recurrence by up to 40% (for HER2-positive cancer). Systemic chemotherapy is usually given sequentially, rather than concurrently with radiation. In terms of sequencing, typically chemotherapy is given before radiation and endocrine therapy is started concurrent with or after radiation therapy.
Table 17–4.Prognostic factors in node-negative breast cancer. |Favorite Table|Download (.pdf) Table 17–4. Prognostic factors in node-negative breast cancer.
|Prognostic Factors ||Increased Recurrence ||Decreased Recurrence |
|Size1 ||T3, T2 ||T1, T0 |
|Hormone receptors ||Negative ||Positive |
|DNA flow cytometry ||Aneuploid ||Diploid |
|Histologic grade ||High ||Low |
|Tumor labeling index ||< 3% ||> 3% |
|S phase fraction ||> 5% ||< 5% |
|Lymphatic or vascular invasion ||Present ||Absent |
|Cathepsin D ||High ||Low |
|HER2 oncogene ||High ||Low |
|Epidermal growth factor receptor ||High ||Low |
|High Oncotype DX Recurrence Score or other genomic prognostic assays ||High score ||Low score |
The long-term advantage of systemic therapy is well established. All patients with invasive hormone receptor–positive tumors should consider the use of hormone-modulating therapy. Most patients with HER2-positive tumors should receive trastuzumab-containing chemotherapy regimens. In general, adjuvant systemic chemotherapy should not be given to women who have small node-negative breast cancers with favorable histologic findings and tumor biomarkers. The ability to predict more accurately which patients with HER2-negative, hormone receptor–positive, lymph node–negative tumors should receive chemotherapy is improving with the advent of prognostic tools, such as Oncotype DX and Mamma-print. These tests are undergoing prospective evaluation in two clinical trials (TAILORx and MINDACT).
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis involving over 28,000 women enrolled in 60 trials of adjuvant polychemotherapy versus no chemotherapy demonstrated a significant beneficial impact of chemotherapy on clinical outcome in non–stage IV breast cancer. This study showed that adjuvant chemotherapy reduces the risk of recurrence and breast cancer–specific mortality in all women and also showed that women under the age of 50 derive the greatest benefit. On the basis of the superiority of anthracycline-containing regimens in metastatic breast cancer, both doxorubicin and epirubicin have been studied extensively in the adjuvant setting. Studies comparing Adriamycin (doxorubicin) and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) to cyclophosphamide-methotrexate-5-fluorouracil (CMF) have shown that treatments with anthracycline-containing regimens are at least as effective as treatment with CMF. The EBCTCG analysis including over 14,000 patients enrolled in trials comparing anthracycline-based regimens to CMF, showed a small but statistically significant improved disease-free and overall survival with the use of anthracycline-based regimens. It should be noted, however, that most of these studies included a mixed population of patients with HER2-positive and HER2-negative breast cancer and were performed before the introduction of trastuzumab. Retrospective analyses of a number of these studies suggest that anthracyclines may be primarily effective in tumors with HER2 overexpression or alteration in the expression of topoisomerase IIa (the target of anthracyclines and close to the HER2 gene). Given this, for HER2-negative, node-negative breast cancer, four cycles of AC or six cycles of CMF are probably equally effective.
When taxanes (paclitaxel and docetaxel) emerged in the 1990s, multiple trials were conducted to evaluate their use in combination with anthracycline-based regimens. The majority of these trials showed an improvement in disease-free survival and at least one showed an improvement in overall survival with the taxane-based regimen. A meta-analysis of taxane versus non-taxane anthracycline-based regimen trials showed an improvement in disease-free and overall survival for the taxane-based regimens. Several regimens have been reported including AC followed by paclitaxel (AC-P) or docetaxel (Taxotere) (AC-T), docetaxel concurrent with AC (TAC), 5-fluorouracil-epirubicine-cyclophosphamide (FEC)-docetaxel and FEC-paclitaxel. Results from CALGB 9741 showed that compared with a standard dose regimen, administration of "dose-dense" AC-P chemotherapy (that is, in an accelerated fashion, in which the frequency of administration is increased without changing total dose or duration) with granulocyte colony stimulating factor (G-CSF) support led to improved both disease-free (82% vs 75% at 4 years) and overall survival (92% vs 90%). Exploratory subset analysis suggested that patients with hormone receptor–negative tumors derived the most benefit from the dose-dense approach.
The US Oncology trial 9735 compared four cycles of AC with four cycles of docetaxel (Taxotere) and cyclophosphamide (TC). With a median of 7 years’ follow-up, this study showed a statistically significantly improved disease-free survival and overall survival in the patients who received TC. Until this, no trial had compared a non-anthracycline, taxane-based regimen to an anthracycline-based regimen.
The three Anthracyclines in early Breast Cancer (ABC) (USOR 06-090, NSABP B-46, NSABP B-49) trials (total N = 4242) each compared the TC regimen to anthracycline/taxane-based chemotherapy regimens (TaxAC) in HER2-negative early-stage breast cancer. A 2016 interim joint analysis showed that the invasive disease-free survival (iDFS) at 4 years was improved by 2.5% with the addition of an anthracycline (P = 0.04) but that the benefit of an anthracycline was primarily seen in triple-negative disease (HR 1.42, 95% CI 1.04, 1.94). Use of an anthracycline in hormone receptor–positive, lymph node–negative disease may actually be harmful to patients (HR 0.69, 95% CI 0.39, 1.19). No survival difference was observed at the time of interim reporting. Given the benefits described above, taxanes are used for most patients receiving chemotherapy for early breast cancer and a balanced discussion regarding the potential risks versus benefits of the addition of anthracyclines is warranted.
The overall duration of adjuvant chemotherapy still remains uncertain. However, based on the meta-analysis performed in the Oxford Overview (EBCTCG), the current recommendation is for 3–6 months of the commonly used regimens. Although it is clear that dose intensity to a specific threshold is essential, there is no evidence to support the long-term survival benefit of high-dose chemotherapy with stem cell support.
Chemotherapy side effects are generally well controlled. Nausea and vomiting are abated with drugs that directly affect the central nervous system, such as ondansetron and granisetron. Infertility and premature ovarian failure are common side effects of chemotherapy and should be discussed with patients prior to starting treatment. The risk of life-threatening neutropenia associated with chemotherapy can be reduced by use of growth factors such as pegfilgrastim and filgrastim (G-CSF), which stimulate proliferation and differentiation of hematopoietic cells. Long-term toxicities from chemotherapy, including cardiomyopathy (anthracyclines), peripheral neuropathy (taxanes), and leukemia/myelodysplasia (anthracyclines and alkylating agents), remain a small but significant risk.
Targeted therapy refers to agents that are directed specifically against a protein or molecule expressed uniquely on tumor cells or in the tumor microenvironment.
Approximately 20% of breast cancers are characterized by amplification of the HER2 oncogene leading to overexpression of the HER2 oncoprotein. The poor prognosis associated with HER2 overexpression has been drastically improved with the development of HER2-targeted therapy. Trastuzumab (Herceptin [H]), a monoclonal antibody that binds to HER2, has proved effective in combination with chemotherapy in patients with HER2-overexpressing metastatic and early breast cancer. In the adjuvant setting, the first and most commonly studied chemotherapy backbone used with trastuzumab is AC-T. Subsequently, the BCIRG006 study showed similar efficacy for AC-TH and a nonanthracycline-containing regimen, TCH (docetaxel, carboplatin, trastuzumab). Both were significantly better than AC-T in terms of disease-free and overall survival and TCH had a lower risk of cardiac and bone marrow (leukemia/myelodysplasia) toxicity. Both AC-TH and TCH are FDA-approved for nonmetastatic, HER2-positive breast cancer. In these regimens, trastuzumab is given with chemotherapy and then continues beyond the course of chemotherapy to complete a full year. The reporting of two trials in 2012 (the Herceptin Adjuvant [HERA] evaluating 1 versus 2 years of trastuzumab and the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure [PHARE] study evaluating 6 versus 12 months of trastuzumab) has confirmed that 1 year of trastuzumab should remain the standard of care. At least one study (N9831) suggests that concurrent, rather than sequential, delivery of trastuzumab with chemotherapy may be more beneficial. Neoadjuvant chemotherapy plus dual HER2-targeted therapy with trastuzumab and pertuzumab (also a HER2-targeted monoclonal antibody that prevents dimerization of HER2 with HER3 and has been shown to be synergistic in combination with trastuzumab) is a standard of care option available to patients with nonmetastatic HER2-positive breast cancer. Retrospective studies have shown that even small (stage T1a,b) HER2-positive tumors have a worse prognosis compared with same-sized HER2-negative tumors and may thus be appropriate for trastuzumab-based regimens. The NSABP B43 study is ongoing to evaluate whether the addition of trastuzumab to radiation therapy is warranted for DCIS.
Cardiomyopathy develops in a small but significant percentage (0.4–4%) of patients who receive trastuzumab-based regimens. For this reason, anthracyclines and trastuzumab are rarely given concurrently and cardiac function is monitored periodically throughout therapy.
Adjuvant hormone modulation therapy is highly effective in decreasing relative risk of recurrence by 40–50% and mortality by 25% in women with hormone receptor–positive tumors regardless of menopausal status.
The traditional regimen had been 5 years of the estrogen-receptor antagonist/agonist tamoxifen until the 2012 reporting of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial in which 5 versus 10 years of adjuvant tamoxifen were compared. In this study, disease-free and overall survival were significantly improved in women who received 10 years of tamoxifen, particularly after year 10. The Adjuvant Tamoxifen (aTTom) study confirmed these results. Though these results are impressive, the clinical application of long-term tamoxifen use must be discussed with patients individually, taking into consideration risks of tamoxifen (such as secondary uterine cancers, venous thromboembolic events, and side effects that impact quality of life). The addition of ovarian suppression to tamoxifen has not been shown to significantly improve recurrence rates or survival compared to tamoxifen alone in randomized clinical trials (Zoladex in Premenopausal Patients [ZIPP] and Suppression of Ovarian Function Trial [SOFT] studies).
AIs, including anastrozole, letrozole, and exemestane, reduce estrogen production and are also effective in the adjuvant setting for postmenopausal women. Approximately seven large randomized trials enrolling more than 24,000 patients have compared the use of AIs with tamoxifen or placebo as adjuvant therapy. All of these studies have shown small but statistically significant improvements in disease-free survival (absolute benefits of 2–6%) with the use of AIs. In addition, AIs have been shown to reduce the risk of contralateral breast cancers and to have fewer associated serious side effects (such as endometrial cancers and thromboembolic events) than tamoxifen. However, they are associated with accelerated bone loss and an increased risk of fractures as well as a musculoskeletal syndrome characterized by arthralgias or myalgias (or both) in the majority of patients. The American Society of Clinical Oncology and the NCCN have recommended that postmenopausal women with hormone receptor–positive breast cancer be offered an AI either initially or after tamoxifen therapy. HER2 status should not affect the use or choice of hormone therapy. Until recently, the use of AIs was restricted to postmenopausal women whose ovaries were not producing estrogen. A combined analysis of the SOFT and Tamoxifen and Exemestane Trial (TEXT) studies showed for the first time that exemestane plus ovarian suppression was associated with a reduced risk of relapse compared to tamoxifen plus ovarian suppression, making this a viable adjuvant therapy option for premenopausal women with high-risk ER-positive breast cancers.
Multiple randomized studies have evaluated the use of adjuvant bisphosphonates in addition to standard local and systemic therapy for early-stage breast cancer and have shown, in addition to improvement in bone density, a consistent reduction in the risk of metastatic recurrence in postmenopausal patients. A meta-analysis evaluating more than 18,000 women with early-stage breast cancer treated with bisphosphonates or placebo showed that bisphosphonates reduce the risk of cancer recurrence (especially in bone) and improve breast cancer–specific survival primarily in postmenopausal women. Side effects associated with bisphosphonate therapy include bone pain, fever, osteonecrosis of the jaw (rare, less than 1%), esophagitis or ulcers (for oral bisphosphonates), and kidney injury. Although the FDA has not yet approved the adjuvant use of bisphosphonates to reduce the risk of breast cancer recurrence, these agents are commonly used, especially in the setting of a breast cancer patient who has concomitant osteopenia or osteoporosis. In addition, denosumab (another bone stabilizing drug), which is an antibody directed against receptor activator of nuclear factor kappa B ligand (RANK-B), is being investigated for its impact on breast cancer recurrence rates.
4. Adjuvant therapy in older women
Data relating to the optimal use of adjuvant systemic treatment for women over the age of 65 are limited. Results from the EBCTCG overview indicate that while adjuvant chemotherapy yields a smaller benefit for older women compared with younger women, it still improves clinical outcomes. Moreover, individual studies do show that older women with higher risk disease derive benefits from chemotherapy. One study compared the use of oral chemotherapy (capecitabine) to standard chemotherapy in older women and concluded that standard chemotherapy is preferred. Another study (USO TC vs AC) showed that women over the age of 65 derive similar benefits from the taxane-based regimen as women who are younger. The benefits of endocrine therapy for hormone receptor–positive disease appear to be independent of age. In general, decisions relating to the use of systemic therapy should take into account a patient’s comorbidities and physiological age, more so than chronologic age.
The use of systemic therapy prior to resection of the primary tumor (neoadjuvant) has become a standard option that in many cases should be discussed with patients prior to surgery. This enables the assessment of in vivo sensitivity of the tumor to the selected systemic therapy. Patients with hormone receptor–negative, triple-negative, or HER2-positive breast cancer are more likely to have a pathologic complete response to neoadjuvant chemotherapy than those with hormone receptor–positive breast cancer. A complete pathologic response at the time of surgery, especially in hormone receptor–negative tumors, is associated with improvement in event-free and overall survival. Neoadjuvant chemotherapy also increases the chance of breast conservation by shrinking the primary tumor in women who would otherwise need mastectomy for local control. Survival after neoadjuvant chemotherapy is similar to that seen with postoperative adjuvant chemotherapy.
1. HER2-positive breast cancer
Dual targeting of HER2 with two monoclonal antibodies, trastuzumab and pertuzumab, showed positive results in two clinical trials in the neoadjuvant setting, the TRYPHAENA and the NEOSPHERE studies. TRYPHAENA was a phase II, open-label study in which 225 patients with operable HER2-positive breast cancer were randomly assigned to six neoadjuvant cycles every 3 weeks of either 5-fluorouracil, epirubicin, cyclophosphamide [FEC] plus trastuzumab [H] and pertuzumab [P] for three cycles followed by docetaxel [T] plus HP for three cycles (Arm A) or FEC for three cycles followed by THP for three cycles (Arm B) or TCHP for six cycles (Arm C). Pathologic complete response (in breast and lymph nodes) was seen in 50.7% of patients in Arm A, 45.3% in Arm B, and 51.9% in Arm C. Symptomatic left ventricular systolic dysfunction developed in two patients in this study, both in Arm B. Declines in left ventricular ejection fraction 10% or more from baseline to less than 50% was observed in 4 patients in Arm A (5.6%), 4 patients in Arm B (5.3%) and 3 patients in Arm C (3.9%).
The NEOSPHERE study randomly assigned 417 patients with HER2-positive breast cancer to four cycles of trastuzumab (H) plus docetaxel (T) (group A), pertuzumab (P) plus TH (group B), PH (group C) or PT (group D). Pathologic complete response in the breast and lymph nodes was seen in 21.5% in group A, 39.3% in group B, 11.2% in group C and 17.7% in group D. In 2013, given the results of these two studies, the FDA granted accelerated approval for neoadjuvant pertuzumab. This is the first medication to receive regulatory approval in the neoadjuvant setting for breast cancer. Based on these clinical trials, three regimens have received FDA approval in the HER2-positive neoadjuvant setting: docetaxel [T], cyclophosphamide [C], trastuzumab [H], and pertuzumab [P] (TCHP) for six cycles; 5-fluorouracil, epirubicin, cyclophosphamide [FEC] for 3 cycles followed by THP for 3 cycles; or THP for 4 cycles (followed by three cycles of postoperative FEC). Pertuzumab is not FDA-approved for the adjuvant setting, though the National Comprehensive Cancer Network guidelines list pertuzumab plus trastuzumab as an appropriate adjuvant therapy to be given concurrently with chemotherapy if pertuzumab was not given in the neoadjuvant setting. After completing chemotherapy (and surgery, if chemotherapy is given in the neoadjuvant setting), all patients should continue to receive trastuzumab to complete a full year.
2. Hormone receptor–positive, HER2-negative breast cancer
Patients with hormone receptor–positive breast cancer have a lower chance of achieving a pathologic complete response with neoadjuvant therapy than those patients with triple-negative or HER2-positive breast cancers. Studies are ongoing to evaluate hormonally targeted regimens in the neoadjuvant setting. Outside of the clinical trial setting, the use of neoadjuvant hormonal therapy is generally restricted to postmenopausal patients who are unwilling or unable to tolerate chemotherapy.
3. Triple-negative breast cancer
No targeted therapy has been identified for patients with breast cancer that is lacking in HER2 amplification or hormone receptor expression. Neoadjuvant chemotherapy leads to pathologic complete response in up to 40–50% of patients with triple-negative breast cancer. Patients who achieve a pathologic complete response seem to have a similar prognosis to other breast cancer subtypes with pathologic complete response. However, those patients with residual disease at the time of surgery have a poor prognosis. Based on the theory that triple-negative breast cancers may be more vulnerable to DNA-damaging agents, several studies are evaluating whether the addition of platinum salts to a neoadjuvant chemotherapy regimen is beneficial in this disease subtype. A randomized phase II trial (GeparSixto) randomly assigned 595 patients with triple-negative or HER2-positive breast cancer to weekly paclitaxel plus weekly liposomal doxorubicin (18 weeks) alone or with weekly carboplatin. Patients with triple-negative disease also received bevacizumab. Those patients with triple-negative disease who received carboplatin had a pathologic complete response rate of 53.2% compared to those who did not receive carboplatin (36.9%; P = 0.005). The 3-year disease-free survival (DFS) data were presented in 2015; the addition of carboplatin improved disease-free survival from 76.1% to 85.8% (HR 0.56, 95% CI (0.33, 0.96), P = 0.0350) Similarly designed studies are ongoing to evaluate the pathologic complete response rates and long-term outcomes associated with incorporating platinums into standard chemotherapy regimens.
4. Timing of sentinel lymph node biopsy in neoadjuvant setting
There is considerable concern about the timing of sentinel lymph node biopsy, since the chemotherapy may affect cancer present in the lymph nodes. Several studies have shown that sentinel node biopsy can be done after neoadjuvant therapy. However, a large multicenter study, ACOSOG 1071, demonstrated a false-negative rate of 10.7%, well above the false-negative rate outside the neoadjuvant setting (less than 1–5%). Some physicians recommend performing sentinel lymph node biopsy before administering the chemotherapy in order to avoid a false-negative result and to aid in planning subsequent radiation therapy. Others prefer to perform sentinel lymph node biopsy after neoadjuvant therapy to avoid a second operation and assess post-chemotherapy nodal status. If a complete dissection is desired, this can be performed at the time of the definitive breast surgery. The SENTINA trial showed similarly poor results for sentinel node biopsy after neoadjuvant therapy. No study has evaluated the impact of no axillary treatment for node-positive patients who become node-negative after neoadjuvant therapy.
Important questions remaining to be answered are the timing and duration of adjuvant and neoadjuvant chemotherapy, which chemotherapeutic agents should be applied for which subgroups of patients, the use of combinations of hormonal therapy and chemotherapy as well as possibly targeted therapy, and the value of prognostic factors other than hormone receptors in predicting response to therapy.
Palliative treatments are those to manage symptoms, improve quality of life, and even prolong survival, without the expectation of achieving cure. In the United States, it is uncommon to have distant metastases at the time of diagnosis (de novo metastases). However, most patients who have a breast cancer recurrence after initial local and adjuvant therapy have a metastatic rather than local (in breast) disease. Breast cancer most commonly metastasizes to the liver, lungs and bone, causing symptoms such as fatigue, change in appetite, abdominal pain, cough, dyspnea, or bone pain. Headaches, imbalance, vision changes, vertigo, and other neurologic symptoms may be signs of brain metastases. Triple-negative (ER-, PR-, HER2-negative) and HER2-positive tumors have a higher rate of brain metastases than hormone receptor–positive, HER2-negative tumors.
A. Radiotherapy and Bisphosphonates
Palliative radiotherapy may be advised for primary treatment of locally advanced cancers with distant metastases to control ulceration, pain, and other manifestations in the breast and regional nodes. Irradiation of the breast and chest wall and the axillary, internal mammary, and supraclavicular nodes should be undertaken in an attempt to cure locally advanced and inoperable lesions when there is no evidence of distant metastases. A small number of patients in this group are cured in spite of extensive breast and regional node involvement.
Palliative irradiation is of value also in the treatment of certain bone or soft-tissue metastases to control pain or avoid fracture. Radiotherapy is especially useful in the treatment of isolated bony metastases, chest wall recurrences, brain metastases and sometimes, in lieu of the preferred option of orthopedic surgery for acute spinal cord compression.
In addition to radiotherapy, bisphosphonate therapy has shown excellent results in delaying and reducing skeletal events in women with bony metastases. Pamidronate and zoledronic acid are FDA-approved intravenous bisphosphonates given for bone metastases or hypercalcemia of malignancy from breast cancer. Denosumab, a fully human monoclonal antibody that targets RANK-ligand, is FDA-approved for the treatment of bone metastases from breast cancer, with data showing that it reduced the time to first skeletal-related event (eg, pathologic fracture) compared to zoledronic acid.
Caution should be exercised when combining radiation therapy with chemotherapy because toxicity of either or both may be augmented by their concurrent administration. In general, only one type of therapy should be given at a time unless it is necessary to irradiate a destructive lesion of weight-bearing bone while the patient is receiving chemotherapy. Systemic therapy should be changed only if the disease is clearly progressing. This is especially difficult to determine for patients with destructive bone metastases, since changes in the status of these lesions are difficult to determine radiographically.
1. Endocrine therapy for metastatic disease
The first targeted therapy for cancer was the use of antiestrogen therapy in hormone receptor–positive breast cancer. The following therapies have all been shown to be effective in hormone receptor–positive metastatic breast cancer: administration of drugs that block or downregulate hormone receptors (such as tamoxifen or fulvestrant, respectively) or drugs that block the synthesis of hormones (such as AIs); ablation of the ovaries, adrenals, or pituitary; and the administration of hormones (eg, estrogens, androgens, progestins); see Table 17–5. Palliative treatment of metastatic cancer should be based on the ER status of the primary tumor or the metastases. Because only 5–10% of women with ER-negative tumors respond, they should not receive endocrine therapy. The rate of response is nearly equal in premenopausal and postmenopausal women with ER-positive tumors. A favorable response to hormonal manipulation occurs in about one-third of patients with metastatic breast cancer. Of those whose tumors contain ER, the response is about 60% and perhaps as high as 80% for patients whose tumors contain PR as well. The choice of endocrine therapy depends on the menopausal status of the patient. Women within 1 year of their last menstrual period are arbitrarily considered to be premenopausal and should receive tamoxifen therapy or ovarian ablation (surgical or hormonal) plus an AI, whereas women whose menses ceased more than a year before are postmenopausal and may receive tamoxifen, fulvestrant, or an AI. Women with ER-positive tumors who do not respond to first-line endocrine therapy or experience progression should be given a different form of hormonal manipulation. Because the quality of life during endocrine manipulation is usually superior to that during cytotoxic chemotherapy, it is best to try endocrine manipulation whenever possible. However, when receptor status is unknown, disease is progressing rapidly or is threatening visceral organs, chemotherapy may be used as first-line treatment.
Table 17–5.Agents commonly used for hormonal management of metastatic breast cancer. |Favorite Table|Download (.pdf) Table 17–5. Agents commonly used for hormonal management of metastatic breast cancer.
|Drug ||Action ||Dose, Route, Frequency ||Major Side Effects |
|Tamoxifen citrate (Nolvadex) ||SERM ||20 mg orally daily ||Hot flushes, uterine bleeding, thrombophlebitis, rash |
|Fulvestrant (Faslodex) ||Steroidal estrogen receptor antagonist ||500 mg intramuscularly days 1, 15, 29 and then monthly ||Gastrointestinal upset, headache, back pain, hot flushes, pharyngitis |
|Toremifene citrate (Fareston) ||SERM ||40 mg orally daily ||Hot flushes, sweating, nausea, vaginal discharge, dry eyes, dizziness |
|Diethylstilbestrol (DES) ||Estrogen ||5 mg orally three times daily ||Fluid retention, uterine bleeding, thrombophlebitis, nausea |
|Goserelin (Zoladex) ||Synthetic luteinizing hormone releasing analog ||3.6 mg subcutaneously monthly ||Arthralgias, blood pressure changes, hot flushes, headaches, vaginal dryness |
|Megestrol acetate (Megace) ||Progestin ||40 mg orally four times daily ||Fluid retention |
|Letrozole (Femara) ||AI ||2.5 mg orally daily ||Hot flushes, arthralgia/arthritis, myalgia, bone loss |
|Anastrozole (Arimidex) ||AI ||1 mg orally daily ||Hot flushes, skin rashes, nausea and vomiting, bone loss |
|Exemestane (Aromasin) ||AI ||25 mg orally daily ||Hot flushes, increased arthralgia/arthritis, myalgia, bone loss |
a. The premenopausal patient
(1) Primary hormonal therapy
The most extensively studied method of endocrine therapy in premenopausal patients is tamoxifen, in large part because it can be given with less morbidity and fewer side effects than cytotoxic chemotherapy and does not require oophorectomy. Tamoxifen is given orally in a dose of 20 mg daily. The average clinical benefit associated with tamoxifen lasts about 12 months.
There is no significant difference in survival or response between tamoxifen therapy and bilateral oophorectomy. Bilateral oophorectomy is less desirable than tamoxifen in premenopausal women because tamoxifen is so well tolerated. However, oophorectomy can be achieved rapidly and safely either by surgery, by irradiation of the ovaries if the patient is a poor surgical candidate, or by chemical ovarian ablation using a gonadotropin-releasing hormone (GnRH) analog. Oophorectomy presumably works by eliminating estrogens, progestins, and androgens, which stimulate growth of the tumor. AIs should not be used in a patient with functioning (premenopausal) ovaries since they do not block ovarian production of estrogen.
(2) Secondary or tertiary hormonal therapy
Patients who do not respond to tamoxifen or ovarian ablation may be treated with chemotherapy or may try a second endocrine regimen, such as GnRH analog plus AI or fulvestrant. Whether to opt for chemotherapy or another endocrine measure depends largely on the sites of metastatic disease (visceral being more serious than bone-only, thus sometimes warranting the use of chemotherapy), the disease burden, the rate of growth of disease, and patient preference. Patients who take chemotherapy and then later have progressive disease may subsequently respond to another form of endocrine treatment (Table 17–5). The optimal choice for secondary endocrine manipulation has not been clearly defined for the premenopausal patient.
Patients who improve after oophorectomy but subsequently relapse should receive fulvestrant, tamoxifen or an AI; if one fails, the other may be tried. Megestrol acetate, a progesterone agent, may also be considered. Adrenalectomy or hypophysectomy, procedures rarely done today, induced regression in 30–50% of patients who previously responded to oophorectomy. Pharmacologic hormonal manipulation has replaced these invasive procedures.
b. The postmenopausal patient
(1) Primary hormonal therapy
For postmenopausal women with metastatic breast cancer amenable to endocrine manipulation, fulvestrant, tamoxifen, or an AI is the initial therapy of choice. AIs may be more effective. The side effect profile of AIs differs from tamoxifen. The main side effects of tamoxifen are nausea, skin rash, and hot flushes. Rarely, tamoxifen induces hypercalcemia in patients with bony metastases. Tamoxifen also increases the risk of venous thromboembolic events and uterine hyperplasia and cancer. The main side effects of AIs include hot flushes, vaginal dryness, and joint stiffness; however, osteoporosis and bone fractures are significantly higher than with tamoxifen. Phase II data from the randomized Fulvestrant fIRst line Study comparing endocrine Treatments (FIRST) suggest that the pure estrogen antagonist fulvestrant may be even more effective than front-line anastrozole in terms of time to progression and overall survival. Results from the phase III FALCON study (same design as FIRST) confirmed that the use of front-line fulvestrant improves progression-free survival by almost 3 months (HR 0.79, 95% CI 0.637, 0.999, P = 0.0486) with the largest treatment effect observed in patients without visceral disease. Overall survival data are needed. The combination of fulvestrant plus anastrozole may also be more effective than anastrozole alone, although two studies evaluating this question have yielded conflicting results.
(2) Secondary or tertiary hormonal therapy
AIs are also used for the treatment of advanced breast cancer in postmenopausal women after tamoxifen or fulvestrant treatment. In the event that the patient responds to an AI but then has progression of disease, fulvestrant has shown efficacy with about 20–30% of women benefiting from use. Postmenopausal women who respond initially to a SERM or AI but later manifest progressive disease may be crossed over to another hormonal therapy. Until recently, patients who experienced disease progression during or after treatment with a SERM or AI were routinely offered chemotherapy. This standard practice changed in 2012 with the approval of everolimus. Everolimus (Afinitor) is an oral inhibitor of the mammalian target of rapamycin (MTOR)—a protein whose activation has been associated with the development of endocrine resistance. A phase III, placebo-controlled trial (BOLERO-2) evaluated the AI exemestane with or without everolimus in 724 patients with AI-resistant, hormone receptor–positive metastatic breast cancer and found that patients treated with everolimus had a significantly improved progression-free survival (7.8 months vs 3.2 months; HR, 0.45; 95% CI, 0.38–0.54; P < 0.0001) but no significant difference in overall survival. Androgens (such as testosterone) have many toxicities and should be used infrequently. As in premenopausal patients, neither hypophysectomy nor adrenalectomy should be performed. Estrogen therapy has also paradoxically been shown to induce responses in advanced breast cancer. A study that evaluated the use of low-dose (6 mg) versus high-dose (30 mg) estradiol daily orally for postmenopausal women with metastatic AI-resistant breast cancer showed that the two doses yielded similar clinical benefit rates (29% and 28%, respectively) and, as expected, the higher dose was associated with more adverse events than the low dose.
(3) Cyclin dependent kinase inhibition
Hormonally driven breast cancer may be particularly sensitive to inhibition of cell cycle regulatory proteins, called cyclin dependent kinases (CDK). A phase II randomized study evaluating letrozole with or without an oral CDK 4/6 inhibitor (palbociclib) for the first-line treatment of postmenopausal women with hormone receptor–positive advanced breast cancer demonstrated a striking and highly significant doubling of progression-free survival with palbociclib compared to the control arm. The 2016 results from the phase III confirmatory study (PALOMA-2) in the first-line setting confirmed a significant 10-month improvement in progression-free survival associated with the use of palbociclib plus letrozole. Moreover, results from the phase III PALOMA-3 study showed the addition of palbociclib to fulvestrant in pretreated patients with ER-positive metastatic breast cancer more than doubled progression-free survival. Palbociclib in combination with letrozole is FDA-approved for patients with previously untreated ER-positive HER2-negative metastatic breast cancer; palbociclib in combination with fulvestrant is FDA-approved for patients whose advanced disease has progressed after hormonally targeted therapy. FDA-approved ribociclib, another CDK 4/6 inhibitor, in combination with letrozole for first-line metastatic hormone receptor–positive breast was shown to significantly improve progression-free survival in a phase III clinical trial (MONALEESA-2). In general, palbociclib and ribociclib are well tolerated; however, they are associated with grade 3/4 neutropenia; thus, monitoring patients closely is required. A third CDK4/6 inhibitor, abemaciclib, is being evaluated in clinical trials.
For patients with HER2-positive tumors, trastuzumab plus chemotherapy significantly improves clinical outcomes, including survival compared to chemotherapy alone. Pertuzumab is an FDA-approved monoclonal antibody that targets the extracellular domain of HER2 at a different epitope than targeted by trastuzumab and inhibits receptor dimerization. A phase III placebo-controlled randomized study (CLEOPATRA) showed that patients treated with the combination of pertuzumab, trastuzumab, and docetaxel had a significantly longer progression-free survival (18.5 months vs 12.4 months; HR, 0.62; 95% CI, 0.51–0.75; P < 0.001) compared with those treated with docetaxel and trastuzumab. Longer follow-up revealed a significant overall survival benefit associated with pertuzumab as well.
Lapatinib, an oral targeted drug that inhibits the intracellular tyrosine kinases of the epidermal growth factor and HER2 receptors, is FDA-approved for the treatment of trastuzumab-resistant HER2-positive metastatic breast cancer in combination with capecitabine, thus, a completely oral regimen. The combination of trastuzumab plus lapatinib has been shown to be more effective than lapatinib alone for trastuzumab-resistant metastatic breast cancer. Moreover, several trials have shown a significant clinical benefit for continuing HER2-targeted agents beyond progression. T-DM1 ado-trastuzumab emtansine (Kadcyla) is an FDA-approved novel antibody drug conjugate in which trastuzumab is stably linked to a derivative of maytansine, enabling targeted delivery of the cytotoxic chemotherapy to HER2-overexpressing cells. T-DM1 is associated with an improved progression-free and overall survival compared to lapatinib plus capecitabine in patients with HER2-positive, trastuzumab-pretreated advanced disease (EMILIA). T-DMI with or without pertuzumab was compared to trastuzumab plus a taxane for the first-line treatment of HER2-positive advanced breast cancer in the phase III MARIANNE study. This study showed that the two ado-trastuzumab containing arms were noninferior (but not superior) to the trastuzumab plus taxane arm. Thus, for the time being, ado-trastuzumab is primarily used in the second-line setting and beyond. Several other drugs targeting HER2 and its associated signaling pathways are in development, including ONT-380, neratinib, and HER2-targeted vaccines.
3. Targeting “triple-negative” breast cancer
Breast cancers lacking expression of the hormone receptors ER, PR, and HER2 have been amenable only to therapy with cytotoxic chemotherapy. This type of “triple-negative” breast cancer, while heterogeneous, generally behaves aggressively and is associated with a poor prognosis. Newer classes of targeted agents are being evaluated specifically for triple-negative breast cancer, although none have been shown to improve outcomes to date. Early phase clinical trials show promise for immune checkpoint inhibitors (such as monoclonal antibodies that target PDL-1 or PD-1) and androgen receptor inhibitors. Research in this area is rapidly expanding with multiple clinical trials of molecularly targeted agents ongoing.
C. Palliative Chemotherapy
Cytotoxic drugs should be considered for the treatment of metastatic breast cancer (1) if visceral metastases are present (especially brain, liver, or lymphangitic pulmonary), (2) if hormonal treatment is unsuccessful or the disease has progressed after an initial response to hormonal manipulation, or (3) if the tumor is ER-negative or HER2-positive. Prior adjuvant chemotherapy does not seem to alter response rates in patients who relapse. A number of chemotherapy drugs (including vinorelbine, paclitaxel, docetaxel, gemcitabine, ixabepilone, carboplatin, cisplatin, capecitabine, albumin-bound paclitaxel, eribulin, and liposomal doxorubicin) may be used as single agents with first-line objective response rates ranging from 30% to 50%.
Combination chemotherapy yields statistically significantly higher response rates and progression-free survival rates, but has not been conclusively shown to improve overall survival rates compared with sequential single-agent therapy. Combinations that have been tested in phase III studies and have proven efficacy compared with single-agent therapy include capecitabine/docetaxel, gemcitabine/paclitaxel, and capecitabine/ixabepilone (see Tables 39–11 and 39–12). Various other combinations of drugs have been tested in phase II studies, and a number of clinical trials are ongoing to identify effective combinations. Patients should be encouraged to participate in clinical trials given the number of promising targeted therapies in development. It is generally appropriate to treat willing patients with multiple sequential lines of therapy as long as they tolerate the treatment and as long as their performance status is good (eg, at least ambulatory and able to care for self, up out of bed more than 50% of waking hours).
et al. First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab
for the treatment of patients with HER2
-positive breast cancer. Clin Cancer Res. 2014 Nov 1;20(21):5359–64.
et al. Everolimus
for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580–91.
et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919–25.
et al. Joint analysis of the ABC (anthracyclines in early breast cancer) trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 (NRG oncology) comparing docetaxel
plus cyclophosphamide (TC
) to anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2
negative breast cancer. J Clin Oncol. 2016;34(Suppl):abstr 1000.
et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014 Jul 12;384(9938):164–72.
et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869):805–16. Erratum in: Lancet. 2013 Mar 9;381(9869):804.
et al. Axillary dissection can be avoided in the majority of clinically node-negative patients undergoing breast-conserving therapy. Ann Surg Oncol. 2014 Jan;21(1):22–7.
et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomized, multi-centre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014 Nov;15(12):1303–10.
Early Breast Cancer Trialists’ Collaborative Group. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomized trials. Lancet. 2015 Oct 3;386(10001):1353–61.
et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the Phase II FIRST Study. J Clin Oncol. 2015 Nov 10;33(32):3781–7.
et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab
(P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. J Clin Oncol. 2015;33(Suppl; abstr 507).
et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib
in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25–35.
et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015 Jan 29;372(5):436–46.
et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol. 2014 Mar 10;32(8):735–44.
et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011 Jul 27;306(4)385–93.
et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011 Feb 9;305(6):569–75.
et al; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2
-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021–8.
et al. Survival after breast-conserving surgery with whole breast or partial breast irradiation in women with early stage breast cancer: a SEER data-base analysis. Breast J. 2016 Dec 18. [Epub ahead of print]
et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013 Oct;14(11):1086–94.
et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013 Jul 1;31(19):2382–7.
et al. Combination of everolimus
with trastuzumab plus paclitaxel
as first-line treatment for patients with HER2
-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816–29.
et al. Progress and controversies: radiation therapy for invasive breast cancer. CA Cancer J Clin. 2014 Mar–Apr;64(2):135–52.
et al. Surgical treatment of primary breast cancer in the neoadjuvant setting. Br J Surg. 2014 Jul;101(8):912–24.
EH. JAMA patient page. Breast cancer and axillary lymph nodes. JAMA. 2013 Oct 9;310(14):1518.
et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435–44.
et al; POEMS/S0230 Investigators. Goserelin for ovarian protection during breast cancer adjuvant chemotherapy. N Engl J Med. 2015 Mar 5;372(10):923–32.
et al; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107–18.
et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. Clin Oncol. 2011 Dec 1;29(34):4491–7.
et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744–52.
et al. Everolimus
plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Ann Oncol. 2014 Dec;25(12):2357–62.
et al; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2
-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013 Jul;14(8):741–8.
et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015 Jul 23;373(4):317–27.
et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997–3005.
et al. Pertuzumab
plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278–84.
et al; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2
-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273–83.
et al. Adjuvant paclitaxel
and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan 8;372(2):134–41. Erratum in: N Engl J Med. 2015 Nov 12;373(20):1989.
et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014 Feb 15;383(9917):603–13.
et al; EMILIA Study Group. Trastuzumab emtansine for HER2
-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783–91.
et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013 Dec;14(13):1269–77.
et al. Neoadjuvant carboplatin in patients with triple-negative and HER2
-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014 Jun;15(7):747–56.
et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med. 2011 Feb 3;364(5):412–21.
et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015 Jul 23;373(4):307–16.
Stage of breast cancer is the most reliable indicator of prognosis (Table 17–6). Axillary lymph node status is the best-analyzed prognostic factor and correlates with survival at all tumor sizes. When cancer is localized to the breast with no evidence of regional spread after pathologic examination, the clinical cure rate with most accepted methods of therapy is 75% to more than 90%. In fact, patients with small mammographically detected biologically favorable tumors and no evidence of axillary spread have a 5-year survival rate greater than 95%. When the axillary lymph nodes are involved with tumor, the survival rate drops to 50–70% at 5 years and probably around 25–40% at 10 years. Increasingly, the use of biologic markers, such as ER, PR, grade, and HER2, is helping to identify high-risk tumor types as well as direct treatment used (see Biomarkers & Gene Expression Profiling). Tumors with marked aneuploidy have a poor prognosis (see Table 17–4). Gene analysis studies can predict disease-free survival for some subsets of patients.
Table 17–6.Approximate survival of patients with breast cancer by TNM stage. |Favorite Table|Download (.pdf) Table 17–6. Approximate survival of patients with breast cancer by TNM stage.
|TNM Stage ||5 Years ||10 Years |
|0 ||95% ||90% |
|I ||85% ||70% |
|IIA ||70% ||50% |
|IIB ||60% ||40% |
|IIIA ||55% ||30% |
|IIIB ||30% ||20% |
|IV ||5–10% ||2% |
|All ||65% ||30% |
Five-year statistics do not accurately reflect the final outcome of therapy. The mortality rate of breast cancer patients exceeds that of age-matched normal controls for nearly 20 years. Thereafter, the mortality rates are equal, though deaths that occur among breast cancer patients are often directly the result of tumor.
In general, breast cancer appears to be somewhat more aggressive and associated with worse outcomes in younger than in older women, and this may be related to the fact that fewer younger women have ER-positive tumors. Disparities in treatment outcome for different racial and ethnic backgrounds have been reported by several studies. These differences appear to be not only due to different socioeconomic factors (and a resulting difference in access to healthcare) but also due to differences in the subtype of breast cancer diagnosed.
For those patients whose disease progresses despite treatment, studies suggest supportive group therapy may improve survival. As they approach the end of life, such patients will require meticulous palliative care (see Chapter 5).
et al. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA. 2015 Jan 13;313(2):165–73. Erratum in: JAMA. 2015 Jun 9;313(22):2287.
et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353–68.
et al. Patient surveillance after initial breast cancer therapy: variation by physician specialty. Am J Surg. 2013 Aug;206(2):218–22.
et al. Racial and ethnic differences in breast cancer survival: mediating effect of tumor characteristics and sociodemographic and treatment factors. J Clin Oncol. 2015 Jul 10;33(20):2254–61.
After primary therapy, patients with breast cancer should be monitored long term in order to detect recurrences and to observe the opposite breast for a second primary carcinoma. Local and distant recurrences occur most frequently within the first 2–5 years. During the first 2 years, most patients should be examined every 6 months, then annually thereafter. Special attention is paid to the contralateral breast because a new primary breast malignancy will develop in 20–25% of patients. In some cases, metastases are dormant for long periods and may appear 10–15 years or longer after removal of the primary tumor. Although studies have failed to show an adverse effect of hormonal replacement in disease-free patients, it is rarely used after breast cancer treatment, particularly if the tumor was hormone receptor–positive. Even pregnancy has not been associated with shortened survival of patients rendered disease free—yet many oncologists are reluctant to advise a young patient with breast cancer that it is safe to become pregnant. The use of estrogen replacement for conditions such as osteoporosis, vaginal dryness and hot flushes may be considered for a woman with a history of breast cancer after discussion of the benefits and risks; however, it is not routinely recommended, especially given the availability of nonhormonal agents for these conditions (such as bisphosphonates and denosumab for osteoporosis). Vaginal estrogen is frequently used to treat vaginal atrophy with no obvious ill effects.
The incidence of local recurrence correlates with tumor size, the presence and number of involved axillary nodes, the histologic type of tumor, the presence of skin edema or skin and fascia fixation with the primary tumor, and the type of definitive surgery and local irradiation. Local recurrence on the chest wall after total mastectomy and axillary dissection develops in as many as 8% of patients. When the axillary nodes are not involved, the local recurrence rate is less than 5%, but the rate is as high as 25% when they are heavily involved. A similar difference in local recurrence rate was noted between small and large tumors. Factors such as multifocal cancer, in situ tumors, positive resection margins, chemotherapy, and radiotherapy have an effect on local recurrence in patients treated with breast-conserving surgery. Adjuvant systemic therapy greatly decreases the rate of local recurrence.
Chest wall recurrences usually appear within the first several years but may occur as late as 15 or more years after mastectomy. All suspicious nodules and skin lesions should be biopsied. Local excision or localized radiotherapy may be feasible if an isolated nodule is present. If lesions are multiple or accompanied by evidence of regional involvement in the internal mammary or supraclavicular nodes, the disease is best managed by radiation treatment of the entire chest wall including the parasternal, supraclavicular, and axillary areas and usually by systemic therapy.
Local recurrence after mastectomy usually signals the presence of widespread disease and is an indication for studies to search for evidence of metastases. Distant metastases will develop within a few years in most patients with locally recurrent tumor after mastectomy. When there is no evidence of metastases beyond the chest wall and regional nodes, irradiation for cure after complete local excision should be attempted. After partial mastectomy, local recurrence does not have as serious a prognostic significance as after mastectomy. However, those patients in whom a recurrence develops have a worse prognosis than those who do not. It is speculated that the ability of a cancer to recur locally after radiotherapy is a sign of aggressiveness and resistance to therapy. Completion of the mastectomy should be done for local recurrence after partial mastectomy; some of these patients will survive for prolonged periods, especially if the breast recurrence is DCIS or occurs more than 5 years after initial treatment. Systemic chemotherapy or hormonal treatment should be used for women in whom disseminated disease develops or those in whom local recurrence occurs.
B. Breast Cancer Survivorship Issues
Given that most women with non-metastatic breast cancer will be cured, a significant number of women face survivorship issues stemming from either the diagnosis or the treatment of the breast cancer. These challenges include psychological struggles, upper extremity lymphedema, weight management problems, cardiovascular issues, bone loss, postmenopausal side effects, and fatigue. One randomized study reported that survivors who received psychological intervention from the time of diagnosis had a lower risk of recurrence and breast cancer–related mortality. A randomized study in older, overweight cancer survivors showed that diet and exercise reduced the rate of self-reported functional decline compared with no intervention. Cognitive dysfunction (also called “chemo brain”) is a commonly reported symptom experienced by women who have undergone systemic treatment for early breast cancer. An interesting study reported that 200 mg of modafinil daily improved speed and quality of memory as well as attention for breast cancer survivors dealing with cognitive dysfunction. This promising study requires validation in a larger clinical trial.
Significant edema of the arm occurs in about 10–30% of patients after axillary dissection with or without mastectomy. It occurs more commonly if radiotherapy has been given or if there was postoperative infection. Partial mastectomy with radiation to the axillary lymph nodes is followed by chronic edema of the arm in 10–20% of patients. Sentinel lymph node dissection has proved to be an accurate form of axillary staging without the side effects of edema or infection. Judicious use of radiotherapy, with treatment fields carefully planned to spare the axilla as much as possible, can greatly diminish the incidence of edema, which will occur in only 5% of patients if no radiotherapy is given to the axilla after a partial mastectomy and lymph node dissection.
Late or secondary edema of the arm may develop years after treatment, as a result of axillary recurrence or infection in the hand or arm, with obliteration of lymphatic channels. When edema develops, a careful examination of the axilla for recurrence or infection is performed. Infection in the arm or hand on the dissected side should be treated with antibiotics, rest, and elevation. If there is no sign of recurrence or infection, the swollen extremity should be treated with rest and elevation. A mild diuretic may be helpful. If there is no improvement, a compressor pump or manual compression decreases the swelling, and the patient is then fitted with an elastic glove or sleeve. Most patients are not bothered enough by mild edema to wear an uncomfortable glove or sleeve and will treat themselves with elevation or manual compression alone. Benzopyrones have been reported to decrease lymphedema but are not approved for this use in the United States. Rarely, edema may be severe enough to interfere with use of the limb. A prospective randomized study has shown that twice weekly progressive weight lifting improves lymphedema symptoms and exacerbations and improves extremity strength.
Breast reconstruction is usually feasible after total or modified radical mastectomy. Reconstruction should be discussed with patients prior to mastectomy, because it offers an important psychological focal point for recovery. Reconstruction is not an obstacle to the diagnosis of recurrent cancer. The most common breast reconstruction has been implantation of a silicone gel or saline prosthesis in the subpectoral plane between the pectoralis minor and pectoralis major muscles. Alternatively, autologous tissue can be used for reconstruction.
Autologous tissue flaps have the advantage of not feeling like a foreign body to the patient. The most popular autologous technique currently is reconstruction using abdominal tissue flaps. This includes the deep inferior epigastric perforator (DIEP) flap and the more traditional transrectus abdominis muscle (TRAM) flap. The free TRAM flap is done by completely removing a small portion of the rectus with overlying fat and skin and using microvascular surgical techniques to reconstruct the vascular supply on the chest wall. A latissimus dorsi flap can be swung from the back but offers less volume than the TRAM flap and thus often requires supplementation with an implant. Reconstruction may be performed immediately (at the time of initial mastectomy) or may be delayed until later, usually when the patient has completed adjuvant therapy. When considering reconstructive options, concomitant illnesses should be considered, since the ability of an autologous flap to survive depends on medical comorbidities. In addition, the need for radiotherapy may affect the choice of reconstruction as radiation may increase fibrosis around an implant or decrease the volume of a flap.
Clinicians are often asked to advise patients regarding the potential risk of future pregnancy after definitive treatment for early-stage breast cancer. To date, no adverse effect of pregnancy on survival of women who have had breast cancer has been demonstrated. When counseling patients, oncologists must take into consideration the patients’ overall prognosis, age, comorbidities, and life goals.
In patients with inoperable or metastatic cancer (stage IV disease), induced abortion may be advisable because of the possible adverse effects of hormonal treatment, radiotherapy, or chemotherapy upon the fetus in addition to the expectant mother’s poor prognosis.
et al. Cancer-related fatigue: implications for breast cancer survivors. Cancer. 2012 Apr 15;118(8 Suppl):2261–9.
et al. Physical activity for cancer survivors: meta-analysis of randomized controlled trials. BMJ. 2012 Jan 30:344:e70.
K. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer. 2011 Mar 1;117(5):1103.
et al. Population-based cancer registries for quality-of-life research: a work-in-progress resource for survivorship studies? Cancer. 2013 Jun 1;119(Suppl 11):2109–23.