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 39–2). Patients with locally advanced (T3, T4) and even inflammatory tumors may be cured with multimodality therapy. When metastatic disease is diagnosed in most patients, 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, HER2 oncogene amplification, and genomic assays 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. In addition, in some cases of triple-negative and HER2-amplified breast cancer, the response to neoadjuvant therapy may determine the need for additional postoperative systemic therapy. 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, ideally 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, although accelerated partial breast irradiation may permit a second breast irradiation.
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 proven 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-specific treatment after lumpectomy; no difference in 10-year survival was found. Omission of axillary dissection is acceptable for women with tumor-free sentinel nodes or those with involvement of one or two sentinel nodes who are treated with lumpectomy, whole breast irradiation, and adjuvant systemic therapy.
Sentinel node. (Used, with permission, from Armando E. Giuliano, MD.)
Breast-conserving surgery with sentinel node biopsy and 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 with irradiation or of axillary dissection over sentinel node biopsy, these conservative procedures appear to be underutilized.
Modified radical mastectomy was previously 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 available 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 with low-risk, early-stage 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 prospective randomized NSABP B-39/RTOG 0413 trial failed to demonstrate noninferiority of partial breast irradiation compared to whole breast irradiation. With 4216 patients randomized and treated on this study, cumulative ipsilateral breast tumor recurrences at 10 years were slightly higher in the partial breast irradiation arm (4.6% vs 3.9%). Toxicity also tended to be less with whole breast irradiation. Another randomized study (“RAPID”) that only allowed patients with node-negative disease enrolled 2135 patients and demonstrated noninferiority. Although the conclusions of these two noninferiority studies were discordant, the rates of in-breast tumor recurrence in both arms was quite low. Guidelines by the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy (ESTRO) indicate that it is appropriate to discuss partial breast radiation for women over the age of 50 with node-negative, hormone receptor–positive, small (T1) tumors with surgical margins of at least 2 mm. Moreover, 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.
et al. Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol. 2017 Mar–Apr;7(2)73–9.
et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA. 2017 Sep 12;318(10):918–26.
et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg. 2016 Sep;264(3):413–20.
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. 2017 May;23(3):292–8.
et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017 Feb 10;35(5):561–4.
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. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet. 2019 Dec 14;394(10215):2155–64.
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.
et al; RAPID Trial Investigators. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet. 2019 Dec 14;394(10215):2165–72.
D. Adjuvant Systemic Therapy
The goal of systemic therapy, including hormone-modulating medications (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 use adjuvant chemotherapy for patients with either node-positive or higher-risk (eg, hormone receptor–negative or HER2-positive) node-negative breast cancer and use 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 approximately 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 for recurrence in node-negative breast cancer. ||Download (.pdf) Table 17–4. Prognostic factors for recurrence in node-negative breast cancer.
|Prognostic Factors ||Increased Recurrence ||Decreased Recurrence |
|Size1 ||T3, T2 ||T1, T0 |
|Hormone receptors (ER, PR) ||Negative ||Positive |
|Histologic grade ||High ||Low |
|S phase fraction ||> 5% ||< 5% |
|Lymphatic or vascular invasion ||Present ||Absent |
|HER2 oncogene amplification ||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 MammaPrint (see Biomarkers and Gene Expression Profiling above). In the MINDACT study, the 5-year distant metastasis–free survival improved by 1.5% in women with high clinical risk but low-risk gene expression as assessed by MammaPrint if they did not receive chemotherapy. In the TAILORx study, patients with an intermediate Oncotype DX recurrence score (11–25) were randomized to receive chemotherapy followed by endocrine therapy or endocrine therapy alone. This study demonstrated no significant benefit associated with adjuvant chemotherapy for patients with a recurrence score of less than 26, though some benefit was observed for women age 50 years or younger with a recurrence score of 16–25. These tests are thus validated tools to enable clinicians to better select patients who can safely omit chemotherapy.
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.
A. ANTHRACYCLINE- AND CYCLOPHOSPHAMIDE-CONTAINING REGIMENS
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.
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. Subsequently, substudy results from the phase III MINDACT trial were presented in which 1301 patients with operable tumors were randomized 1:1 to standard anthracycline/cyclophosphamide-based therapy (with taxane in the 30% of patients with node-positive disease) or docetaxel plus capecitabine (DC). The 5-year disease-free survival was similar for the anthracycline arm (88.8%) and DC arm (90.7%) (P = 0.263) and 5-year overall survival was also similar (96.2% anthracycline vs 96.3% DC, P = 0.722).
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. An interim joint analysis showed that the invasive disease-free survival 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). No survival difference was observed at the time of interim reporting. In contrast, the West German Study Group phase III PlanB study compared six cycles of adjuvant TC to four cycles of EC followed by four cycles of docetaxel (EC-D) in 2449 patients with intermediate to high risk, HER2-negative breast cancer. Dose reductions were higher in the anthracycline arm (19.7% vs 6.6%, P < 0.001) and grade 3/4 toxicities were consistently and significantly higher in the anthracycline arm. TC demonstrated noninferiority to EC-D with a 5-year disease-free survival of 90% for each arm (HR TC vs EC-D = 0.996; 95% CI 0.77–1.29). In contrast to the ABC study, subset analysis indicated a similar disease-free survival in each treatment arm regardless of recurrence score, nodal status, Ki67 reactivity, grade, or triple-negative subtype. A Danish phase III study was conducted to compare six cycles of TC to six cycles of EC-D in 2012 high-risk patients with TOP2A normal breast cancer. The 5-year disease-free survival was 87.9% for EC-D vs 88.3% for DC (HR, 1.00; P = 1.00). While it is generally agreed that taxanes should be used for most patients receiving chemotherapy for early breast cancer, data relating to the benefits of anthracyclines are conflicting; thus, a balanced discussion regarding the potential risks versus benefits of the addition of anthracyclines is warranted, especially in hormone receptor–positive disease.
C. DURATION AND DOSE OF CHEMOTHERAPY
The ideal 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. Data suggest that the timing and sequencing of anthracycline-taxane–based chemotherapy may be important. Multiple trials beginning in the 1980s sought to demonstrate whether dose-intensification of adjuvant chemotherapy by shortening the intervals between cycles (“dose-dense”), or by giving chemotherapy at full dose sequentially rather than concurrently at reduced doses is associated with better outcomes. The EBCTCG meta-analysis included 37,298 patients treated on 26 trials and showed a significant 3.4% absolute decrease and 14% relative risk reduction in breast cancer recurrences with dose-intensification. Moreover, the absolute 10-year breast cancer mortality was improved by 2.4%. While impressive, the benefit of dose-intensification appeared to be strongest in node-positive disease. Its benefit, if any, in HER2-positive disease in the era of HER2-targeted therapy has not been validated. Additionally, the use of dose-intensification in (non-anthracycline) taxane-based regimens has not been evaluated.
D. CHEMOTHERAPY SIDE EFFECTS
Chemotherapy side effects, which are discussed in Chapter 39, are generally well controlled. Nausea and vomiting are abated with medications 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, is 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 with a goal, in general, to complete a full year. Seven comparative trials (HERA, FinHER, SOLD, ShortHER, PHARE, Hellenic Oncology study, PERSEPHONE) have evaluated the ideal length (2 years, 1 year, 6 months, 9 weeks) of adjuvant trastuzumab. All but one of these studies confirmed that 1-year is the ideal length of trastuzumab, though the PERSEPHONE study demonstrated noninferiority of 6 months of trastuzumab compared to 12 months, indicating that for selected patients with lower risk disease, a shorter duration of trastuzumab may be adequate. 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 stage II/III HER2-positive breast cancer (see Neoadjuvant Therapy). The phase III randomized placebo-controlled adjuvant “APHINITY” study evaluated 1 year of adjuvant pertuzumab in combination with trastuzumab. With a median follow up of 74 months, the 6-year invasive disease-free survival was 2.8% better with the year of pertuzumab (90.6% vs 87.8%, stratified HR 0.76, 0.64, 0.91). This benefit appeared to be restricted to those with node-positive disease where the absolute invasive disease-free survival benefit was 4.5% (87.9% vs 83.4%). However, no significant overall survival advantage has been demonstrated. Its use in the adjuvant setting is primarily restricted to patients with high-risk, node-positive disease. Neratinib, an orally bioavailable dual HER1 (EGFR), HER2 tyrosine kinase inhibitor, is FDA-approved as adjuvant therapy. The phase III placebo-controlled EXTENET study demonstrated that neratinib improves invasive disease-free survival when given for 1 year after completion of a year of standard adjuvant trastuzumab-based therapy (median follow-up 5.2 years, stratified HR 0.73, 95% CI 0.57, 0.92, P = 0.0083). Neratinib is associated with gastrointestinal toxicity, most notably moderate to severe diarrhea in approximately 40% of patients who did not use antidiarrheal prophylaxis. Measures to mitigate this side effect are being evaluated in the CONTROL clinical trial (NCT02400476). Pending those final results, patients should be treated with upfront prophylaxis with loperamide.
Patients who undergo neoadjuvant trastuzumab-based chemotherapy and have residual disease remaining at the time of surgery have a comparatively poor outcome compared to those who achieve a pathologic complete response. In the phase III randomized KATHERINE trial, 1486 patients with residual disease after standard neoadjuvant trastuzumab/taxane-based therapy (18% of whom also received neoadjuvant pertuzumab) were randomized to receive the antibody-drug conjugate trastuzumab emtansine or standard trastuzumab for 14 cycles after surgery. Patients treated with trastuzumab emtansine had a statistically significantly improved 3-year invasive disease-free survival (88% vs 77%), associated with a 50% relative risk reduction. These data led to the FDA approval of adjuvant trastuzumab emtansine in 2019 for patients with residual disease after standard trastuzumab-containing neoadjuvant therapy.
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). Ovarian suppression in addition to tamoxifen has been shown to significantly improve 8-year disease-free survival (83.2% vs 78.9%) and 8-year overall survival (93.3% vs 91.5%) compared to tamoxifen alone in the randomized Suppression of Ovarian Function Trial [SOFT] study, though the benefits appeared to be seen primarily in chemotherapy-treated patients with higher risk disease.
AIs, including anastrozole, letrozole, and exemestane, reduce estrogen production and are also effective in the adjuvant setting for postmenopausal women. AIs should not be used in a patient with functioning (premenopausal) ovaries since they do not block ovarian production of estrogen. At least seven large randomized trials enrolling more than 24,000 postmenopausal patients with hormone receptor–positive nonmetastatic breast cancer 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 with triptorelin was associated with a reduced risk of relapse compared to tamoxifen, 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, the 2017 jointly published guidelines of the Cancer Care Ontario and American Society of Clinical Oncology recommend that bisphosphonate use (zoledronic acid or clodronate) be considered in the adjuvant therapy plan for postmenopausal breast cancer patients. In addition, denosumab (another bone stabilizing medication), which is an antibody directed against receptor activator of nuclear factor kappa B ligand (RANK-L), was evaluated in two phase III adjuvant trials with discordant results. The “D-CARE” study randomized patients with early-stage breast cancer (all biologic subtypes) to receive denosumab or placebo and failed to demonstrate a reduction in breast cancer recurrences or deaths. It is speculated that one possible reason for this negative result may be due to the fact that premenopausal patients (who do not have a demonstrated metastatic recurrence benefit from bisphosphonates) were included in the study. In contrast, the ABCSG-18 trial restricted enrollment to postmenopausal women and did show an improvement in disease-free survival with denosumab.
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) is 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 (meaning no residual invasive cancer at the time of surgery) 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%). Long-term outcomes from this trial were reported in 2018, demonstrating similar disease-free and progression-free survival outcomes for the three arms. Left ventricular ejection fraction declines of at least 10% from baseline to less than 50% were observed in 11%, 16%, and 12% of patients in Arms A, B, and C, respectively.
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 are FDA-approved 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). After completing surgery, patients should resume HER2-targeted therapy (trastuzumab emtansine if there is residual disease at the time of surgery, trastuzumab with or without pertuzumab if pathologic complete response is achieved with consideration for the use of neratinib as extended adjuvant therapy for high-risk disease). Dual HER2-targeted therapy without standard cytotoxic chemotherapy has been evaluated in the neoadjuvant setting as well. The phase III KRISTINE study evaluated the antibody medication conjugate, trastuzumab emtansine (T-DM1, Kadcyla) in combination with pertuzumab compared to standard TCHP treatment. While the T-DM1/P arm was well tolerated and yielded a pathological complete response in 44% of patients, TCHP performed significantly better with a pathological complete response rate 56%. Thus, the use of T-DM1 in the neoadjuvant setting outside of a clinical trial is not recommended. Three-year invasive disease-free survival was similar in both arms.
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 indicate similar response rates with neoadjuvant endocrine therapy compared to neoadjuvant chemotherapy. Typically, responses are not appreciated unless 4–6 or more months of therapy are given. Outside of the clinical trial setting, the use of neoadjuvant hormonal therapy is generally restricted to postmenopausal patients who are unable or unwilling to tolerate chemotherapy.
3. Triple-negative breast cancer
No targeted therapy has yet demonstrated meaningful improvements in long-term outcomes for patients with curable 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 have evaluated whether the addition of platinum salts to a neoadjuvant chemotherapy regimen is beneficial in this disease subtype, several of which have shown improved outcomes (pathologic complete response and disease-free survival) with platinum use. 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 phase II studies including the Cancer Leukemia Group (CALGB) 40603 and the Adjuvant Dynamic Marker-Adjusted Personalized Therapy (ADAPT) triple-negative trial showed improved pathological complete response rates with platinum-based neoadjuvant therapy. Other studies are ongoing to evaluate the pathologic complete response rates and long-term outcomes associated with incorporating platinums into standard chemotherapy regimens. One randomized phase III study, “CREATE-X,” indicated that the use of eight cycles of adjuvant capecitabine improved disease-free survival and overall survival in patients with residual disease after standard neoadjuvant therapy. This benefit was primarily observed in those with triple-negative breast cancer. As such, it has become a standard option available to patients who do not experience a complete response after neoadjuvant therapy.
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%). If three nodes are removed and isotope and dye are used, the false-negative rate falls to an acceptable level. 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. An effective approach for sentinel node biopsy for patients who had involved nodes pre-chemotherapy is to place a clip in the positive node and be sure to excise it at the time of sentinel node biopsy. No study has evaluated the survival impact of no axillary treatment for node-positive patients who become node-negative after neoadjuvant therapy. Important questions remain to be answered involving the use of neoadjuvant therapy, including which neoadjuvant agents to use, duration of treatment, and additional postoperative therapy.