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Key Clinical Updates in HER2-Low Expressing Breast Cancer

A practice-changing phase 3 trial comparing T-DXd with single-agent chemotherapy (DESTINY-Breast04) demonstrated a significantly improved progression-free and overall survival with T-DXd in patients whose metastatic disease had progressed after standard chemotherapy (and endocrine therapy, if hormone receptor–positive), leading to its FDA approval in this setting.

Modi S et al; DESTINY-Breast04 Trial Investigators. N Engl J Med. [PMID: 35665782]


  • Risk factors: Age, nulliparity, childbirth after age 30, family history of breast cancer or deleterious mutations (BRCA1, BRCA2, or others), and personal history of breast cancer or some types of proliferative conditions.

  • Early findings: Mammographic abnormalities and no palpable mass, or single, nontender, firm to hard mass with ill-defined margins.

  • Later findings: Skin or nipple retraction; axillary lymphadenopathy; reast enlargement, edema, erythema, 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 American women. In the United States, it is second only to lung cancer as a cause of cancer death except in Black and Hispanic women for whom breast cancer is the leading cause of cancer death. In 2022, there were approximately 287,850 new cases of invasive breast cancer and 43,250 women died from breast cancer in the United States. Worldwide, breast cancer is diagnosed in approximately 2.3 million women, and about 685,000 die of breast cancer each year, with the highest rates of diagnosis in Australia/New Zealand, Europe, and North America and lowest rates in Eastern/Middle Africa and South Central Asia. These regional differences in incidence are likely due to the variable availability of screening mammography as well as differences in reproductive, nutrition, 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 childbirth after age 30) and as the incidence of obesity has risen. Globally, breast cancer has surpassed lung cancer as the most commonly diagnosed cancer among women.

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 imparts a high risk of developing breast cancer. Germline mutations in the BRCA family of tumor suppressor genes or other breast cancer susceptibility 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. ...

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