Clinical Pearls & Morning Reports
Breast cancers that are positive for estrogen receptor (ER) and negative for human epidermal growth factor receptor 2 (HER2) are the most common subset of breast cancers, accounting for 65% of cases of breast cancer among women less than 50 years of age and 75% of cases among older women. Read the NEJM Review Article here.
Q: Does higher ER expression in ER-positive breast cancer correlate with higher or lower rates of tumor-cell proliferation?
A: ER-positive breast cancer is heterogeneous. Tumors vary with respect to quantitative levels of ER, progesterone receptor (PR) expression (which is ER-driven), histologic grade, degree of proliferation (as measured by Ki-67 labeling or other indexes), patterns of gene expression, and the type and frequency of genomic alterations. These features are highly interrelated, with important clinical implications. Low-grade (well-differentiated) tumors have higher ER and PR expression and lower rates of proliferation, whereas intermediate- and high-grade tumors have lower levels of ER and may lack PR expression, with higher rates of cell proliferation.
Q: What percentage of ER-positive cancers are associated with hereditary cancer genes?
A: Hereditary cancer genes account for 8 to 10% of ER-positive cancers; such genes include CHEK2 (1% of cases) and genes associated with homologous recombination deficiency, such as BRCA1 (2%), BRCA2 (2%), ATM (0.5 to 1%), and PALB2 (0.5 to 1%).
A: Adjuvant endocrine therapy for 5 to 10 years is recommended for nearly all patients with ER-positive breast cancer to prevent metastatic disease, local–regional recurrence, and contralateral tumors. Five years of treatment with tamoxifen, a selective modulator of ER function, has been the traditional standard of care, regardless of menopausal status, reducing both distant and local–regional recurrence by 10 to 30% when ER expression is moderate and by 40 to 50% when ER expression is high, with carryover effects lasting 15 or more years. In recent years, the options for adjuvant endocrine treatment have broadened beyond tamoxifen. Aromatase inhibitors block the conversion of androgens into estrogens, suppressing residual estrogen levels by more than 90% in postmenopausal women. These agents are contraindicated in premenopausal women who are not undergoing ovarian suppression, because compensatory physiological responses induce ovarian estrogen production. Aromatase inhibitor therapy results in a greater reduction in the risk of recurrence than 5 years of tamoxifen, such that most postmenopausal women should consider aromatase inhibitor treatment either as initial therapy or after 2 to 3 years of tamoxifen.
A: Cyclin-dependent kinases 4 and 6 (CDK4/6) are important regulators of cell-cycle progression in many cell types, including ER-positive breast cancer. In randomized trials, adding CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) to either aromatase inhibitors in first-line therapy or fulvestrant in second-line therapy for advanced breast cancer improved progression-free and overall survival among both premenopausal and postmenopausal women and delayed the time to initiation of other cytotoxic chemotherapy. Additional targeted therapies can improve tumor control in refractory, ER-positive breast cancers. Between 30 and 40% of ER-positive tumors harbor an activating mutation in the alpha isoform of PI3K (PIK3CA), measurable on tumor or cell-free DNA. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors olaparib and talazoparib are each associated with high clinical response rates (>60%) among women with ER-positive breast cancers harboring germline BRCA1, BRCA2, or PALB2 mutations.