A 47-year-old woman, gravida 2 para 2, comes to the office after noticing a pea-sized lump in her right breast while taking a shower. Her medical history is significant for 3 pack-years of cigarette use during her 20s. She underwent infertility treatment and in vitro fertilization for both of her pregnancies. The patient has no family history of breast or ovarian cancer. A clinical breast examination confirms the presence of a firm, fixed nodule in the right breast with a small patch of overlying puckered skin. Mammogram findings are highly suspicious for malignancy, and a needle biopsy reveals infiltrating ductal carcinoma. A right mastectomy and axillary lymph node dissection are scheduled. Overexpression of which of the following markers is most likely to be associated with aggressive disease in this patient?
Human epidermal growth factor receptor 2 (HER2, also called ERBB2) is a member of the epidermal growth factor receptor family. It is overexpressed in 20%-30% of breast cancers. HER2 is a transmembrane glycoprotein with tyrosine kinase activity that acts to increase cell proliferation. It is present in diminutive amounts in normal breast and ovarian cells. In breast cancer, HER2 overexpression (positivity) is associated with poorly differentiated, rapidly growing tumors. Clinically, HER2 status is used to predict therapeutic response to anti-HER2 monoclonal antibodies (eg, trastuzumab).
(Choice A) Overexpression of the anti-apoptotic BCL-2 protein is classically observed in follicular lymphomas, but it also occurs in a variety of other malignancies, including breast cancer. Unlike in lymphomas, increased expression of BCL-2 in breast cancer is associated with a favorable prognosis.
(Choices B and E) Breast cancers that express high levels of estrogen and/or progesterone receptors are typically associated with improved outcomes. Activation of these receptors acts as a stimulus for tumor growth. Therefore, anti-estrogen therapy (eg, aromatase inhibitors, tamoxifen) is used to treat hormone receptor-positive breast cancer.
(Choice D) Overexpression of a mutated form of p53 is found in many human cancers, including breast cancers. However, the degree of protein expression does not correlate well with clinical outcomes. Rather, the effects on prognosis are more dependent on the specific mutation (eg, nonsense, gain of function).
Educational objective:
Estrogen- or progesterone-receptor positivity in breast cancer indicates expected sensitivity to tamoxifen and aromatase inhibitor treatment. HER2 overexpression in breast cancer suggests a more aggressive tumor that typically responds to therapy with the anti-HER2 monoclonal antibody trastuzumab.