Breast CA Breast Cancer Pathophysiology Breast cancer is a globally pervasive disease that significantly impacts all races and affects both sexes1,2. Cancerous abnormalities of the breast occur in two types of tissue – ductal epithelium and lobular epithelium. Although most breast cancers arise from within the ductal epithelium, malignant cells can also originate within lobular (milk-producing) glands.2,3 Aberrations of other breast structures, such as sarcomas and lymphomas, are not typically associated with breast cancer,3 although some proliferative and non-proliferative benign breast conditions can carry a higher risk of breast cancer development.4 Risk Factors for Breast Cancer Risk factors for breast cancer development are multifactorial, and include factors that span personal and family history, breast tissue density and specific exposures4. Being female is the main risk factor for breast cancer, with a 100-fold increase in risk compared to men4. Suspected hereditary components account for a smaller portion of breast cancer cases4. The most common cause of hereditary breast cancer is a BRCA1 or BRCA2 genetic mutation inheritance,4,5 conferring a 7 in 10 chance of developing breast cancer by the age of 804. Women with either of these mutations are also more likely to be diagnosed with this cancer not only at a younger age, but also cancer in bilateral breasts, as well as ovarian cancer.4 Other genetic mutations are far less common, and generally do not increase risk of breast cancer development as significantly as BRCA mutations4. Breast Cancer Classification Breast cancer classification is categorized into four main subtypes6 focusing on pathological assessment of hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor 2 (HER2) status2. Each has their own role in tumor development and can be targeted for anti-tumoral directed therapy. Estrogen and progesterone can promote growth of tumors that express receptors for these hormones.6,7,8 Hormone receptor-positive breast cancers are particularly prominent, with approximately two of every three cancers testing positive for hormone receptors8. HER2 is a gene that produces HER2 (HER2/neu) proteins, which help control how healthy breast cells grow, divide, and repair. However, HER2 can be associated with aggressive types of breast cancer if the HER2 gene is amplified (too many protein copies made) and the protein overexpressed (too many HER2 receptors created)6,7,9. Hormone and HER2 receptor factors have value in determining disease stage, recurrence estimation, and prognostic therapeutic response2. The four main subtypes of breast cancer include: Subtype HR+/HER2 – is the most prevalent (67%), more than six times higher than triple negative cancers6. HER2-positive subtypes are much less common, with 2012-2016 data revealing a total of 14% of cases for both Luminal B and HER2-enriched subtypes combined6. Prognostic and Predictive Factors Clinical and pathological characteristics of tumors can potentially influence therapy choice and even expected outcomes, or prognosis10. Tissues can be evaluated for such features through conventional histology, immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), molecular and genetic profiling7,10. For example, certain histologic types can have prognostic importance, such as medullary carcinoma and variants of invasive ductal carcinomas (adenoid cystic and tubular carcinomas), which can have favorable natural histories2. Alternatively, triple-negative subtyping tends to have the worst survival of all four breast cancer classifications6. Above all, stage at diagnosis (localized, regional or distant) may have the greatest impact in determining long-term survival6. Of particular importance in prognosis determination and therapeutic response prediction to endocrine and HER2-directed therapies are ER, PR, and HER2 status10. The American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) consensus panel has published guidelines to help standardize the use, reporting, and interpretation of ER, PR, and HER2 assessments10. ER and PR assessments should be conducted on all invasive breast cancers, ER assessments on all ductal carcinomas in situ (DCIS), and all new primary or newly metastatic breast cancers should undergo HER2 assessment following methodologies outlined in the ASCO/CAP testing guidelines2. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Female Breast Cancer. Available at https://seer.cancer.gov/statfacts/html/breast.html. Accessed: September 9, 2019. Breast Cancer. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2019 – July 2, 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed: September 9, 2019. American Cancer Society. What is Breast Cancer? Available at: https://www.cancer.org/cancer/breast-cancer/about/what-is-breast-cancer.html. Accessed: September 19, 2019. American Cancer Society. Breast Cancer Risk Factors You Cannot Change. Available at: https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/breast-cancer-risk-factors-you-cannot-change.html. Accessed: September 9, 2019. National Cancer Institute. Genetics of Breast and Gynecological Cancers (PDQ®) – Health Professional Version. Available at: https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq#_2_toc. Accessed: September 9, 2019. National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed: September 9, 2019. American Cancer Society. Breast Cancer HER2 Status. Available at: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed: September 9, 2019. BreastCancer.org. Hormone Receptor Status. Available at: https://www.breastcancer.org/symptoms/diagnosis/hormone_status. Accessed: September 10, 2019. BreastCancer.org. HER2 Status. Available at: https://www.breastcancer.org/symptoms/diagnosis/her2. Accessed: September 10, 2019. National Cancer Institute. Breast Cancer Treatment (PDQ®) – Health Professional Version. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed: September 9, 2019.