Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• For patients with early-stage breast cancer, gene expression assays can be used to determine the likelihood of recurrence and the potential benefit of adjuvant chemotherapy
• For example, the Oncotype Dx assay, which is based on the expression profile of 21 genes, provides a score (ie, recurrence score) that is both prognostic and predictive of chemotherapy benefit
• Node-negative tumors with a recurrence score of 0 to 10 have a very good prognosis, with a low rate of distant recurrence at 10 years
• Conversely, tumors with a high recurrence score (> 25) have higher risk for recurrence and have been shown to benefit from chemotherapy in retrospective studies
• In the TAILORx studies, postmenopausal patients with node-negative, HR+ early breast cancer and intermediate recurrence score (11 to 25) did not derive a significant benefit from chemotherapy, which is thus not recommended for this subgroup of patients

• The addition of abemaciclib to adjuvant endocrine therapy:
  • Was evaluated in the phase 3 monarchE trial:
    • That enrolled patients with high-risk, early-stage breast cancer:
      • With high risk defined as:
        • ≥ 4 axillary nodes or
        • 1 to 3 axillary nodes with:
          • Grade 3 histology
          • A large primary tumor (equal or greater than 5 cm)
          • High Ki67 score:
            • Defined as ≥ 20%
    • At a median 27 months of follow up:
      • The addition of abemaciclib led to statistically significant improvements in:
        • Invasive disease-free survival (IDFS) (HR, 0.70; 95% CI, 0.59-0.82; nominal P < 0.0001)
        • Distant relapse-free survival (DRFS) (HR, 0.69; 95% CI, 0.57-0.83; nominal P < 0.0001)
      • These findings were consistent with those from earlier data analyses
      • A low Ki-67 level was prognostic of better outcome:
        • However, it was not predictive of benefit from abemaciclib in this study
    • Results from a prespecified overall survival (OS) interim analysis were presented at the 2022 San Antonio Breast Cancer Symposium:
      • All patients were no longer receiving abemaciclib at a median follow-up of 42 months
      • Invasive DFS and DRFS benefits were sustained beyond the treatment period
      • OS data remained immature at time of analysis (Table 1.1)

Table 1.1. Efficacy Results From the monarchE Study Presented at SABCS 2022

• Most women don’t have any symptoms at diagnosis of breast cancer, which typically follows abnormalities at breast imaging detected through screening programs
• However, approximately 1 in 6 women with breast cancer present with symptoms other than a breast lump
• Of note, women with non-lump breast symptoms often delay seeking help, which is concerning as longer intervals to diagnosis have been associated with lower survival rates
• In the United States, approximately 6% of tumors are metastatic at presentation, which not rarely are diagnosed in patients with neglected tumors

• Koo and colleagues collected and analyzed data from more than 2300 women with symptomatic breast cancer diagnosed in the United Kingdom
• A total of 56 presenting symptoms were reported
• Among them, breast lump was the most common (83%), followed by nipple abnormalities (7%), breast pain (6%), and breast skin abnormalities (2%)
• More rarely, patients presented with non-breast symptoms suggestive of metastatic disease, such as back pain (1%) and weight loss (0.3%)

• In 2022, both the US Food and Drug Administration and the European Union approved adjuvant olaparib, a PARP inhibitor, for the treatment of patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm) and a diagnosis of HER2-negative, high-risk, early-stage breast cancer treated with neoadjuvant or adjuvant chemotherapy
• A diagnostic companion test for germline BRCA status is needed to select patients for this treatment
• Olaparib was approved on the basis of findings of the OlympiA trial, a phase 3 trial in which patients carrying a germline BRCA alteration and a diagnosis of HER2-negative, high-risk, early-stage breast cancer were randomly assigned to receive 1 year of olaparib or placebo after (neo)adjuvant chemotherapy
• A statistically significant improvement in invasive disease-free survival and overall survival was demonstrated in patients in the olaparib arm compared with the placebo arm
• The safety profile of olaparib was consistent with previously reported side effects

• As with other early breast cancers (eg, hormone-positive or triple-negative), risk for recurrence of a HER2-positive tumor is generally dependent on tumor size, presence of positive axillary lymph nodes, tumor grade, and other histologic and patient factors
• Before the development of effective anti-HER2 therapies, such as trastuzumab, novel anti-HER2 tyrosine kinase inhibitors (TKIs), or antibody drug conjugates (ADCs) HER2 positivity was associated with poor prognosis
• The degree of HER2 positivity (ie, IHC 2+/FISH amplified vs IHC 3+) is not correlated with recurrence risk, although it may be associated with greater responsiveness to anti-HER2–targeted therapies
• Patients with early-stage, HER2-positive tumors with clinically positive lymph nodes are candidates for neoadjuvant systemic treatment with chemotherapy and pertuzumab plus trastuzumab

• According to the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO), decisions about adding chemotherapy to adjuvant endocrine therapy are individualized on the basis of patient and disease factors, including results of genomic assays
• Most cases of small ER-positive, PR-positive, HER2-negative, node-negative breast cancer have a good prognosis with endocrine therapy alone and do not require adjuvant chemotherapy
• By contrast, tumors that are high-grade, with higher measures of proliferation and lower levels of ER/PR expression, tend to be less sensitive to endocrine treatment and are more likely to benefit from adjuvant chemotherapy
• Although assessment of response to neoadjuvant endocrine therapy or chemotherapy is used in the setting of locally advanced breast cancer, particularly when the size and/or location of the tumor preclude breast-conserving surgery, patients with very small, early, HER2-negative, hormone-positive cancers are generally treated with surgery first, followed by radiation therapy and consideration of adjuvant therapy with an endocrine regimen, chemotherapy, or both
• Ki67 is an indirect measure of cell proliferation
• Although a high Ki67 score is often considered a marker for poorer prognosis in early breast cancer, it cannot predict the benefit of chemotherapy as a single measure
• Recently, the International Ki67 in Breast Cancer Working Group concluded that Ki67 has limited value for treatment decisions due to questionable analytical limitations

• Inflammatory breast cancer is an aggressive type of breast cancer that requires urgent workup and treatment
• Detection by mammography is limited due to low sensitivity; hence, diagnosis of inflammatory breast cancer is based on clinical factors and defined as a rapid onset of breast erythema, edema and/or peau d’orange, and/or warm breast, with or without an underlying palpable mass
• Immediate referral to medical and surgical oncologists is essential when inflammatory breast cancer is suspected
• Because it is not uncommon for women with inflammatory breast cancer to have metastatic disease at the time of diagnosis, inflammatory breast cancer should be staged with full-body imaging, such as PET-CT or CT of the chest, abdomen, and pelvis, plus a bone scan
• When the presence of metastatic disease is ruled out, inflammatory breast cancer is treated with chemotherapy upfront (ie, neoadjuvant), before surgery
• Axillary adenopathy may or may not be present
• Crusting and retraction of nipples may or may not occur

• Although women with at least one first-degree relative with a history of breast cancer have a two- to three fold excess risk of developing the disease, only 5% to 10% have an identifiable hereditary predisposition
• On average, women with a germline BRCA1 mutation have a 72% risk of developing breast cancer by age 80 years
• For those with a germline BRCA2 mutation, the risk is 69%
• The highest rates of BRCA1 mutations occur among Ashkenazi Jewish women
• Because of the high lifetime risk for breast cancer in germline BRCA mutation carriers, both American and European guidelines recommend considering prophylactic surgery, such as double mastectomy
• Other women at high risk of developing breast cancer because of a hereditary predisposition may opt for frequent imaging
• Breast cancers that develop in germline BRCA1 mutation carriers are more likely to be high-grade, as well as triple-negative or basal-like subtype, whereas those with BRCA2 mutations are more likely to develop a high-grade, hormone receptor–positive/HER2-negative tumor

• One of the most important factors to be considered with breast cancer diagnosis is breast cancer subtype
• There are three major breast cancer subtypes: luminal-like, HER2-positive, and triple-negative, which are identified by the expression of hormone receptors and HER2 by breast cancer cells
• Of note, these subtypes have different biologic features, prognosis, and response to treatment
• Although all breast cancers may recur despite treatment, those defined as triple-negative breast cancer (TNBC), which lack specific targets for effective treatments, are considered high risk
• Hence, up to 40% of early-stage breast cancer patients will experience recurrence after standard treatment
• Tumors expressing hormone receptors (ie, estrogen and progesterone receptors) are defined as luminal-like, are typically less aggressive, and have a good prognosis
• HER2-positive breast tumors are biologically aggressive tumors, but the outcome has dramatically improved with anti-HER2 targeted therapies