Adjuvant and Neoadjuvant Systemic Therapies for Triple-Negative Breast Cancer

Guidelines in a Changing Landscape

With the rapid pace of new therapies and data in oncologic care, best practices for the care of patient with early-stage TNBC are dynamic. Guidelines based on data from clinical trials and expert opinions aim to facilitate the reach of high-quality cancer care for patients globally. They evaluate the quality of evidence supporting the recommendations and cover topics including initial evaluation, therapy decisions, and surveillance. Newer guidelines also provide insight into best practices for management of toxicities, genetic testing, and other supportive care. Organizations such as the National Comprehensive Cancer Network, St. Gallen International Consensus Panel, American Society for Clinical Oncology, European Society for Clinical Oncology, and the Society for Immunotherapy of Cancer work to create and regularly update these guidelines.

Biology Defining Therapy: Breast Cancer Subtypes

The category of TNBC is defined by lack of expression of the estrogen receptor (<1%), progesterone (<1%), and HER2 receptors (immunohistochemistry 0 or 1+ or 2+ and fluorescence in situ hybridization [FISH]–negative). Most recently, the College of American Pathologist guidelines specified that ER 1% to 10% is considered low positive, for which there are more limited data regarding endocrine responsiveness, and tumors that have low positive hormone receptors may have significant biologic overlap with estrogen and progesterone receptor–negative breast cancers. TNBC is associated with a higher grade and Ki-67 than estrogen receptor–positive breast cancers. Although the optimal assays or cutoffs are not well defined, a subset of TNBCs express PD-L1 on the tumor and tumor infiltrating lymphocytes (TILs). Additionally, TNBC has higher tumor mutational burden (TMB) than other breast cancer subtypes. These features have been associated with a higher likelihood of benefit from immunotherapies, which is reflected in promising data from a number of immune checkpoint inhibitors (ICI) clinical trials.

Gene-expression profiling has led to several methods of subclassification of TNBC. Lehmann and colleagues categorized TNBC into six molecular subtypes: basal-like 1, basal-like 2, mesenchymal, mesenchymal stem-like, immunomodulatory, and luminal androgen receptor. By PAM50 analysis, the majority of TNBCs fit the basal molecular subtype, but some TNBCs are luminal B, HER2, and normal-like. Another system of molecular characterization of TNBCs subdivides tumors into luminal androgen receptor, mesenchymal, basal-like immunosuppressed, and basal-like immune-activated. These subtypes are also varied in mutational profiles, activity of different signaling pathways, and tumor-immune profiles, suggesting variable sensitivity to different therapeutic strategies. While this suggests the rationale for more tailored therapeutic approaches for different subtypes, clinical trials have yet to demonstrate conclusive evidence that molecular subtype should guide choice of therapies in early-stage TNBC.

Considering Chemotherapy

Chemotherapy reduces the risk of distant recurrence in the majority of patients with early-stage TNBC, with a greater absolute risk reduction, when matched by stage, compared to those with hormone receptor–positive breast cancer. However, the decision regarding chemotherapy administration for patients with TNBC is based on disease features (i.e., breast cancer stage, pathologic features), which influence the recurrence risk, and patient factors (i.e., performance status, age and life-expectancy, competing comorbidities, patient preferences), which influence tolerance and competing risks. Factors such as tumor size, number of lymph nodes involved, grade, and Ki-67 all impact recurrence risk, with higher-risk clinical features suggesting a greater benefit from chemotherapy. Although studies evaluating genomic assays included some patients with TNBC, they have not demonstrated added utility beyond clinical risk in selecting a subgroup of TNBC patients who would not benefit from chemotherapy, thus they are not routinely used in clinical care.

Prospective clinical trials evaluating the benefit of chemotherapy typically incorporated patients with tumors >1 cm or with nodal involvement, and have consistently shown improved outcomes with the addition of adjuvant chemotherapy. Data for chemotherapy benefit in patients with T1a and T1b tumors are less clear, with observational data having multiple confounding factors. However, one meta-analysis suggested that chemotherapy benefit seen in tumors <1 cm is primarily in those with T1b tumors.

Sequencing of Therapy

Multidisciplinary input, often from radiologists, radiation oncologists, surgeons, and medical oncologists, is required to determine the best sequence of therapy. Although earlier studies showed no disease-free survival (DFS) or OS benefit between neoadjuvant (NAT) and adjuvant chemotherapy, the response to NAT helps to identify the cohort of patients with poor prognosis who may benefit from adjuvant capecitabine or PARP inhibition, which has changed this paradigm. Additionally, the improvement in pathologic complete response (pCR) and EFS with neoadjuvant immunotherapy and chemotherapy supports NAT for many patients with TNBC. NAT should be considered the standard approach for most patients with TNBC with tumors greater than 2 cm (>cT2) or nodal involvement (cN+), and some cT1c (tumors that are >cT1c who are candidates for anthracycline-based therapy). NAT can allow for surgical downstaging, provide valuable prognostic information to guide adjuvant therapy, and accommodate special circumstances for which a delay in surgery is preferred (i.e., recent thromboembolic event).

NAT can downstage an inoperable tumor (such as locally advance breast cancer or inflammatory breast cancers) to an operable tumor or reduce the extent of surgery required (mastectomy to lumpectomy, axillary lymph node dissection to sentinel lymph node dissection, total mastectomy to skin-sparing mastectomy). NAT using an anthracycline-taxane regimen can result in a pCR rate of 25% to 40%, which can be improved by about 10% to 20% with the addition of a platinum and by an additional 10% to 20% with the addition of immunotherapy. The pCR rate with anthracycline, taxane, platinum, and immunotherapy can reach about 60% in patients with stage II and III TNBC. Even those without a pCR may have enough of a clinical response to NAT to allow for a more limited surgical intervention.

Moreover, the prognostic information gained from whether a pCR was achieved can help identify patients at higher risk for recurrence who would benefit from further adjuvant therapy. For those with residual disease, the extent or volume can be captured with the residual cancer burden (RCB) index. Those with a pCR (ypT0/is ypN0) or RCB 0 have an overall favorable prognosis, with 5-year EFS of 91%, whereas the recurrence rates are 80%, 66%, and 28% for those with RCB I, II, and III, respectively, with similar findings in other cohorts. The magnitude of residual disease provides valuable information regarding adjuvant approaches, as studies have shown no benefit from further adjuvant chemotherapy after NAT in those with a pCR but an EFS and OS advantage for adjuvant therapy when given in those patients with residual disease, as discussed in upcoming sections.

On the other hand, upfront surgery with consideration of postoperative adjuvant chemotherapy is preferred in some circumstances. In cases of uncertain clinical staging, such as tumors with extensive noninvasive components, immediate surgery allows for definitive pathologic staging and appropriate selection of chemotherapy. Definitive pathologic staging is helpful for cT1N0 TNBC for which no chemotherapy, or chemotherapy with an anthracycline-free, less intensive regimen are potential options. If the tumor is not palpable on clinical examination at the onset, imaging midway thru NAT or alternatively adjuvant chemotherapy may be preferred in order to ensure treatment resistance to NAT is not missed. If fertility preservation or other medical considerations prechemotherapy will result in significant delay initiating NAT, upfront surgery with adjuvant chemotherapy may be favored. This approach may be considered in cases of significant comorbidities or poor performance status where the tolerance of chemotherapy may be poor.