CE / CME
Pharmacists: 0.50 contact hour (0.05 CEUs)
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Nurses: 0.50 Nursing contact hour
Released: September 15, 2022
Expiration: September 14, 2023
Denise A. Yardley, MD:
There is a huge need for the development of therapies for TNBC. TNBC accounts for only 10% to 20% of all breast cancers but has a more aggressive biology.1,2 Tumor size and nodal status are independent prognostic factors in TNBC because tumor size is not reflective of nodal status, with some patients having small tumors and significant nodal involvement and others having large tumors without nodal involvement.3,4
A pCR with neoadjuvant chemotherapy is achieved by up to 40% of patients with early-stage TNBC and is associated with better outcomes.1,5-7 The risk of recurrence is highest within the first 3 years of diagnosis, and distant recurrence is common, frequently occurring without prior local recurrence.6 Patients with TNBC also have a higher risk of death in the 5 years post diagnosis compared with other types of breast cancer.4 All of these factors highlight the need for new therapies in early-stage TNBC that improve patient outcomes. Immunotherapy is a novel approach for TNBC.
Neoadjuvant chemotherapy has long been a mainstay of TNBC treatment due to the chemosensitivity of TNBC. Current guidelines recommend considering neoadjuvant chemotherapy for TNBC tumors ≥2 cm.8 Patients with TNBC who achieve a pCR have significant improvement in event‑free survival (EFS) and overall survival (OS).7,9,10 Patients whose tumors respond poorly to chemotherapy and have residual disease either in the breast or lymph nodes have worse outcomes.
Neoadjuvant chemotherapy helps downstage the tumor prior to surgery.11 This also facilitates and enables not only germline testing for mutations with an inherently higher risk of breast cancer, such as BRCA1 and 2, but also genetic counseling, as well as discussions regarding risk reducing breast surgery and consultations for reconstructive plastic surgery. Furthermore, patients who demonstrate residual disease can follow up with adjuvant capecitabine based on the CREATE-X trial, with or without immunotherapy.12
The mechanism of action and efficacy of immunotherapy are well established in solid tumors.13 Breast cancer, due to its heterogeneity, has been late in defining the role of immunotherapy, although there were early signals in TNBC. The addition of chemotherapy to immunotherapy makes sense because chemotherapy disrupts tumor architecture, decreases tumor size, and leads to antigen shedding that helps initiate the immune response.14
In the setting of metastatic TNBC, the benefits of immunotherapy are limited to patients with PD‑L1–expressing tumors. However, the immunologic microenvironment of early-stage TNBC is different in terms of the level of antigen presentation, PD-L1 expression, intratumor heterogeneity, and the number of tumor‑infiltrating immune cells.15 These differences are why neoadjuvant immunotherapy is being explored in all patients with early-stage TNBC regardless of PD-L1 status.
Neoadjuvant immunotherapy is now a standard of care for patients with early-stage TNBC based on data from the ongoing KEYNOTE-522 trial. This trial randomized 1174 adults with newly diagnosed T1cN1-2 or T2-4N0-2 TNBC with tissue samples available for PD-L1 testing.16,17 Patients were stratified by nodal status, tumor size, and carboplatin schedule before being randomized 2:1 to receive pembrolizumab plus chemotherapy vs placebo plus chemotherapy. The chemotherapy regimen was carboplatin plus paclitaxel for 4 cycles followed by 4 cycles of an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide. Pembrolizumab was given at a dose of 200 mg every 3 weeks for 8 cycles prior to surgery. Following surgery, patients received 9 additional cycles of pembrolizumab or placebo.
The primary endpoints of the trial are pCR (ypT0/Tis ypN0) and EFS by local review. Secondary endpoints are pCR (ypT0 ypN0 and ypT0/Tis), OS, EFS, and adverse events (AEs).
The characteristics of the enrolled patients reflect the characteristics of patients with TNBC in the community in that 52% of patients were lymph node positive, 75% had stage II tumors, and 56% were premenopausal.
In this analysis, at a median follow-up of 39.1 months, the EFS rate was 84.5% with the addition of pembrolizumab vs 76.8% with chemotherapy alone (HR: 0.63; 95% CI: 0.48-0.82; P = .001).17 In a subgroup analysis, EFS was improved with pembrolizumab plus chemotherapy regardless of nodal status or PD-L1 expression. These data led pembrolizumab plus chemotherapy to become a standard of care for early TNBC regardless of patient PD‑L1 status. Note that this contrasts with the use of pembrolizumab in the metastatic setting, which is indicated for patients with positive PD-L1 expression and a CPS ≥10.
Patients in both arms who achieved a pCR had EFS rates above 90% when this analysis was done, which is fantastic for such an aggressive biology.17 Patients with residual disease after either therapy had worsened EFS that ranged from a rate of 56.8% with chemotherapy alone to 67.4% with the addition of pembrolizumab to chemotherapy.
The I-SPY2 trial demonstrated that patients with residual TNBC following neoadjuvant therapy have poor long‑term EFS.18,19 Thus, lowering the residual cancer burden improves survival.
In KEYNOTE-522, the addition of neoadjuvant pembrolizumab to chemotherapy allowed more patients to achieve a pCR or near‑pCR than chemotherapy alone, resulting in better outcomes.20,21 Pembrolizumab plus neoadjuvant chemotherapy is approved by the FDA and now a standard of care for patients with high-risk, early-stage TNBC.
KEYNOTE-522 builds on evidence from other clinical trials of immunotherapy plus chemotherapy in early-stage TNBC, as shown on this slide. I would like to call attention to the NeoTRIPaPDL1 study, which evaluated chemotherapy with and without atezolizumab.22 The chemotherapy component was carboplatin and paclitaxel—but no anthracycline—which makes this study unique. Compared with the other studies shown here, patients did not receive the same pCR benefit with the addition of immunotherapy (48.6% vs 44.4% for chemotherapy alone). This suggests that anthracyclines are an important component of these combinations.
Although the safety profile of immunotherapy is now well known, immune-related AEs (irAEs) are new to many breast cancer oncologists. Immunotherapy causes various irAEs.23,24 The most common any-grade irAEs in KEYNOTE-522 were infusion reactions (18.0% of patients), hypothyroidism (15.1%), and severe skin reactions (5.7%).16,17 Other endocrine toxicities were observed, including hyperthyroidism (5.2%), adrenal insufficiency (2.6%), and hypophysitis (1.9%), but these were less common than hypothyroidism. Healthcare professionals must watch for symptoms related to immunotherapy and weigh the potential risks and benefits of immunotherapy for each patient.
One key challenge in patients who have residual disease is how long to continue immunotherapy. Patients in the KEYNOTE‑522 trial continued immunotherapy with pembrolizumab for 9 additional cycles after surgery regardless of their response to neoadjuvant immunotherapy. If patients are unlikely to benefit from continuing immunotherapy, it is hard to justify the toxicity risk.
For patients achieving a residual disease burden of 0 or 1, there was no difference in outcomes in those receiving adjuvant immunotherapy vs those in the placebo group. Thus, if a patient is not tolerating immunotherapy with a residual disease burden of 0 or 1, it may be reasonable to discontinue immunotherapy.25
The CREATE‑X trial was completed before interim results were available for KEYNOTE-522. CREATE-X was a randomized, open-label phase III trial evaluating adjuvant capecitabine for residual disease in HER2-negative early breast cancer following neoadjuvant therapy and surgery.12 The trial enrolled 910 patients who had not previously received fluoropyrimidines and randomized them 1:1 to receive capecitabine (plus hormonal therapy if hormone receptor positive) or, depending on hormone receptor status, either hormonal therapy alone or no further therapy.
The primary endpoint was disease-free survival (DFS), and secondary endpoints were OS, time from preoperative chemotherapy to recurrence or death, safety, and cost effectiveness.
The trial was terminated early for efficacy.12 The 5-year DFS rate with capecitabine was 74.1% vs 67.6% with no capecitabine (HR: 0.70; 95% CI: 0.53-0.92; P = .01). The 5-year OS rate also was significantly improved with capecitabine at 89.2% vs 83.6% (HR: 0.59; 95% CI: 0.39-0.90; P = .01).
The subgroup of patients with residual TNBC derived the most benefit from capecitabine, as shown by an HR of 0.58 (95% CI: 0.39-0.87) compared with an HR of 0.84 (95% CI: 0.55-1.17) in those with hormone receptor–positive disease.12 Based on these data, capecitabine is a standard of care for patients with residual TNBC following neoadjuvant chemotherapy.
An important question is how to treat patients with TNBC with residual disease following immunotherapy. There are no definitive guidelines, but I personally continue immunotherapy and consider adding capecitabine. Although combination immunotherapy/capecitabine has not been studied in the adjuvant setting in breast cancer, this combination has been safely used in other solid tumors, notably gastric/gastroesophageal junction (GEJ) cancers.
Safety data supporting use of capecitabine plus pembrolizumab in other solid tumors come from the KEYNOTE-062 trial, which is comparing pembrolizumab alone vs pembrolizumab plus chemotherapy (cisplatin plus 5-fluorouracil or capecitabine) vs placebo plus chemotherapy in 763 patients with advanced PD-L1–positive gastric/GEJ cancers.26 Treatment continues until disease progression, unacceptable toxicity, patient withdrawal, or 2 years of therapy. This trial has reported no new safety signals with capecitabine plus immunotherapy in patients with advanced gastric/GEJ cancers.
The prognosis is poor for patients with residual TNBC, and I want to provide them with opportunities to improve their outcomes. Given the safety data for pembrolizumab plus capecitabine in gastric/GEJ cancers, I feel comfortable using this combination in my patients who have residual TNBC following neoadjuvant chemotherapy.
There are other options for patients with early-stage TNBC and residual disease. The OlympiA trial is evaluating the PARP inhibitor olaparib vs placebo in 1836 patients with germline BRCA1/2-mutated, HER2-negative, very high–risk primary breast cancer.27 All patients had completed definitive local therapy and ≥6 cycles of neo/adjuvant chemotherapy. This trial enrolled a subgroup with hormone receptor–positive/HER2-negative disease and a subgroup with TNBC. The latter required that patients who had received neoadjuvant therapy could not have achieved a pCR, whereas those who had received adjuvant therapy must have had ≥ pN1 or ≥ pT2 disease.
Patients were randomized to receive 1 year of olaparib vs placebo. The primary endpoint is invasive DFS, with secondary endpoints of distant DFS, OS, and safety.
In a prespecified interim analysis, the 3-year invasive DFS rate was significantly improved from 77.1% with placebo to 85.9% with olaparib for a difference of 8.8% and a stratified HR of 0.58 (99.5% CI: 0.41-0.82; P <.001).27 In the TNBC subgroup, the HR was 0.56 (95% CI: 0.43-0.73), with consistent benefit across patients who had received prior chemotherapy in the neoadjuvant vs adjuvant settings.
Preliminary data for the combination of olaparib and immunotherapy are promising, but we currently do not have enough data to use a combination. In the case of patients with germline BRCA1/2 mutations, I think PARP inhibitors will end up having a stronger recommendation than capecitabine. Regardless, we need to determine how to sequence and/or combine these agents safely.
When treating early‑stage TNBC, the first step is determining who is a candidate for neoadjuvant therapy. In my practice, I consider almost all patients whose tumors are approximately 2 cm for neoadjuvant therapy, bearing in mind that capecitabine is an option for residual disease.
I consider neoadjuvant immunotherapy plus chemotherapy for all patients with tumors ≥2 cm. I then reevaluate what to do postoperatively based on residual disease, presence/absence of targetable germline mutations, and eligibility for capecitabine and/or pembrolizumab.
For tumors <1 cm, I consider surgery followed by adjuvant therapy, as these patients have lower-risk TNBC. Chemotherapy remains the mainstay of adjuvant therapy for this population. The amount of chemotherapy sufficient to treat lower‑risk TNBC remains to be determined, so we are still working to tailor the chemotherapy regimens in this population.
With the addition of new agents, we need to figure out how to sequence and/or combine drugs. In the case of the KEYNOTE‑522 and the CREATE‑X regimens, it is unclear whether the timing of drugs relative to one another is important, if the data with capecitabine are still relevant, and if there is a need to combine the therapies.
The ideal composition of the chemotherapy backbone remains a very provocative yet unanswered question. Data from the NeoTRIP trial suggest that anthracyclines are an important part of the backbone, but we do not yet know if this translates into an OS benefit. Other drugs used in the metastatic setting, such as sacituzumab govitecan, also may benefit patients with early-stage TNBC.
Patients who achieve a pCR with immunotherapy may not need a full year of therapy to benefit, whereas those who have residual disease following neoadjuvant chemotherapy may not always benefit from immunotherapy. The use of biomarkers may allow us to identify patients who will not benefit and spare them from the risk of toxicity.
These questions will be addressed in clinical trials in the future and hopefully will allow us to further improve the long-term outcomes for patients with early-stage TNBC.
When treatment options are presented to patients, the benefits and potential toxicities of the therapy should be discussed, and patients should share their concerns. The treatment options we have discussed today are associated with distinct safety profiles, from irAEs with pembrolizumab to myelosuppression with olaparib. Healthcare professionals should counsel patients in advance about the toxicities they may experience with each treatment option and how these toxicities may be managed. During patient visits, the care team should ask patients about their symptoms to identify AEs early and provide appropriate supportive care.
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