A Dynamic Treatment Landscape Emerges for Early-Stage TNBC

Triple-negative breast cancer (TNBC) is a biologically complex subtype characterized by an aggressive nature and heterogeneity. Standard chemotherapy has historically been the mainstay of treatment for patients with diagnoses of early-stage TNBC, but there remains an unmet need to identify novel therapies that improve outcomes and, equally important, to discern which patients may benefit from a given treatment.

Immunotherapy

The anti–PD-1 monoclonal antibody pembrolizumab (Keytruda) has shown impressive antitumor activity in the metastatic and curative settings for patients with TNBC. In the phase 3 KEYNOTE-355 trial (NCT02819518), the addition of pembrolizumab to chemotherapy significantly improved progression-free survival (PFS) vs chemotherapy alone among patients with previously untreated locally advanced inoperable or metastatic TNBC and combined positive score of at least 10. Specifically, the median PFS was 9.7 months with pembrolizumab/chemotherapy vs 5.6 months with placebo/chemotherapy (HR, 0.65; 95% CI, 0.490.86; P = .0012).¹

In the curative space, neoadjuvant systemic therapy is favored for patients with early TNBC—specifically for tumors that are larger than 2 cm or with nodal involvement—and may be considered for smaller tumors in certain cases. Potential benefits of neoadjuvant chemotherapy include goal of downstaging the primary tumor and/or axilla to allow more surgical options (ie, breast-conserving surgery vs mastectomy) and assessment of the biology of the cancer via chemotherapy response, which can have prognostic and therapeutic implications. In I-SPY2 (NCT01042379), a phase 2 adaptively randomized platform trial for high-risk, stage II/ III breast cancer evaluating multiple investigational arms in different subtypes in parallel fashion, the addition of pembrolizumab to neoadjuvant chemotherapy (taxane-based and anthracycline-based) more than doubled the pathologic complete response (pCR) rate in hormone receptor–positive/HER2-negative and triple- negative subtypes.²

Investigators of the phase 3 KEYNOTE-522 trial (NCT03036488) evaluated the role of pembrolizumab added to chemotherapy for high-risk (stage II/III) TNBC in the neoadjuvant setting. The chemotherapy backbone consisted of paclitaxel/carboplatin followed by anthracycline (doxorubicin or epirubicin)/cyclophosphamide. After surgery, patients received adjuvant pembrolizumab (n = 784) or placebo (n = 390) every 3 weeks for up to 9 cycles. The pCR rate was 64.8% in the pembrolizumab/chemotherapy group vs 51.2% in the placebo/chemotherapy group, yielding an absolute benefit of 13.6% (95% CI, 5.4-21.8; P < .001).

At median follow-up of 39.0 months, 84.5% of patients who received pembrolizumab plus chemotherapy were alive and had not experienced an event-free survival (EFS) event vs 76.8% of those who received chemotherapy alone (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).³ These updated findings regarding EFS benefit led to the FDA approval of pembrolizumab plus chemotherapy for highrisk early-stage TNBC as neoadjuvant therapy, followed by pembrolizumab as single-agent in the adjuvant setting.⁴ Notably, pembrolizumab benefit was seen irrespective of PD-L1 status.

Olaparib Proves Effective in Mutant Disease

Breast cancers associated with BRCA mutations are more prone to double-strand DNA breaks that cannot be repaired because of a defective homologous recombination repair pathway. PARP inhibition leads to synthetic lethality and cancer cell apoptosis. Two PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), have demonstrated PFS benefit compared with chemotherapy in patients with germline BRCA mutations and HER2-negative metastatic breast cancer, in the OlympiAD (NCT02000622) and EMBRACA (NCT01945775) trials, respectively.^5,6

The phase 3 OlympiA trial (NCT02032823) was designed to explore the role of olaparib in the adjuvant setting among patients with HER2-negative early breast cancer with BRCA germline mutations after receipt of neoadjuvant or adjuvant chemotherapy. Patients with TNBC were required to have a primary tumor measuring at least 2 cm or node-positive disease if treated in the adjuvant setting, or presence of residual disease (no pCR) post neoadjuvant chemotherapy.

One year of adjuvant olaparib led to a statistically significant improvement in both invasive and distant disease-free survival (DFS), with absolute benefits of 8.8% and 7.1%, respectively (TABLE⁷). The 3-year invasive DFS rate was 85.9% in the olaparib group vs 77.1% in the placebo group (HR, 0.58; 95% CI, 0.41-0.82; P < .001). The 3-year distant DFS rate was 87.5% in the olaparib group vs 80.4% in the placebo group (HR, 0.57; 95% CI, 0.39-0.83; P < .001).⁷

Residual Disease Post-Neoadjuvant Therapy

The presence of increasing amounts of resid-ual disease after neoadjuvant systemic therapy has been shown to correlate with inferior prognosis compared with those patients who achieve a pCR or have mini-mal residual cancer burden (RCB). Symmans et al investigated long-term prognosis in each breast cancer phenotype related to RCB post neoadjuvant chemotherapy.⁸ Among those with TNBC, good prognoses were seen for patients who achieved a pCR or RCB-I; outcomes were inferior for those with RCB-II or RCB-III (estimated 5-year relapse-free survival rates: pCR 94%, RCB-I 89%, RCB-II 62%, RCB-III 26%).⁸ Thus, efforts have been focused on developing strategies to improve outcomes for patients who have a less robust response to neoadjuvant therapy.

In the phase 3 CREATE-X trial (UMIN000000843), patients with HER2-negative breast cancer with residual disease after neoadjuvant chemotherapy (anthracy-cline, taxane, or both) were randomized to capecitabine for 6 to 8 cycles, or standard postsurgical management (control group). This study demonstrated DFS and OS bene-fit with the addition of capecitabine vs control in the TNBC subgroup. The 5-year DFS rates were 69.8% vs 56.1%, respectively (HR, 0.58); the 5-year OS rates were 78.8% vs 70.3%, respectively (HR, 0.52).⁹ As a result, adjuvant capecitabine became standard of care for patients with residual TNBC post neoadjuvant therapy.

The phase 3 ECOG-ACRIN EA1131 trial (NCT02445391) randomized 410 patients with stage II/III TNBC who had at least 1 cm of residual disease after completion of neoadjuvant therapy (taxane with or without anthracycline) to platinum-based chemo-therapy or capecitabine. After a median follow-up of 20 months, the 3-year invasive DFS rates were 42% with platinum and 49% with capecitabine (HR, 1.06) for patients with basal subtype TNBC. Furthermore, grade 3/4 toxicities were higher in the plati-num arm.¹⁰ This trial was therefore stopped early because of the improbability of demonstrating noninferiority.

New Indications, New Questions

The treatment of early-stage TNBC is evolving rapidly. Although these advances provide additional options for patients, they simultaneously create more questions for oncologists. Considerations include selection of patients for various therapies, how to sequence agents, and monitoring of adverse effects. As more experience is gained with these treatments and guidelines build on data and approvals, questions will gradually be answered, although new ones surely will arise as the early TNBC field continues to expand.

References

1. Cortes J, Cescon DW, Rugo HS, et al; KEYNOTE-355 Investiga-tors. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inopera-ble or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9
2. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the on-going phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650
3. Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol. 2021;32(9):P1198-P1200. doi:10.1016/j.annonc.2021.06.014
4. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. Updated July 27, 2021. Accessed September 22, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembroli-zumab-high-risk-early-stage-triple-negative-breast-cancer
5. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450. Published correction in N Engl J Med. 2017;377(17):1700. doi:10.1056/NEJMx170012
6. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905
7. Tutt ANJ, Garber JE, Kaufman B, et al; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
8. Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060. doi:10.1200/JCO.2015.63.1010
9. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645
10. Mayer IA, Zhao F, Arteaga CL, et al. Randomized phase III postoperative trial of platinum-based chemotherapy versus capecitabine in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: ECOG-ACRIN EA1131. J Clin Oncol. 2021;39(23):2539-2551. doi:10.1200/JCO.21.00976