Clinical Edge Journal Scan

Commentary: Evaluating first-line regimens in breast cancer, March 2023

Dr. Roesch scans the journals, so you don't have to!

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Erin Roesch, MD

The KEYNOTE-522 study has established a regimen of carboplatin/paclitaxel/pembrolizumab followed by doxorubicin/cyclophosphamide/pembrolizumab as standard neoadjuvant therapy for early-stage triple-negative breast cancer (TNBC). The pembrolizumab-chemotherapy group demonstrated improvements in pathologic complete response (pCR; 64.8% vs 51.2%) and event-free survival vs placebo-chemotherapy (estimated 3-year event-free survival 84.5% vs 76.8%; hazard ratio 0.63; P < .001). [1,2] The single-arm phase 2 NeoImmunoboost trial investigated nab-paclitaxel plus pembrolizumab followed by epirubicin/cyclophosphamide/pembrolizumab among 50 patients with early TNBC. The pCR rate was 66% overall, 59.6% for those who received a pre-chemotherapy pembrolizumab boost, and 73.9% for those without the pre-chemo boost ( Fasching PA et al ). This latter finding differs from that of the GeparNuevo study, which showed higher pCR rates when durvalumab was given before the start of neoadjuvant chemotherapy. [3] The most common grade 3/4 adverse events in NeoImmunoboost were neutropenia, fever, and other blood/lymphatic system disorders. As expected, rates of peripheral neuropathy were higher in this study vs in KEYNOTE-522 (54.7% vs 19.7%). Although the platinum-containing chemotherapy backbone is standard for neoadjuvant treatment of TNBC, the high pCR rate in NeoImmunoboost suggests that the nab-paclitaxel regimen can be considered for those in whom a contraindication to platinum therapy exists. Additionally, an immunotherapy boost cannot be recommended presently, but future randomized studies will, I hope, further inform its role.

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT). [4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% ( Hunt et al ). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS. [6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) ( Arpino et al ). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

  1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
  2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
  3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
  4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
  5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat . 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
  6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

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