“Triple-negative breast cancer remains the most challenging subtype to treat because of its aggressive phenotype and limited treatment options,” stated Erica Michelle Stringer-Reasor, MD, who spoke at an education session on current approaches to treatment and future directions during the 2023 ASCO Annual Meeting.1 Dr. Stringer-Reasor is Director, Breast Cancer Program, University of Alabama Birmingham, O’Neal Comprehensive Cancer Center.
“Neoadjuvant chemotherapy is the preferred approach to treat stage II or III triple-negative breast cancer. Pathologic complete response remains a validated surrogate biomarker for prediction of long-term clinical benefit with neoadjuvant chemotherapy because it has been shown to correlate with improved long-term event-free survival and overall survival,” she explained.
Erica Michelle Stringer-Reasor, MD
The pathologic complete response Residual Cancer Burden (RCB) score is used to evaluate response to neoadjuvant therapy. A score of 0 is the most desirable, showing no residual disease. An RCB index score of 1 signifies minimal disease burden, RCB II equals moderate disease burden, and a score of RCB IIII signifies extensive disease burden.
“The RCB index score is associated with improved event-free and disease-free survival across all breast cancer subtypes. The score is more specific for highly proliferative tumor types, such as triple-negative breast cancer,” she said.2
Over time, several major clinical trials have demonstrated the benefits of dose-dense chemotherapy for long-term outcomes in early-stage triple-negative breast cancer.3,4 “Historically, the intensity and frequency of chemotherapy improve response,” Dr. Stringer-Reasor continued.
“Dose-dense regimens are now considered standard of care for the management of triple-negative breast cancer. The current standard of care is either weekly paclitaxel or dose-dense paclitaxel, as both have manageable side-effect profiles as well as similar disease-free and overall survival,” she told listeners.
Immunotherapy
More recently, immunotherapy is being incorporated into neoadjuvant and adjuvant therapies for early-stage triple-negative breast cancer, based on the results of large phase III trials. Once such trial is KEYNOTE-522, which included more than 1,100 patients and was the first trial to set the stage for an immune checkpoint inhibitor as part of neoadjuvant therapy for triple-negative breast cancer.5
In that trial, patients with T1c tumors or lymph node–positive, early-stage triple-negative breast cancer were treated with pembrolizumab as part of taxane-based neoadjuvant therapy plus anthracycline vs no pembrolizumab. After surgery, patients were randomly assigned to additional pembrolizumab vs placebo.
The pembrolizumab-treated patients had higher rates of pathologic complete response, which correlated with improved event-free survival. Moreover, pembrolizumab was associated with decreased local and distant recurrence rates. PD-L1 status did not predict pathologic complete response. The use of weekly carboplatin as part of the regimen increased the chances of attaining pathologic complete response.5
“Pembrolizumab is the only approved immunotherapy for the treatment of early-stage triple-negative breast cancer in combination with anthracycline/taxane-based chemotherapy plus carboplatin,” Dr. Stringer-Reasor told the audience.
Randomized trials that evaluated an immune checkpoint inhibitor plus anthracycline-based chemotherapies include KEYNOTE-5225 and IMpassion031.6 “In the clinic, patients present with other diagnoses and comorbidities, which affect our ability to treat them with anthracycline-based regimens,” she explained.
Neoadjuvant Carboplatin
Three randomized trials evaluated the addition of neoadjuvant carboplatin for the treatment of triple-negative breast cancer: the phase II CALGB 40603; the phase II GeparSixto; and the phase III BrighTNess.7-9 All three trials demonstrated higher pathologic complete response rates with the addition of carboplatin. However, higher pathologic complete response rates did not translate to improved event-free survival.
The largest phase III trial to evaluate the addition of carboplatin to sequential taxane-anthracycline neoadjuvant therapy in triple-negative breast cancer included 720 patients with highly aggressive stage II or III disease. In this study, younger patients (ie, ≤ age 50) were more likely to achieve pathologic complete response, and high pathologic complete response rates correlated with improved event-free survival plus overall survival in that age group.10
“The disease-free survival results are concordant with GeparSixto and BrighTNews but discordant with CALGB 40603,” stated Dr. Stringer-Reasor.
In patients with contraindications to anthracycline-based chemotherapy, it may be possible to move to a nonanthracycline-containing regimen, based on the recent NeoPACT study.11
NeoPACT was a single-arm, phase II study to evaluate neoadjuvant pembrolizumab and carboplatin plus docetaxel for 18 weeks of treatment. The study included 120 patients with stage I to III triple-negative breast cancer and a mix of patient characteristics. A total of 18% were Black; 39% had node-positive disease; and 83% had stage II or III disease. As shown in larger trials, the pathologic complete response rate was higher in patients who received carboplatin. No patient experienced disease progression during neoadjuvant treatment.
Future directions for the treatment of triple-negative breast cancer include studies of the addition of small amounts of radiation to pembrolizumab as part of neoadjuvant chemotherapy; chemotherapy-sparing regimens such as neoadjuvant niraparib and dostarlimab-gxly for BRCA1/2-mutated or PALB2-deficient triple-negative breast cancer; and the use of antibody-drug conjugates such as sacituzumab govitecan-hziy with or without pembrolizumab.
Capecitabine and Olaparib for High-Risk Disease
“Patients with residual disease following neoadjuvant chemotherapy are at high risk of recurrence and have poor prognosis,” said Heather Han, MD, of Moffitt Cancer Center, who also spoke at the education session.
Current options for these patients include adjuvant capecitabine and olaparib, based mainly on the CREATE-X trial and the OlympiA trial, respectively.12,13 “Since 2015, capecitabine has remained standard of care for this high-risk group of patients with triple-negative breast cancer,” Dr. Han stated.
The randomized CREATE-X trial enrolled 910 patients with HER2-negative breast cancer and residual invasive breast cancer after neoadjuvant therapy with anthracycline, taxane, or both.12 About 30% had triple-negative breast cancer; among these patients, the disease-free survival rate was 69.8% with the addition of capecitabine vs 56.1% for placebo. Overall survival rate was 78% vs 70.3%, respectively.
A PARP inhibitor was established as a treatment option for the subset of patients with triple-negative breast cancer and germline BRCA1/2 mutations.— Heather Han, MD
Tweet this quote
The randomized OlympiA trial evaluated olaparib for patients with germline BRCA1/2 mutations treated with prior neoadjuvant or adjuvant therapy with anthracycline and/or taxane.13 A total of 82% had triple-negative breast cancer. At 3.5 years of follow-up, patients treated with olaparib had improved invasive disease–free survival (absolute benefit of 7.3%) and improved 4-year overall survival (absolute benefit of 3.4%). Olaparib was well tolerated with minor side effects.14
“Thus, a PARP inhibitor was established as a treatment option for the subset of patients with triple-negative breast cancer and germline BRCA1/2 mutations,” Dr. Han said.
Trials evaluating combinations such as pembrolizumab plus capecitabine and the combination of the immune checkpoint inhibitor durvalumab plus olaparib are under way, but there are no efficacy data yet, explained Dr. Han. “In day-to-day practice, in higher risk patients at risk of recurrence, it is reasonable to consider combinations of pembrolizumab and capecitabine or durvalumab plus olaparib [depending on tumor characteristics],” she noted.
Management Options
For patients with stage I disease who achieve pathologic complete response, no further therapy is required. If they have residual disease plus a germline BRCA1/2 mutation, olaparib is recommended, and if they do not have germline BRCA mutations, capecitabine is preferred, according to Dr. Han.
For stage II to III disease, if patients achieve pathologic complete response on neoadjuvant therapy, continue pembrolizumab for nine cycles if toxicity is not an issue. For patients with residual disease and germline BRCA1/2 mutation, olaparib plus or minus pembrolizumab can be considered in the absence of randomized trial data. For residual disease in the absence of germline BRCA mutations, capecitabine plus or minus pembrolizumab can be considered.
“Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitor,” Dr. Han noted. She emphasized the importance of enrolling patients in clinical trials.
Future Directions
There is a need for optimal prognostic and predictive biomarkers to be further investigated and validated to inform escalation and de-escalation of therapy. “Improved biomarkers are needed beyond pathologic complete response, particularly in the area of neoadjuvant chemotherapy, including immune checkpoint inhibitors,” Dr. Han stated. Tissue biomarkers include genomic and immune signatures, and liquid biopsy with circulating tumor DNA (ctDNA) can detect minimal residual disease. Trials incorporating ctDNA and evaluating the association between ctDNA and outcomes are ongoing.
Well-designed clinical trials incorporating biomarkers are needed to evaluate new therapies and new combinations that include antibody-drug conjugates [eg, sacituzumab govitecan and datopotamab deruxtecan], targeted therapies, and combining agents with immune checkpoint inhibitors,” Dr. Han said.
DISCLOSURE: Dr. Stringer-Reasor has received honoraria from Breast Cancer Index, Eli Lilly, and Milan; has served as a consultant or advisor to AstraZeneca, Daiichi Sankyo/AstraZeneca, Immunomedics, Eli Lilly, Merck, Novartis, Oncogen, and Seagen; has served on the speakers bureau for Eli Lilly; has received research funding from Susan G. Komen for the Cure and V Foundations; and has been reimbursed for travel, accommodations, and expenses from Canadian Therapeutics and Eli Lilly. Dr. Han has served as a consultant or advisor to Daiichi Sankyo/AstraZeneca Immunomedics/Gilead, and Novartis; has served on the speakers bureau for Eli Lilly; and has received institutional research funding from AbbVie, Arvinas, Department of Defense, GI Therapeutics, GlaxoSmithKline, Horizon Oncology Research, Marker Therapeutics, Novartis, Pfizer, Phoenix Pharmaceuticals, Quantum Leap Health, Seagen, and Zymeworks.
REFERENCES
1. Han HS, Vikas P, Costa RLB, et al: Early-stage triple-negative breast cancer journey: Beginning, end, and everything in between. 2023 ASCO Annual Meeting. Education Session. Presented June 3, 2023.
2. Yau C, van der Noordaa M, Wei J, et al: Residual cancer burden after neoadjuvant therapy and long-term-survival outcomes in breast cancer: A multi-center pooled analysis. 2019 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 13, 2019.
3. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003.
4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Increasing the dose density of chemotherapy by more frequent administration or sequential scheduling: A patient-level meta-analysis of 37,298 women with early breast cancer in 26 randomised trials. Lancet 393:1440-1452, 2019.
5. Schmid P, Cortés J, Dent R, et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.
6. Mittendorf EA, Zhang H, Barrios CH, et al: Neoadjuvant atezolizumab in combination with sequential paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): A randomised, double-blind, phase 3 trial. Lancet 396:1090-1100, 2020.
7. Shepherd JH, Ballman K, Polley MYC, et al: CALGB 40603 (Alliance): Long-term outcomes and genomic correlates of response and survival after neoadjuvant chemotherapy with or without carboplatin and bevacizumab in triple-negative breast cancer. J Clin Oncol 40:1323-1334, 2022.
8. von Minckwitz G, Schneeweiss A, Loibl S, et al: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial. Lancet Oncol 15:747-756, 2014.
9. Geyer CE, Sikov WM, Huober J, et al: Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from the BrighTNess trial, a randomized phase III trial. Ann Oncol 33:384-394, 2022.
10. Gupta S, Nair NS, Hawaldar R, et al: The addition of platinum to sequential taxane-anthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer: A phase III randomized controlled trial. 2022 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 9, 2022.
11. Sharma P, Stecklein SR, Yoder R, et al: Clinical and biomarker results of neoadjuvant phase II study of pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer (NeoPACT). 2022 ASCO Annual Meeting. Abstract 513.
12. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.
13. Tutt ANJ, Garber J, Gelber RD, et al: Prespecified event-driven analysis of overall survival in the OlympiA phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. ESMO Virtual Plenary 2022. Abstract VP1-2022. Presented March 16, 2022.
14. Tutt ANJ, Garber JE, Kaufman B, et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.
