Approximately 12% of all breast cancers are triple negative breast cancers (TNBC), meaning that they are estrogen-receptor negative (ER-), progesterone-receptor negative (PR-), and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones estrogen or progesterone, nor through an overactive HER2 pathway.
For women with early-stage TNBC, optimal treatment requires surgery, radiation therapy, and systemic treatment with chemotherapy, immunotherapy or precision cancer medicines.
Surgical removal of the cancer is required for all women with early stage cancers and may be performed immediately and then followed by systemic “adjuvant” treatment or systemic treatment can be immediately delivered to reduce the size of the cancer prior to surgery. Systemic treatment before surgery is referred to as “neoadjuvant” and is increasingly the preferred approach for managing TNBC.
Women can choose between mastectomy or breast-conserving therapy (lumpectomy plus radiation therapy) which have been compared in women with very early-stage (T1-2N0) TNBC. Five-year survival without a local recurrence was 96% among women treated with breast-conserving surgery and 90% among women treated with mastectomy without radiation therapy. In other words, women treated with breast-conserving therapy had a lower risk of recurrence in the breast, chest wall, or lymph nodes than women treated with mastectomy without radiation therapy. At the time of the analysis, overall survival was similar in the two groups.
Neoadjuvant Therapy
Neoadjuvant therapy has the potential advantage of offering immediate treatment, improving surgical resection, and providing additional information about the cancer that can direct further treatment.
In order to speed the availability of promising drugs for high-risk, early-stage TNBC, the US Food and Drug Administration (FDA) drafted new guidelines for clinical trials in 2012.4 The FDA decided to allow a short-term outcome known as a pathologic complete response (pCR) to provide the basis for accelerated approval of a drug. A pCR refers to a complete disappearance of invasive cancer from both the breast and sampled lymph nodes of the surgically removed tissue following the administration of neoadjuvant therapy.
Giving a drug in the neoadjuvant setting among patients with early-stage TNBC allows doctors to assess its effectiveness when the breast cancer is removed by surgery. If the cancer is completely absent at surgery it is referred to as a “pathologic complete remission” or pCR. If the addition of the drug produces a higher pCR rate than previous therapy, the drug may be considered for accelerated approval. The FDA’s accelerated approval program is providing earlier access to promising drugs for TNBC.
The current standard treatment of women with TNBC is neoadjuvant therapy consisting of chemotherapy combined with an immune checkpoint inhibitor followed by surgical removal of the cancer and radiation therapy for women opting for breast conserving therapy. The surgically removed cancer is evaluated and additional post surgical adjuvant therapy is determined based on the pCR and testing for BRCA germline mutations.
Neoadjuvnt Chemotherapy in Early Stage TNBC
Dose dense taxane anthracycline chemotherapy is the standard chemotherapy backbone for neoadjuvant treatment of TNBC. Research suggests that the addition of carboplatin chemotherapy significantly improves overall survival. The breast pCR rate is reported to improve from 41% to 61% for individuals under 50 years of age receiving carboplatin in addition to taxane-anthracycline chemotherapy.
At a median follow-up of 68 months 71% of platinum treated patients survived without recurrence compared with 64% of those treated with Taxol and no platinum. In patients 50 years or younger there was an absolute increase of 12.5 percentage points. Post-menopausal patients did not benefit from the addition of carboplatin.
The addition of carboplatin to taxane-anthracycline neoadjuvant chemotherapy became the standard treatment in patients with TNBC who are younger than or equal to 50 years of age or who are premenopausal.
PD-1 Immune Checkpoint Inhibitors
PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 are called checkpoint inhibitors and enhance the ability of the immune system to fight cancer and when added to chemotherapy further improve treatment outcomes for women with TNBC.
Keytruda
Keytruda (pembrolizumab) is a fully humanized monoclonal antibody checkpoint inhibitor that binds with high-affinity to the PD-1 receptor. Neoadjuvant Keytruda has been reported to be significantly more effective than chemotherapy at eradicating cancer confined to the breast prior to surgery. When administered in combination with standard chemotherapy Keytruda increases the pCR nearly threefold in patients with TNBC.5
This was confirmed in the KEYNOTE 522 clinical trial which enrolled 1,174 patients with locally advanced TNBC to receive treatment with standard chemotherapy with or without the addition of Keytruda followed by definitive surgery and radiation therapy. After completion of local therapy patients were treated with additional adjuvant Keytruda. Keytruda treated patents were less likely to have evidence of cancer in their surgically removed breast tissue and more likely to survive without evidence of cancer recurrence. Overall 65% off Keytruda treated patients had a pCR compared to only 51% of women not treated with Keytruda.10
Keytruda (pembrolizumab) is a fully humanized monoclonal antibody checkpoint inhibitor that binds with high-affinity to the PD-1 receptor. Results in advanced TNBC have been mixed. In heavily pretreated patients with recurrent or metastatic TNBC positive for PD-1 Keytruda has been reported to produce a response rate of 18.5%1 however a trial directly comparing single agent Keytruda to chemotherapy in recurrent TNBC found that Keytruda was no better.2
Updated results at 3 and 5 years remain positive,6,8 5-year outcomes were updated during the 2023 San Antonio Breast Cancer Symposium. With a median follow-up of 63.1 months, the 5-year survival rate was without cancer recurrence was 81% following treatment with neoadjuvant-adjuvant Keytruda combined with chemotherapy compared to 72% for individuals treated with chemotherapy alone.
In patients with stage II TNBC, the 5-year rates were 85% and 77% and they were 68% and 57% for individuals with stage III disease. Patients who achieved a pCR fared even better. Overall survival follow-up is still ongoing and are expected to be available in 2024.
Imfinzi
The GeparNuevo clinical trial evaluated whether the addition of Imfinzi (durvalumab), another PD-L1 antibody, to neoadjuvant chemotherapy would increase the pCR rate in patients with early-stage TNBC. In this trial patients with stage I-III TNBC were treated with Imfinzi or placebo, in combination with nab-paclitaxel, epirubicin and cyclophosphamide chemotherapy. A numerical increase in the pCR rate was initially reported with Imfinzi compared to placebo (53.4% vs. 44.2%, respectively). At the 2021 Annual Meeting of the American Society of Clinical Oncology, the investigators reported that 86% of patients treated with Imfinzi survived cancer free compared to 77% of those not receiving Imfinzi. The addition of Imfinzi also improved the 3 year overall survival rate from 83% to 95%. Longer survival with Imfinzi was observed regardless of PD-L1 status, stromal TILs, stage, age or pCR.7
BRCA
As many as 20% of individuals with TNBC have the BRCA gene and can benefit from an additional 1 year of treatment with the PARP inhibitor Lynparza. Lynparza can be administered after completion of standard neoadjuvant or adjuvant chemotherapy, surgery and radiation and significantly delays cancer progression and improves survival in patients with BRCA 1/2 germline mutations in high-risk early TNBC. Women with TNBC should ensure they have undergone germline testing to determine if additional treatment with a PARP inhibitor might be beneficial.
- More About PARPs in TNBC
The search for effective treatments for TNBC remains challenging, but the potential for earlier access to promising drugs is good news for women with this tough-to-treat form of cancer.
Connect With Others for Support and information
Cancer Connect was the first social network created for people with breast cancer. Founded by oncologists to support cancer patients and their caregivers, over 40 million individuals have accessed Cancer Connect programs since 1997. Cancer Connect is used by leading cancer centers like Dana Farber, Roswell Park and The James at Ohio State to support their patients. Join the conversation, ask questions, share your experience, and learn how the best cancer centers are treating cancer from others. Share your experience, ask a question, or start a conversation by posting on Cancer Connect.
Reference:
- Abdulkarim BS, Cuartero J, Hanson J et al. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. Journal of Clinical Oncology. Early online publication June 13, 2011.
- Szeja S, Hatch S. Outcomes associated with adjuvant radiation after lumpectomy for elderly women with T1-2N0M0 triple-negative breast cancer: SEER analysis. Journal of Clinical Oncology. 2015; 33 (sup 28S; abstr 39).
- Zumsteg ZS, Morrow M, Arnold B et al. Breast-conserving therapy achieves locoregional outcomes comparable to mastectomy in women with T1-2N0 triple-negative breast cancer. Annals of Surgical Oncology. Early online publication May 19, 2013.
- Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. New EnglandJournal of Medicine. 2012;366:2438-2441.
- Gupta S, Nair NS, Hawaldar RW, et al. Addition of platinum to sequential taxane-anthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer: A phase III randomized controlled trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS5-01
- https://www.merck.com/news/keytruda-pembrolizumab-plus-chemotherapy-before-surgery-and-continued-as-a-single-agent-after-surgery-showed-statistically-significant-event-free-survival-efs-result-versus-neoadjuvant-chemo/
- Loibl S, Schneeweiss A, Huober J, et al. Durvalumab improves long-term outcome in TNBC: Results from the phase II randomized GeparNUEVO study investigating neoadjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer. J Clin Oncol. 2021;39:15_suppl,506.
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Schmid P, Cortés J, Dent R, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: Updated event-free survival results from the phase 3 KEYNOTE-522 study. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract LBO1-01.
