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Tackling Triple Negative Breast Cancer

Published February 28th, 2022

About 1 in 8 women will develop breast cancer in their lifetimes1. While the majority of these women who have this disease can be treated effectively or even cured, about 15%-20% will be diagnosed with a particularly aggressive subtype called triple negative breast cancer, or TNBC for short2.TNBC grows faster than other types of breast cancer, is more likely to have spread before being found, and is more likely to return after treatment2

TREATMENT FOR TNBC

For women who are diagnosed with early-stage TNBC (cancer that has not spread to distant organs), treatment has historically been comprised of combination chemotherapy regimens aimed at directly killing the rapidly expanding cancer cells3. However, these drugs result in only about 30% of patients achieving a complete response, which means about 70% of patients are susceptible to relapse4. Indeed, five years following diagnosis, early-stage TNBC relapses in about 45% of patients, whereas for the less aggressive, non-TNBC breast cancers, this figure is only about 25%5. Furthermore, if TNBC relapses, it is also more likely to have spread to other organs than other types (metastatic cancer).

For women who are diagnosed with metastatic TNBC, unfortunately the numbers are even worse. Less than 10% of late-stage TNBC patients will survive five years, compared to more than a third of late-stage, non-TNBC patients6.

IMMUNOTHERAPY TRANSFORMS TREATMENT OUTCOME OF TNBC

Immunotherapy treatment enables the immune system to target cancer cells directly. While immunotherapy has been extraordinarily successful over the last decade in some cancers, such as melanoma, initial studies in most breast cancer patients did not yield much enthusiasm. However, in November of 2020, the FDA granted approval for an immunotherapy drug called pembrolizumab, also known as Keytruda, in late-stage TNBC. Keytruda works by blocking a “stop” signal that cancer cells often transmit to the body’s immune cells. This takes the brakes off the immune system and allows it to attack the cancer cells more readily. In clinical trials, using Keytruda in combination with chemotherapy in late-stage TNBC delayed progression by nearly 60%, providing many months of valuable additional time7.

Moreover, in July of 2021, the FDA approved Keytruda for use in early-stage TNBC. In clinical trials, incorporating Keytruda into treatment regimens resulted in more than 60% of patients achieving a complete response (compared to ~30% historically)8, and reduced relapse at 3 years from ~25% to 15%9.

These results with Keytruda in both late and early-stage TNBC offer a clear improvement over historical treatment and represent promise for this difficult-to-treat cancer.

TRODELVY: TARGETED CHEMOTHERAPY FOR TNBC

The repertoire of therapies that have recently shown potential for treating TNBC also includes creatively engineered molecules that are designed to specifically target cancer cells and then deliver a toxic chemotherapy “payload”. Sacituzumab govitecan, also known as Trodelvy, is comprised of an antibody that binds a protein commonly found on TNBC cells, and the antibody is linked to a drug called SN-38. SN-38 is an extremely powerful chemotherapy and is too toxic to give to patients on its own. But, when it is bound to an antibody that seeks out cancer cells, it becomes safe and effective.

In metastatic TNBC, the use of Trodelvy was associated with responses in more than 35% of patients who had many previous lines of therapy, compared with just 5% with additional conventional chemotherapy. It also nearly doubled the survival time for late-stage patients10. Trodelvy was FDA approved for late-stage TNBC in April 2021 and is currently in clinical trials for early-stage disease.

A HOPEFUL FUTURE FOR TNBC

These recently approved therapies represent an important step forward in the treatment of TNBC, but research into new treatments continues. Novel combinations are being explored that combine immunotherapy with additional chemotherapies. Precision medicine guided approaches are taking shape that implement new biomarkers to guide decisions about chemotherapies, targeted therapies, immunotherapies, and ways to reduce toxicity11. Overall, more patients are now being cured of TNBC and living longer with the disease than ever before, and there is additional hope on the horizon.

REFERENCES:

1          DeSantis, C. E. et al. Breast cancer statistics, 2019. CA Cancer J Clin 69, 438-451, doi:10.3322/caac.21583 (2019).

2          Anders, C. & Carey, L. A. Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22, 1233-1239; discussion 1239-1240, 1243 (2008).

3          Amjad, M. T., Chidharla, A. & Kasi, A. in StatPearls     (2022).

4          Biswas, T., Efird, J. T., Prasad, S., Jindal, C. & Walker, P. R. The survival benefit of neoadjuvant chemotherapy and pCR among patients with advanced stage triple negative breast cancer. Oncotarget 8, 112712-112719, doi:10.18632/oncotarget.22521 (2017).

5          Goncalves, H., Jr. et al. Survival Study of Triple-Negative and Non-Triple-Negative Breast Cancer in a Brazilian Cohort. Clin Med Insights Oncol 12, 1179554918790563, doi:10.1177/1179554918790563 (2018).

6          Hsu, J. Y., Chang, C. J. & Cheng, J. S. Survival, treatment regimens and medical costs of women newly diagnosed with metastatic triple-negative breast cancer. Sci Rep 12, 729, doi:10.1038/s41598-021-04316-2 (2022).

7          Cortes, J. et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396, 1817-1828, doi:10.1016/S0140-6736(20)32531-9 (2020).

8          Schmid, P. et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 382, 810-821, doi:10.1056/NEJMoa1910549 (2020).

9          Schmid, P. et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 386, 556-567, doi:10.1056/NEJMoa2112651 (2022).

10        Bardia, A., Hurvitz, S. A. & Rugo, H. S. Sacituzumab Govitecan in Metastatic Breast Cancer. Reply. N Engl J Med 385, e12, doi:10.1056/NEJMc2108478 (2021).

11        Bianchini, G., De Angelis, C., Licata, L. & Gianni, L. Treatment landscape of triple-negative breast cancer – expanded options, evolving needs. Nat Rev Clin Oncol 19, 91-113, doi:10.1038/s41571-021-00565-2 (2022).

About the Author

Ross Keller, PhD

Research Director

Dr. Keller is focused on providing decision-grade information to cancer patients regarding the best treatments options. He has experience in genomics, cancer evolution, tumor modeling, and early-stage drug development.