March 3 is World Triple-Negative Breast Cancer (TNBC) Day. In this article, we highlight the latest research advances in TNBC.
The most common type of breast cancer is hormone-dependent, due to the presence of estrogen and/or progesterone receptors (ER-positive and/or PR-positive). The second most common type is HER2-positive breast cancer, where there are too many copies of the human epidermal growth factor receptor 2 (HER2) gene.
TNBC doesn’t present these three receptors (ER-negative, PR-negative, HER2-negative), hence its name. Therefore, TNBC does not respond to hormonal therapies nor to HER2-targeted treatments.
Facts about TNBC
What are the treatments for TNBC ?
One of the main problems is that TNBC has limited therapeutic options, compared to other breast cancer types, making it more difficult to treat.
Following analysis of “triple-negative” tumours, it was discovered that TNBC is further categorized into six molecular subtypes, and that each tumour has its own unique characteristics, making the development of therapies all the more complex.
Fortunately, science and research into TNBC are proving successful and a better understanding of the disease is helping to develop more personalized and targeted treatments. Here are some examples of the latest advances that have considerably improved TNBC prognosis.
PARP inhibitors
Studies have shown that some TNBC are associated with mutations in BRCA1. This finding has paved the way for therapies designed specifically to target tumours bearing BRCA1 mutations, such as compounds that block PARP (an enzyme involved in the DNA restoration process). These types of targeted therapies are increasingly being explored to treat TNBCs.
Olaparib (brand name Lynparza) was the first oral PARP inhibitor approved by Health Canada for the adjuvant treatment of early-stage, high-risk recurrent TNBC in BRCA mutation carriers. It has been available in Quebec since fall 2023.
Immunotherapy
Immunotherapy is another promising treatment avenue is immunotherapy. This type of therapy aims to harness the immune system to kill the cancer cells.
Studies of the microenvironment of TNBC tumours have demonstrated that T and B lymphocytes (types of white blood cells responsible for immune defence) do not respond adequately to the cancer threat. Researchers are working to reactivate them to do their immune fonction. For example, therapies called checkpoint inhibitors (monoclonal antibodies), targeting specific proteins (of the PD-1 / PD-L1 pathway), prevent tumors from escaping the immune system. This type of therapies has revolutionized the treatment of certain TNBCs. In recent years, pembrolizumab (brand name Keytruda), a checkpoint inhibitor combined with chemotherapy, has been approved in Canada to treat early-stage high-risk, locally recurrent unresectable, or metastatic TNBC, expressing the PD-L1 protein.
The vaccine approach is also being evaluated in numerous clinical studies. In particular, a California-based biotech company has developed a vaccine designed to trigger an immune response targeting the destruction of TNBC cells. A Phase 1 clinical trial with 16 participants involved administering three doses of the vaccine two weeks apart. In December 2023, the results of the clinical trial showed that the majority of patients had developed significant immune responses, and that the vaccine was safe and well tolerated. The next phases of the study will provide further information on the vaccine’s efficacy and optimal doseing. Ultimately, the aim of this vaccine would be to prevent recurrence of TNBC, and potentially even to prevent its initial appearance.
Antibody-drug conjugates (ADC)
ADC therapy involves delivering a chemotherapeutic agent directly into the tumour cell, using an antibody to bind specifically to the cancer cell and destroy its DNA. Chemotherapy will therefore target tumour cells only, sparing healthy cells and reducing the side effects of treatment.
In 2021, an antibody-drug conjugate, sacituzumab govitecan (brand name Trodelvy), was approved by Health Canada for people affected by unresectable, metastatic TNBC, after two lines of therapy. This treatment targets Trop-2, a protein on the surface of cancer cells involved in several cellular processes that regulate cancer growth and invasion.
Datopotamab deruxtecan (Dato-DXd) is another ADC designed to target the Trop-2 protein. Durvalumab (brand name Imfinzi), meanwhile, is an immunotherapy involving the immune system to detect and eliminate cancer cells. The TROPION-Breast04 international randomized Phase 3 clinical trial, launched in November 2023, will involve 1,700 participants worldwide with breast cancers, including TNBC. The first participant in this study was recruited in Montreal. This clinical trial will assess whether the combination of these molecules in neoadjuvant treatment followed by adjuvant Imfinzi, with or without chemotherapy, is more effective and safer than existing treatments for people with stage 2-3 TNBC.
HER2-low
It is estimated that 60% of patients previously classified as HER2-negative may, in fact, be considered HER2-low, opening the way to new treatment options, including antibody conjugates.
Trastuzumab deruxtecan (brand name Enhertu) is a new treatment combining an anti-HER2 antibody (trastuzumab, a drug already known and used for HER2-positive) with a cytotoxic molecule (deruxtecan) for breast cancer patients with low HER2 receptor overexpression.
For patients whose cancer has been considered “triple-negative” (HER2-negative /HR-negative) but who are in fact HER2-low / HR-negative, a preliminary study has revealed encouraging results with the use of Enhertu versus chemotherapy. But these results are exploratory, and further studies are needed.
Promising projects
The Quebec Breast Cancer Foundation funds promising projects exploring new treatment options. Here are a few examples of co-funded projects for TNBCs :
The breast cancer biobank (Fonds de Recherche du Québec – Santé [FRQS] co-funding)
The Quebec Breast Cancer Foundation co-funds a biobank, that stores data and biological material (tissue, blood samples, etc.) from thousands of people with breast cancer. These data and samples remain available to researchers for several years. This sharing tool considerably facilitates the study and understanding of the disease, including TNBC, and enables the development of more targeted therapeutic approaches.
Five centres across Québec participate in the collection of breast cancer biological samples. Since its creation by Dr. Anne-Marie Mes-Masson, dozens of research projects have used samples from this biobank, including several studies related to TNBC. Of particular note is the discovery by Dr. Morag Park’s team of the mechanisms by which tumours evade the immune system in TNBC.
To learn more about the breast cancer biobank, we invite you to read our blog post titled Do you know what is a biobank? You can also watch Dr Anne-Marie Mes-Masson’s video titled La Biobanque et son importance en recherche clinique (in French only).
Developing new medication for “HER2-positive” and “triple-negative” breast cancer – Dr Jerry Pelletier (Institute for Research in Immunology and Cancer – Commercialization of Research [IRICoR] co-funding)
mRNA (a particular photocopy of DNA) enables the fabrication of proteins by a process called “translation”. Alterations can occur during this manoeuvre, causing abnormal proliferation of the cell. The work of Dr. Pelletier’s team focuses on this process and researchers discovered chemical compounds capable of stopping these alterations, thus preventing tumour proliferation and metastasis.
The next goal is to develop those chemical compounds into clinical drugs and to test their efficiency against HER2+ and TNBC types. This project will expand the arsenal of therapies available to treat breast cancer.
A new toolbox for studying the role of galectins – Dr Yves Saint-Pierre (Consortium québécois sur la découverte du médicament [CQDM] co-funding)
Galectins are a class of proteins with immunosuppressive properties (stopping the activation of the immune system) and that are expressed at an abnormally high level in tumour cells, associated with several cancers, including TNBC. The cancerous cells are undetected by the immune system and can grow unchecked. Dr. Saint-Pierre’s team developed a toolbox to specifically prevent the action of galectins. It could be useful for the futur development of targeted treatments for TNBC that will provide more options to breast cancer patients.
To discover more promising projects, take a look at the last Quebec Breast Cancer Foundation impact report!
If you are interested in participating in a clinical trial, talk to your doctor. Learn more about clinical trials.
References
- BCRF. Treating Triple-Negative Breast Cancer: Recent Progress and What’s to Come. Breast Cancer Research Foundation. Published January 20, 2021. Accessed February 25, 2021. https://www.bcrf.org/sabcs-2020-triple-negative-breast-cancer-treatment-updates
- Kimmons L. Advances in BRCA-associated and triple-negative breast cancer treatment and understanding | MD Anderson Cancer Center. Accessed February 25, 2021. https://www.mdanderson.org/publications/cancer-frontline/2020/05/asco-studies-show-advances-in-treatment-and-understanding-of-brca-associated-and-triple-negative-breast-cancer.html?_ga=2.209600978.1506952407.1613750653-1686389815.1613750653
- Medina MA, Oza G, Sharma A, et al. Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. Int J Environ Res Public Health. 2020;17(6):2078. doi:10.3390/ijerph17062078
- The Nobel Prize in Physiology or Medicine 2018. The Nobel Prize in Physiology or Medicine 2018. NobelPrize.org. Accessed February 25, 2021. https://www.nobelprize.org/prizes/medicine/2018/summary/
- Hosseini M, Seyedpour S, Khodaei B, Loghman AH, Seyedpour N, Yazdi MH, Rezaei N. Cancer Vaccines for Triple-Negative Breast Cancer: A Systematic Review. Vaccines (Basel). 2023 Jan 9;11(1):146. doi: 10.3390/vaccines11010146. PMID: 36679991; PMCID: PMC9866612.
- Gruosso T, Gigoux M, Manem VSK, Bertos N, Zuo D, Perlitch I, Saleh SMI, Zhao H, Souleimanova M, Johnson RM, Monette A, Ramos VM, Hallett MT, Stagg J, Lapointe R, Omeroglu A, Meterissian S, Buisseret L, Van den Eynden G, Salgado R, Guiot MC, Haibe-Kains B, Park M. Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers. J Clin Invest. 2019 Apr 1;129(4):1785-1800. doi: 10.1172/JCI96313. Epub 2019 Mar 18. PMID: 30753167; PMCID: PMC6436884.
- Anixa Biosciences and Cleveland Clinic Present Positive New Data from Phase 1 Study of Breast Cancer Vaccine,https://ir.anixa.com/press-releases/detail/1030/anixa-biosciences-and-cleveland-clinic-present-positive-new