Negative breast cancer

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What is triple-negative breast cancer?

Negative breast cancer

Rather, the question should be: what is NOT triple negative breast cancer? It is neither a hormone-dependent cancer (meaning estrogen-dependent [ER+]) or progesterone-dependent [PR+]), such as about 70% of breast cancers, nor a cancer with overexpression of the HER2 gene.

Hormone and HER2 receptors allow targeted treatments: this means that triple-negative breast cancer has no obvious therapeutic target and will generally be treated with chemotherapy.

Unfortunately, this type of breast cancer is often more aggressive than others[1]. It is frequently diagnosed at a more advanced stage, in younger women (under age 40) and is more likely to return. [2]

Previously, triple-negative cancer seemed to be a single type of cancer without any specific therapeutic target. However, thanks to advances in research in recent years, different subtypes have been identified enabling researchers to develop targeted therapies!

Overview of the various advances in its treatment

Immunotherapy

This field continues to evolve, particularly with checkpoint inhibitor treatments that can target PD-1 or PD-L1 proteins. But what are we talking about here?

The role of our immune cells is to destroy bacteria, viruses, or even abnormal cells such as cancer cells. In order not to be always activated or activated against healthy cells, they have a receptor called PD-1 that plays the role of a “lock”: if it is locked with the right key, the immune cells remain inactive. Otherwise, they play their role.

Unfortunately, the tumour cells of some triple-negative breast cancers possess this key, called PD-L1, and can thus inactivate our immune cells. Immunotherapy aims to prevent the interaction between the key and the lock, either by targeting the PD-L1 key on the tumour cell or by targeting access to the PD-1 lock. This way, the immune cells are activated and can do their job of destroying the tumour cells.  

In practice, what does this mean?

As of November 2021, anti-PD-1 therapy in combination with chemotherapy is approved in Canada for women with unresectable, metastatic, triple-negative breast cancer with the PD-L1 marker. Studies of this therapy have shown a significant improvement in patient survival compared to treatment with chemotherapy and placebo[3].

In Europe, a clinical study[4] is also under way to test whether an anti-PD-L1 immunotherapy treatment, which is effective in patients with metastatic triple-negative breast cancer, could be effective as neoadjuvant treatment (before surgery) in women with localized (non-metastatic) triple-negative breast cancer.

Antibody-drug conjugates

One of the new developments of late 2021 is Health Canada’s approval of an antibody-drug combination treatment[5] for women with triple-negative, unresectable, metastatic breast cancer following two lines of therapy. Here is how the treatment works : the chemotherapeutic agent is sent directly into the tumour cell, using an antibody that will bind specifically to the tumour cell, thus destroying its DNA.

Chemotherapy will therefore target only the tumour cells and spare the healthy ones, thus reducing the side effects of the treatment. 

Targeting BRCA gene mutations: PARP inhibitors

PARP (poly[ADP-ribose] polymerase) proteins act in a complementary way with another BRCA protein in DNA repair. In the case of a BRCA mutation, the BRCA1 or 2 genes no longer function normally, and repair therefore depends on other mechanisms, such as PARP.

The cancer cell will have to use the PARP-related mechanism to repair the DNA mutations. PARP-inhibiting therapies will then target these proteins and prevent their action. Without the repair process using BRCA (caused by the mutation), nor the one using PARP (blocked by the treatment), the tumour cell is left without a DNA repair solution and accumulation of DNA mutations will lead to its death.

Discovering new cell-signalling pathways

One of the future solutions for targeting triple-negative breast cancer is uncovering characteristics that are unique to it. This is what a Quebec researcher and his team have done by analysing and “silencing” one by one the 20,000 genes of the human genome. The team discovered two signalling pathways that appear to be specific to triple-negative breast cancer. Bottom line: two switches with specific functions.

One of the pathways is activated and promotes the tumour cell development, while the other pathway is inhibited when it should play a role in tumour suppression.  Following this discovery, the researchers examined and found drugs that would reverse these functions: inactivating the pathway involved in tumour development and activating the pathway involved in its suppression.

Good news! The initial results are very promising. The study will now be able to move on to the clinical phase, with the hope of achieving the same results in the patients.

Our investments in triple-negative breast cancer research

The Quebec Breast Cancer Foundation proudly supports research on all types of breast cancer. Here is a list of several ongoing triple-negative breast cancer projects co-financed by the Foundation:

  • Jerry Pelletier: Rationally designed approaches to target mRNA translation in eradicating poor-outcome breast cancers
  • Anne-Marie Mes-Masson: Development of small-molecule inhibitors of Ran GTPase as anti-cancer agents
  • John White: Bifunctional vitamin D analogues as novel therapeutics against triple-negative breast cancer
  • Jean-François Côté: Role of ERK3 MAP kinase signaling in the progression and metastasis of triple-negative breast cancer

Sources:

Les faiblesses du cancer du sein révélées – Québec Science (quebecscience.qc.ca)

https://www.canada.ca/fr/sante-canada/services/medicaments-produits-sante/medicaments/liste-drogues-ordonnance/avis-concernant-modifications/additions-multiples-2021-10-21.html

https://www.fondation-arc.org/projets/traiter-efficacement-cancers-sein-triples-negatifs-avant-evolution-metastatique-mobilisant-systeme-immunitaire-prism-sein

https://ascopost.com/issues/december-10-2021/keynote-355-final-analysis-reveals-survival-benefit-with-pembrolizumab-in-triple-negative-breast-cancer/

[1]Triple Negative Breast Cancer – An Overview (nih.gov)

[2]  Triple-negative breast cancer: clinical features and patterns of recurrence – PubMed (nih.gov)

[3] https://ascopost.com/issues/december-10-2021/keynote-355-final-analysis-reveals-survival-benefit-with-pembrolizumab-in-triple-negative-breast-cancer/

[4] https://www.fondation-arc.org/projets/traiter-efficacement-cancers-sein-triples-negatifs-avant-evolution-metastatique-mobilisant-systeme-immunitaire-prism-sein

[5] https://www.canada.ca/fr/sante-canada/services/medicaments-produits-sante/medicaments/liste-drogues-ordonnance/avis-concernant-modifications/additions-multiples-2021-10-21.html