Breast cancer is most often curable. Unfortunately, there remain certain forms which are refractory to currently available treatments. Researchers around the world are trying to find ways to eradicate these stubborn tumors that endanger the lives of patients. But what are these formidable tumors which still escape doctors’ therapeutic arsenal?
It was following a routine mammogram in 2022 that Claire Larocque was discovered to have breast cancer, even though she had no symptoms or suspicious masses. In his bad luck, Mme Larocque can, however, count on therapeutic options capable of combating the type of cancer from which she suffers.
We recognize four subtypes of breast cancer, two of which are called hormone-sensitive or hormone-dependent, and which are clinically called luminal A or luminal B. The cells of these cancers have receptors that are sensitive to estrogens and progesterone, two female hormones that promote the growth of tumors. There are some very good medications that target these female hormones to stop them from activating the receptors on the tumor. These pharmacological agents, which include tamoxifen, are a form of hormonal therapy.
These two subtypes of breast cancer account for 75% to 80% of all cases of breast cancer. Luminal B is distinguished from luminal A (which represents 40% to 50% of cases) by the fact that it proliferates more quickly. “It grows faster and is a little more aggressive. Furthermore, in half of patients with luminal B, [les cellules de] the tumor also expresses HER2 (Human Epidermal Growth Factor Receptor-2) receptors on their surface, which stimulate their growth and therefore make the cancer a little more dangerous. But hormonal treatment often succeeds in eliminating all cancer cells, even if they carry a few HER2 receptors. In certain cases, we can add drugs that block HER2,” explains Jean-François Côté, director of the Cytoskeletal Organization and Cell Migration Research Unit at the Montreal Clinical Research Institute (IRCM).
Surgical intervention is necessary in almost all cases of breast cancer. For luminal A and B, we will also carry out radiotherapy in addition to hormonal therapy. And if the tumor has a high number of HER2 receptors, we will add a little chemotherapy. Since M’s cancerme Larocque was found to be triple positive, meaning the tumor cells had estrogen receptors, progesterone receptors and many HER2 receptors on their surface, she had to undergo a complete mastectomy in March 2023 Then, as her cancer had reached the lymph nodes (stage 3), she was given two chemotherapies, radiotherapy, Herceptin (trastuzumab), which blocks HER2 receptors, as well as hormone therapy, which she must continue. for two to five years.
Mme Larocque therefore has access to a vast pharmacopoeia. However, this is not the case for people with the other two subtypes, including HER2-positive breast cancer, whose tumors do not have estrogen and progesterone receptors (they are therefore negative for these two markers). , but are characterized by an amplification of HER2 receptors. “These cancers therefore do not respond to hormonal therapies, such as tamoxifen. Doctors thus lose an important weapon. But research over the last twenty years has enabled the development of monoclonal antibodies [comme l’Herceptin] which specifically target the HER2 protein on cancer cells, which are thus attacked. With this precision medicine, the five-year survival rates — which are between 70% and 80% — are very good,” says Mr. Côté.
Recurrences
The fourth subtype of breast cancer, triple negative, is, as its name suggests, negative for all three types of receptors (estrogen, progesterone and HER2), which are no longer overexpressed on the tumor . “So we don’t have any medicine to attack them. All that remains is classic chemotherapy. Generally, patients have rather favorable responses to the first treatment, but recurrence rates are quite high thereafter. There are approximately 40% deaths four to five years after chemotherapy. Scientists are seeking to identify targets that could be attacked with drugs,” specifies the IRCM researcher.
But the tumors that are most refractory to treatment are those that are composed of metastatic cells, he emphasizes. Metastatic spread occurs when cancer located in the breast leaks cells into the bloodstream. These cells often die caught by the red and white blood cells which circulate at 100 km/h. Those that survive will enter a secondary organ such as the lung or liver, where most often they will die or go dormant, because this new environment is not favorable for them. “They find themselves alone among cells which do not secrete the growth factors necessary to keep them active, or even alive. This great stress means that they must choose between dying or going dormant. Then, at a given moment, several months, several years, even decades, later, for reasons that we do not understand, they can wake up and metastasize which are very difficult to treat,” explains- he.
[Certains] therefore do not respond to hormonal therapies, such as tamoxifen. Doctors thus lose an important weapon.
In recent years, Mr. Côté has studied dormant cells. “We let the cells go dormant in mice, then we tried to identify therapeutic targets that would make it possible to eliminate them,” he explains.
“We then deleted the genes present in the dormant cells one by one, which made it possible to identify those which are essential for the survival of the cells. Our hypothesis is that by targeting one of these genes, we could make these cells disappear,” he says. The researchers therefore administered to the mice an already known pharmacological inhibitor of the Pik3c3 protein that produces one of these vital genes for dormant cells. They were thus able to significantly reduce the load of dormant metastatic cells in their mouse model. They have already submitted a scientific article on this discovery.
But how can we know if dormant cells are lurking in a secondary organ? “Unfortunately, we don’t have the technology to see them. These cells are like a needle in a haystack. They are disseminated in the large population of cells in the lung or liver. They do not form a tumor, because otherwise we would see this one. It is therefore a big problem not to be able to detect metastatic recurrences before patients have large tumors,” says Mr. Côté. Researchers are actively working to solve this problem, because treating it as early as possible helps a lot.