Effectiveness of Immunotherapy in Managing Breast Cancer

Avishek Roy

Scientific Liaison Manager
4baseCare

Breast cancer is the most common cancer in women, and patients with metastatic breast cancer have a 5-year overall survival rate of only 27%.   The number of new breast cancer diagnoses has been relatively constant over the last decade, although mortality rates have decreased since 2006. Despite substantial advancements in breast cancer screening and treatment, over 2 million women worldwide are diagnosed with cancer each year. While prognosis varies by biologic subtype, there is still a significant unmet need for further therapeutic options to assist metastatic breast cancer patients to live longer. Precision oncology holds the promise of genuinely individualized therapy, with every breast cancer patient receiving the most appropriate diagnostics and targeted treatments based on the tumor’s genetic profile, as determined by a panel of gene assays and another predictive and prognostic testing. Precision medicine and immunotherapy are changing the landscape of cancer treatment.

The concept of using the immune system to fight cancer has been around for over a century. However, breast cancer has remained one of the cancers that have received the least attention in the past due to its poor immunogenic potential and low mutational burden. Fortunately, in recent years, immunotherapy for breast cancer has progressed dramatically. The USFDA has approved a number of immunotherapeutic treatments, including adoptive cell therapies, vaccinations, and, most significantly, immune checkpoint blockade. The first breast cancer immunotherapy treatment was approved by the USFDA in March 2019, and the second in November 2020, both for patients with advanced or metastatic triple-negative breast cancer (TNBC).

Immunotherapy is the use of drugs to enhance a person’s immune system so that it can better identify and eliminate cancer cells. Immunotherapy is a type of treatment that focuses on particular proteins in the immune system to improve the immune response. Monoclonal antibodies, for example, act in several ways to control cancer cells and may be classified as targeted therapy since they block a specific protein on the cancer cell to prevent it from developing. The immune system’s capacity to prevent itself from attacking normal cells in the body is crucial. It accomplishes this by using proteins (or “checkpoints”) on immune cells that must be activated (or deactivated) in order to initiate an immune response. These checkpoints are occasionally used by breast cancer cells to escape being targeted by the immune system. Targeting these checkpoint proteins with drugs, aids in the restoration of the immune response against breast cancer cells. There are several immunotherapy medicines approved by the USFDA to treat breast cancer.

Immune checkpoint inhibitors:
Pembrolizumab (PD-1 inhibitor): It is a drug that targets PD-1 (a protein on immune system T cells that normally helps keep them from attacking other cells in the body). These drugs increase the immune response against breast cancer cells by inhibiting PD-1.  In the treatment of triple-negative breast cancer, it can be used with chemotherapy. The phase Ib KEYNOTE-012 study, which examined pembrolizumab in extensively pretreated metastatic TNBC, was one of the first trials using checkpoint inhibitor monotherapy in breast cancer.

In 2019, Atezolizumab, another PD-1 inhibitor, was approved for use. It suppresses PD-L1, and improves the body’s immunological response by shrinking or slowing the development of breast cancer cells. Atezolizumab is approved for use in combination with chemotherapy to treat advanced triple-negative breast cancer tumors that express the PD-L1 protein. But voluntarily it got withdrew from treating breast cancer treatment in August 27th 2021.

Dostarlimab: It is used to treat mismatch repair deficient (dMMR) advanced-stage breast cancer that has developed during or after therapy if no other treatment alternatives are available. The dMMR biomarker is found in less than 1% of breast tumors.

Ipilimumab (CTLA-4 inhibitor): CTLA-4 is another checkpoint protein found on certain T cells. When CTLA-4 attaches to a cell’s B7 protein, it prevents the T cell from destroying it. The CTLA-4 inhibitor drug works by preventing the CTLA-4 protein from attaching to B7 on immune cells. T cells are forced to become activated in order to target cancer cells as a result of this. The FDA has approved it for the treatment of advanced-stage skin cancer. It’s also being researched as a treatment for breast cancer and other malignancies.

Vaccines and Adoptive Cellular Therapy (ACT):
Cancer vaccines work by stimulating a type of immunity that attacks and kills cancer cells. Breast cancer vaccines have historically been evaluated as single medicines in individuals with metastatic disease. Multiple vaccine formulations may be safely delivered and induce antigen-specific immune responses in peripheral blood in early-phase studies, but there was no indication of clinical efficacy. To date, most vaccinations have been designed to target specific tumor antigens. There is interest in discovering neoantigens and creating vaccines to target them, due to recent breakthroughs in genomic profiling and the capacity to pinpoint mutations inside a tumor. It has been observed that neoantigen identification by T cells has a role in the response to Immune checkpoint inhibitor therapy, implying that a combined therapy strategy involving a neoantigen vaccination and Immune checkpoint inhibitors might be successful. In stage II-III TNBC, a study testing a neoantigen DNA vaccine alone or in combination with durvalumab is currently underway (NCT03199040). CAR T-cell therapy is now being investigated in solid tumours, including breast cancer, with active studies targeting ERBB2 (NCT02713984), cMET (NCT01837602), mesothelin (NCT02792114), and mucin-1 (NCT02587689).

Despite the fact that immunotherapy has demonstrated encouraging outcomes in the treatment of several cancers, there are still numerous obstacles to overcome. Immunotherapy’s side effect profile continues to be a challenge for most medical oncologists. Chemotherapy has well-known adverse effects, Immunotherapy, on the other hand, hyperactivates the immune system, resulting in immune-related adverse events that can range from minor flu-like symptoms, lethargy, and body aches to more serious symptoms affecting several organs.

While tremendous progress has been made, immunotherapy in the field of breast cancer has yet to demonstrate its full potential value. With a better knowledge of tumor, microenvironment, and host factors driving treatment combination decisions, it is expected that combination therapy strategies will be the way forward for immunotherapy in breast cancer. In order to uncover effective ways for increasing the immune response against breast cancers, careful research design with suitable end objectives and correlative studies will be important. If immunotherapy is individualized to both the disease and the individual, it is believed that breast cancer would become a chronic condition that is both treated and preventable.