By Dr. Amreen Husain, Genentech Immuno-Oncology Global Development Team Leader
Immunotherapy is the story of the decade in cancer therapy. We’ve seen exciting advances across several tumor types, with significant improvement in long-term outcomes. Yet some cancers, including breast cancer, have shown little response to this new class of medicines, particularly when used alone. We believe advancing our understanding of breast cancer biology and pursuing innovative combination approaches could overcome inherent challenges in breast cancer immunotherapy and potentially advance treatment for subtypes of the disease with limited treatment options.
Breast cancer has traditionally been seen as non-immunogenic or “cold,” meaning it doesn’t provoke an immune response. It has significantly fewer mutations compared to highly immunogenic tumors that have shown success with immunotherapy, such as melanoma, lung, and bladder cancers. Unlike breast cancer, those cancers are often associated with environmental causes that cause extensive DNA damage. Melanoma, for example, has roughly ten times more mutations than breast cancer. Without extensive mutations, the immune system is less likely to identify breast cancer cells as foreign and mark them for destruction.
However, researchers have discovered a subset of people with breast cancer who do show an immune response to their disease. Tumor-infiltrating lymphocytes, or TILs, are found in these tumors, showing immune cells have recognized the tumor, multiplied, and infiltrated it — so-called “hot” tumors. Having these TILs has also been associated with a better prognosis, suggesting TILs can alter the disease course. A key insight is that the proportion of people with TILs varies depending on the molecular subtype of the tumor. In breast cancer, people with hormone receptor-positive tumors are unlikely to have TILs in their tumors, whereas the triple-negative subtype has the highest rate of TILs. Identifying this immunogenicity is an important opportunity, especially considering the limited treatment options for triple-negative disease.
But simply identifying tumors with TILs is not a solution. Only a minority of breast tumors have TILs, and even fewer show the highest levels associated with an improved prognosis. Even with TILs present, indicating an immune response to the tumor, that doesn’t guarantee they can kill cancer cells. In these cases, breast cancer cells may be employing mechanisms that suppress the immune response. Immunotherapies called checkpoint inhibitors could help block these evasion mechanisms, allowing the immune response to resume and kill tumor cells.
Immune biomarkers might help identify which breast tumors will be susceptible to a given immunotherapy strategy, better defining the patient population who might benefit and likewise identifying those unlikely to respond and needing another approach. PD-L1 expression in the tumor, for example, could help select people for PD-L1 checkpoint inhibition. Biomarkers could also help select people for rational combinations of two immunotherapies that can further activate the immune response.
Tumors that lack TILs are another challenge. Since immunotherapy doesn’t kill cancer cells directly, but rather enables TILs to do their job, we also need strategies to bring TILs into these tumors. One approach is to kill tumor cells with chemotherapy or radiation, causing new antigens to be released and recognized by the immune system. In turn, this can draw tumor-specific lymphocytes into the tumor. Combining an immune checkpoint inhibitor with chemotherapy, for example, may help increase the number of people with breast cancer who could benefit from immunotherapy. This will have to be done carefully, as not all chemotherapies will be equal in this role.
We won’t identify a one-size-fits-all solution. Breast cancer is many diseases with widely varying biology. It will take methodical research to personalize immunotherapy for breast cancer in hopes of widening the pool of people who can benefit, particularly in subtypes of the disease that continue to have poor outcomes. Our approach to developing new cancer medicines has always depended on deepening our knowledge of biology, and that will be crucial for advancing breast cancer immunotherapy.
Progress in breast cancer immunotherapy is a template for other “non-immunogenic” solid tumors. Every tumor type likely has a subset amenable to immunotherapy. We can start with identifying that subset, but also pursue innovative approaches to turning cold tumors hot. With this approach, we hope to continue expanding the number of people who benefit from immunotherapy.
For more information on Genentech’s work in cancer immunotherapy, visit www.gene.com/immunotherapy.