IMMUNOTHERAPY FOR BREAST CANCER

For some cancers such as melanoma and leukemia, immunotherapy has produced responses so durable that there is hope for the possibility of a cure in an increasing proportion of patients.^[1,2] In recent years, these novel therapies have also demonstrated efficacy in battling metastatic breast cancer.^[3,4,5]

"Breast cancer may not respond as well to immunotherapy compared with other cancers because, in general, breast cancers have a lower tumor mutational burden," said N. Lynn Henry, MD, PhD, associate professor of internal medicine, Huntsman Cancer Institute, University of Utah, in Salt Lake City. "Tumors with a high mutational burden respond better to immunotherapy."

According to Mary Disis, MD, director of tumor vaccine medical oncology and medical oncologist at the University of Washington Medicine in Seattle, breast cancer is immunogenic and the disease can stimulate the immune system, just not at the same level as melanoma. Disis noted, "We need to figure out what additional manipulations we need to do to assist breast cancer in stimulating the immune system better."

The Latest in Immunotherapy 

To date, only two immunotherapy drugs have been approved for use in treating triple-negative breast cancer (TNBC): pembrolizumab and atezolizumab.^[3,4,5]Pembrolizumab was approved specifically for the low percentage of breast cancers that have high levels of microsatellite instability or mismatch repair deficiency.^[4] The programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab received US Food and Drug Administration accelerated approval in combination with paclitaxel as treatment for metastatic TNBC that expresses PD-L1 based on a specific companion assay.^[5] Atezolizumab is also being tested in combination with other drugs, such as capecitabine or gemcitabine for TNBC.^[6]

"In the IMpassion130 clinical trial of patients with untreated ER-, PR-, and HER2-negative metastatic breast cancer, just over 40% of patients were PD-L1– positive, which implies there may be a more substantial proportion of patients who may benefit from immunotherapy regimens than was previously appreciated," explained Henry. "Based on results available to date, a subset of patients experience durable responses following treatment with immunotherapy regimens, but to a lesser degree compared with that seen with other malignancies, such as melanoma or non–small cell lung cancer." She also noted that immunotherapy is being used off-label in breast cancer on the basis of anecdotal evidence.

Immune checkpoint inhibitors appear to be more effective in TNBC. In an early-phase trial of pembrolizumab (KEYNOTE-086), patients with ER-, PR-, and HER2- negative breast cancer who were previously untreated had improved response rates with treatment compared with those who had previously received treatment for metastatic disease.^[7] "Response rates, however, are still not as high as desired, and many additional trials of combination regimens with immunotherapy plus either chemotherapy or targeted therapies are ongoing," said Henry.

Immunotherapies are more effective in TNBC because these tumors have more mutations.^[8] "Mutations can appear dangerous to the immune system," said Disis. She pointed out that one of the major effects of trastuzumab (Herceptin) is to cause antibody- dependent cell- mediated cytotoxicity. "[Trastuzumab] binding to the tumor will draw in cells of the innate immune system to jump- start HER2-specific immunity. Studies have shown that trastuzumab can 'vaccinate' patients with breast cancer [against] their tumors, and the greater the level of cell immunity developed after trastuzumab therapy, the better the clinical outcome," said Disis. "We have two out of three subtypes of breast cancer responding to an immune therapy. I would expect all patients with breast cancer could mount clinically effective antitumor immunity if we could figure out what is preventing them from doing so at a baseline."

The Role of Biomarkers 

"Biomarkers for immunotherapies include PD-1, PD-L1, and TILs," said Lidia Schapira, MD, associate professor of medicine (oncology) at Stanford University Medical Center. Increased TILs also predict patients who will have improved response to chemotherapy and improved survival, particularly in patients with the HER2-negative and TNBC subtypes.^[9,10] Schapira also noted that immune checkpoint inhibitors produce less response in breast cancer than in melanoma.

"The immune checkpoint inhibitors take off the brakes on immune cells, particularly T cells, which are infiltrating the tumor," said Sasha Stanton, MD, PhD, assistant professor at the Cancer Vaccine Institute in Seattle, Washington. "Therefore, the number of antitumor T cells present will determine the efficacy of the immune response." In PD-L1–positive metastatic breast cancer, single- agent pembrolizumab produces a response in 18.5% of patients with TNBC.^[11]In addition, the recent IMpassion 130 trial, which combined nab-paclitaxel and the anti–PD-L1 therapy atezolizumab, showed a benefit in overall survival and progression- free survival in patients with triple- negative PD-L1– positive tumors.^[3]

According to Stanton, the majority of all of the breast cancer subtypes have some immune infiltrate in their tumors. "One reason for the increased immune infiltrate in melanoma and lung cancer is that these cancers have a lot of mutations that increase immune recognition of the tumor," said Stanton. "Breast cancer typically does not have these mutations." A recent study^[8] identified TILs that are reactive to mutations in the tumor and used these to treat a patient with metastatic breast cancer along with immune checkpoint inhibitors. This approach provided a complete response despite considerable disease.

Furthermore, there is an ongoing clinical trial giving patients with TNBC genetically modified T cells against the ROR1 protein that is expressed on breast cancer cells (chimeric antigen receptor [CAR] T cells), and there are further CAR T- cell clinical trials coming out in HER2-negative cancer and TNBC.^{[12,13,14,15]} "I do not think that immune therapy will be less effective in breast cancer, but we have to better understand the immune environment in breast cancer and how to use and develop immune therapies so they can benefit breast cancer," said Stanton.

To date, most of the trials of immunotherapy have been conducted in patients with TNBC.^{[16,17,18,19,20,21,22,23]} However, a few early phase trials, such as PANACEA, which are testing pembrolizumab plus trastuzumab in trastuzumab-resistant advanced HER2-positive breast cancer, have been conducted in patients with HER2-positive tumors and shown promising results.^[24] "Similarly, there have been a few trials in ER-positive populations, although immunotherapy monotherapy to date has not appeared very effective in that setting," said Henry. "Numerous clinical trials of combination immunotherapy approaches are underway or being planned for both HER2-positive and hormone receptor–positive breast cancer." Researchers eagerly await results from several clinical trials testing immunotherapies in metastatic breast cancer, including A-BRAVE, IMpassion030, and NeoTRIPaPDL1 (Table).

"Breast cancer weakly stimulates the immune system. We need to make that stimulation stronger so that we can 'unleash it' with immune checkpoint inhibitors," said Disis. "The key to immunotherapy in breast cancer, to make it work, will be combination therapy. Not two immune checkpoint inhibitors, but rather an immune stimulator to start and then build a regimen that will allow a breast cancer– specific immune response to flourish."

Treatment: The Challenges 

A number of challenges exist in treating breast cancer with immunotherapy, including identification of biomarkers predictive of treatment response, development of rational combination regimens that can increase the likelihood of response, and toxicities from therapy. Immunotherapies are associated with a unique spectrum of immune-related adverse events that fall into four main categories: gastrointestinal, hepatic, endocrine, and dermatologic.^{[25,26,27,28,29]}Diarrhea/colitis and hepatitis are the most common adverse events leading to discontinuation of immune checkpoint inhibitors.^[29]

"The types, patterns, and severity of the toxicities differ depending on whether a regimen includes a single immunotherapy, such as a PD-1 inhibitor, or combination immunotherapy, such as a PD-1 inhibitor plus a CTLA-4 inhibitor. They tend to be quite different from what is seen with cytotoxic chemotherapy," said Henry. To date, oncologists who specialize in breast cancer have limited experience with immunotherapy toxicities unless they have conducted clinical trials including the agents, but with the approval of atezolizumab for breast cancer, this will change.

"It will be important for oncologists to establish relationships with specialists in these fields who have experience managing immunotherapy toxicities," said Henry. "A number of academic centers have reported establishing teams of specialists so that they can address toxicities rapidly," she added.

According to Disis, the key to autoimmune toxicities is to recognize the constellation of symptoms early and treat symptoms or stop the drugs. "We have come a long way in knowing how to intervene and prevent serious adverse events," said Disis.

Schapira said that oncologists are learning to handle the immune side effects that can affect any person and any organ with varying degrees of severity. "It may take months to see a response, so it is also difficult to know when to stop these drugs," said Schapira.

Although available data suggest that immunotherapies are well tolerated in terms of health-related quality of life compared with other anticancer therapies, instruments designed specifically to report quality of life for this category of drugs are needed. Despite the broad clinical trials experience of immunotherapies across cancer types, relatively few randomized studies examine patient-reported outcomes and health-related quality of life.^[30]

Ongoing efforts are aimed at identifying biomarkers, which will allow a better selection of patients with breast cancer undergoing specific immunotherapies.^[22] "I think we will have to understand further how studying a tumor's PD-L1 expression is associated with response, and pathology groups will have to incorporate PD-L1 expression in breast tumors, particularly with the IMpassion130 results," said Stanton. "However, there are also a lot of tumor-associated autoantibodies in the serum of patients with breast cancer. I think that identifying antibody biomarkers to identify patients who have breast cancer from other benign lesions would also be an important focus."

Many laboratories across the country, including the Cancer Vaccine Institute at the University of Washington, are working on understanding the immune environment in breast cancer to be able to better tailor therapies to the subtypes. "If we can increase the immune recognition of the tumor through vaccines, we can increase antitumor T cells that can then be activated with immune checkpoint therapies," said Stanton. "Furthermore, there is more focus now on using immune therapy for breast cancer prevention." She believes vaccines will be important in patients who have ductal carcinoma in situ or other preinvasive breast cancer for whom progression to invasive breast cancer is the highest concern.

"A vaccine that provides long-term immunologic surveillance and destruction of developing breast cancers would be an important therapy for patients who previously had breast cancer and now want to prevent a recurrence or for patients with preinvasive cancer who want to prevent invasive cancer," said Stanton. "There are clinical trials now in these populations evaluating breast cancer vaccines, and I think the results of these trials will be important in moving immunotherapy forward in earlier stage breast cancer."

Dr Disis has grant funding from Pfizer, EMD Serono, Seattle Genetics, Janssen, Silverback Therapeutics, Celgene, and EpiThany; is an inventor on immunotherapy patents held by the University of Washington; and is a stockholder in EpiThany. Dr Stanton has received research funding from Precigen. Dr Henry and Dr Schapira have disclosed no relevant financial relationships.