Dr George Speaks on Advances in Triple Negative Breast Cancer

Dr George Speaks on Advances in Triple Negative Breast Cancer


In this video, Dr George speaks on the exciting advancements in triple-negative breast cancer.



My name is Mridula George, I'm one of the breast medical oncologist at Rutgers Cancer Institute in New Brunswick, New Jersey. I'm an assistant professor at Rutgers Robert Wood Johnson Medical School, I treat patients with stage 1 to stage 4 breast cancer and my preferred pronouns are she/her.

What is the current standard of care for triple‑negative breast cancer (TNBC)?

The current standard of care for triple‑negative breast cancer depends on the stage of which the patient's diagnosed so, when a patient's diagnosed with breast cancer, we do a nodal staging to determine if the cancer has spread to the local lymph nodes, we sometimes stage patients to see if there is distant metastasis, if the cancer has spread beyond the local area of the breast and the regional lymph nodes so, depending on the stage of the cancer, the treatments also vary.

Stage 1 to 3 breast cancer is treated with curable intent so, patients would be eligible to get chemotherapy, immunotherapy in a subgroup of patients, surgery, and radiation therapy but, in stage 4 breast cancer, the goal of treatment is more palliative, is to control the disease, prevent rapid progression of the disease, and the mainstay of treatment in patients with stage 4 metastatic breast cancer is chemotherapy, could be targeted therapy in a subgroup of patients, and antibody drug conjugates.

How have screening measures and therapeutic options for TNBC evolved in recent years?

Current guidelines recommend screening mammogram for women over the age of 40 so that patients are detected early if they have breast cancer. If patients have first degree relatives with breast cancer, they start screening early on. Patients who have germline mutations and certain genes that increases the risk of breast cancers, like BRCA1, BRCA2, PALB2, CHEK2, depending on these mutations, patients would be eligible to start screening for breast cancer as early as the age of 25.

Are there any key publications, approvals, or data sets of note you'd like to mention?

There have been a lot of exciting studies in triple‑negative breast cancer in the last few years. One of the most important studies that came out, the results that came out last year, was from KEYNOTE‑522.

This was a study which evaluated the combination of pembrolizumab in combination with an anthracycline‑based chemotherapy in patients with early‑stage triple‑negative breast cancer. The patients were randomized 2:1 and patients got neoadjuvant pembrolizumab with chemotherapy or neoadjuvant chemotherapy with a placebo.

The primary endpoints were pathologic complete response and event‑free survival and the study met both co‑primary endpoints in terms of pathologic complete response, in the patients that received pembrolizumab and chemotherapy, 64.8 percent had a pathologic complete response, whereas in the patients that received only chemotherapy without the pembrolizumab, the pathologic complete response rate was about 51.2 percent. In terms of event‑free survival, the three‑year event‑free survival was 84.5 percent with pembrolizumab and chemotherapy, compared to 76.8 percent with chemotherapy alone.

This was statistically significant, and this received FDA approval and patients who have early‑stage triple‑negative breast cancer are eligible to receive this combination.

In terms of another important study that showed benefit in patients with triple‑negative breast cancer is the use of PARP inhibitors. PARP inhibitors are used in the metastatic setting for patients with BRCA1 or BRCA2 mutation. The OlympiA study looked at the addition of olaparib for one year after completion of adjuvant radiation for patients with triple‑negative breast cancer or hormone receptor‑positive, HER2‑negative breast cancer and the primary endpoint was invasive disease‑free survival and, the three‑year invasive disease‑free survival was 85.9 percent in the olaparib group versus 77.1 percent in the placebo group and the hazard ratio was 0.58, and the three‑year distant disease‑free survival also was statistically significant, 87.5 percent in the olaparib group, compared to 80.4 in the placebo group. This study is very relevant for patients who have germline BRCA1 or BRCA2 tumors and this is a targeted therapy that's available in this adjuvant setting for this disease group.

The other important studies are the approval of pembrolizumab in the metastatic study based on the data from KEYNOTE‑355 and it showed there was an improvement in progression‑free survival as well, as overall survival in the first‑line setting for patients with CPS score greater than 10 and metastatic triple‑negative breast cancer with keytruda or pembrolizumab.

Another important study is the ASCENT study. It was a randomized Phase III study which looked at sacituzumab, which is an antibody drug conjugate, compared to physician's choice of chemotherapy. It could be eribulin, vinorelbine, capecitabine, or gemcitabine in patients who had refractory relapsed triple‑negative breast cancer and the primary endpoint was progression‑free survival. Sacituzumab, which is the antibody drug conjugate, the progression‑free survival was 5.6 months versus 1.7 months in the control group, which was also statistically significant and there was also median overall survival benefit of 12.1 months in the sacituzumab arm, compared to 6.7 months in the chemotherapy arm and this is a significant improvement in survival in this disease group.

Please briefly describe any research you are currently conducting and the impact it has on detecting and treating TNBC.

We have multiple studies ongoing at Rutgers Cancer Institute of New Jersey. One important study that I would like to mention is the IRENE study, which is looking at oncolytic viruses to study its impact in patients with metastatic triple‑negative breast cancer.

In KEYNOTE‑355, it showed that there was a benefit in using pembrolizumab in patients who are PD‑L1‑positive but, only 40 percent of patients are PD‑L1‑positive so, we're conducting a study looking at the combination of an oncolytic virus called pelareorep, in combination with a PD1 inhibitor to see if the addition of oncolytic viruses can upregulate the PD‑L1 expression.

Preclinical studies have shown that the addition of the virus causes upregulation of PD‑L1 expression, which we know positively influences the treatment response with a checkpoint inhibitor. We're doing this study right now in patients who have progressed after one or two lines of systemic therapy in the metastatic setting and patients will receive a checkpoint inhibitor, a PD1 inhibitor, with an oncolytic virus, the oncolytic virus is an intravenous administration, which is very unique compared to other oncolytic viruses in the market, which require intratumoral administration.

With this pelareorep, it's given intravenously, just like any other chemotherapy administration and the checkpoint inhibitor is also given intravenous. This is an ongoing study, it's still in the early stages, we haven't seen any safety concerns and the study is continuing to enroll patients here at Rutgers Cancer Institute and Ohio State University.

The other study that we have is in the adjuvant setting, it's a vaccine study. Studies have looked at this protein called global H and about 40 percent of patients can have an expression of global H and we have an ongoing study looking at the role of administering a vaccine over a two‑year period in patients who have completed chemotherapy, surgery, and radiation in the early‑stage triple‑negative breast cancer.

We also have the I‑SPY trial that's open and that has a triple‑negative breast cancer cohort and that's for patients with stage 1 to 3 triple‑negative breast cancer as well.

We have other studies that are opening, especially looking at the role of sacituzumab in the first‑line setting for metastatic triple‑negative breast cancer and that should be opening soon, I think that's going to be a very important study to enroll patients on.

What existing data or circumstances led you to evaluate this?

KEYNOTE‑355 did show a benefit with checkpoint inhibitors but, the benefit's only seen in patients who have PD‑L1 expression. A large majority of our patients do not have PD‑L1 expression so, by adding an oncolytic virus, we are stimulating the tumor microenvironment, and this can upregulate PD‑L1 expression. By giving the oncolytic virus, we're priming the tumor microenvironment and creating a more conducive environment for the checkpoint inhibitor to work so, that was the rationale for doing the study.

Were any of the outcomes of your research particularly surprising?

It's still early so it's hard to say but the first part of the study was to see if the combination was safe and tolerable and so far, we are not seeing any safety concerns with the combination.

How will these findings affect the treatment landscaped for these patients?

In terms of the IRENE study with regards to the oncolytic virus, its regimen does not have chemotherapy so there may be a subgroup of patients we could possibly eliminate chemotherapy if this study shows benefit. Obviously, triple‑negative breast cancer is just not one disease type, there are different subtypes within triple‑negative breast cancer. We have to look at the biomarkers and try to identify why certain subgroups of patients respond, whereas other subgroups do not show a significant response. So, more research needs to be done to understand the biomarkers and what's driving the response.

How do you personally encourage patients to enroll in clinical trials?

For every patient I see, I screen them for clinical trials. I encourage patients to go on studies, especially if it's a drug that's not currently approved and has good track record from the early phase studies to show benefit, especially if it's going to be very similar to standard of care. I encourage them to participate and also discuss the benefits that the study may have on them but, we also don't know if it's going to be definitely beneficial.

I also talk to them about the potential benefits for patients who are diagnosed with breast cancer much later on. By enrolling in the study, they're helping understand how breast cancer behaves and how their participation in the study can change the treatment landscape for this disease.

Aside from your own research, what upcoming therapies in the TNBC space are you most excited about?

There are a lot of interesting clinical trials going on, one clinical trial that I'm looking forward to seeing the data is the SWOG study, which looked at pembrolizumab in the adjuvant setting in patients who had residual breast cancer after neoadjuvant therapy. We know that from KEYNOTE‑522, all patients received pembrolizumab in the neoadjuvant setting and in the adjuvant setting but, it would be interesting to see, in patients who did not receive neoadjuvant checkpoint inhibitors and had residual disease, does the addition of pembrolizumab change disease‑free survival in this subgroup?

There are a lot of targeted therapies being studied, there is a LIV1 antibody, it's an antibody drug conjugate by Seattle Genetics that's still in early phase clinical studies. The PIK3 inhibitors have been approved for hormone receptor‑positive breast cancer. The drug that's currently in the market is alpelisib by Novartis.PIK3 overexpression can be seen in about 15 to 20 percent of patients with triple‑negative breast cancer so, it would be interesting to see how the addition of PIK3 inhibitor can change disease outcomes in triple‑negative breast cancer.

What are some immediate action items that oncologists and other oncology healthcare professionals can employ to better meet the needs of these patients?

I think as the different studies are being done, it's very important for oncologists to stay on top of the data that's coming out and that can be very difficult. But, in terms of biomarkers, we're trying to study biomarkers for triple‑negative breast cancer. We have a PD‑L1‑positive or PD‑L1 negative in the metastatic first‑line setting and that can influence the use of pembrolizumab and then patients have BRCA 1 or 2, that can influence the use of a PARP inhibitor in the adjuvant setting or in the metastatic setting. So, when patients are diagnosed with breast cancer, we should refer them for genetic counseling to detect any germline mutations, which would open additional lines of therapy in this setting.

Is there anything else of interest you’d like to add?

Besides all the different biomarkers that we talked, another important area is the role of circulating tumor DNA. There's a lot of companies evaluating that and monitoring that it's still very early, but there are clinical trials being done to understand the ctDNA kinetics in early‑stage breast cancer and how to monitor them to understand the subgroup of patients who may have disease recurrence. So, the use of ctDNA is still in early phase but, that's up and coming and an important thing to consider for our patients, especially if you have ongoing clinical trials.