The Need for Genomic Testing Recognized During Breast Cancer Awareness Month

Daniel A. Vorobiof, MD

Due to the vast advancements achieved in the breast cancer treatment paradigm over the last few years, physicians are able to better identify important disease characteristics, such as the BRCA1 or BRCA2mutation, which can help improve treatment-decision making for patients with breast cancer. As treatments continue to evolve, they will become more personalized with the emergence of targeted therapies. Thus, genomic testing wil be an important component of screening patients with breast cancer.

One of the latest milestones in the breast cancer space has been the approval of several CDK4/6 inhibitors. These include abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali), which were all approved in combination with hormone therapy by the FDA for the treatment of patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. The use of a CDK4/6 inhibitor with hormone therapy has shown great improvements in progression-free survival in patients, particularly with advanced disease, or stage IV disease.

Other targeted agents and similar precision medicine therapeutic strategies have been approved or are showing promise in clinical trials, which further highlight the need for conducting genomic testing in patients with breast cancer.

In an interview with Targeted Oncology, Daniel A. Vorobiof, MD, medical director, Belong. Life, discussed the evolution of the breast cancer treatment landscape and the emerging role of genomic testing in this space. He also shared advice for community oncologists treating patients with breast cancer.

TARGETED ONCOLOGY: In terms of diagnostics, what have been some of the most important milestones in the breast cancer field?

Vorobiof: These days, we can better identify some of the hereditary cancer syndromes. A number of genetic mutations such as BRCA1/2, are already known for years to increase a person's risk of developing certain cancers, including breast cancer and ovarian cancer. Now lately, we have information regarding pancreas and prostate cancer too. With the new generation gene sequencing techniques, we are also starting to understand better and identify other hereditary cancer syndromes that can put people at risk of developing breast and/or other cancers.

Regarding other testing, for 15 years, we are treating patients with breast cancer with chemotherapy as part of their treatment. Now we can select those patients better, and we can select those patients that might or might not require chemotherapy treatment. We probably over treated many of our old patients in the past. Now, recent clinical trials over the past 5 years have confirmed that some genomic essays that look at different genes, and they look at different genes in the primary breast tumor. That gene expression shows whether or not it will be responsive to chemotherapy, or whether endocrine therapy alone would be a better choice. Patients results are shown as risks percentages, and those occurring in the low to mid risk range could skip chemotherapy safely, avoiding the predictable side effects known to chemotherapy drugs.

Recently, 2 years ago, we even went a little bit further, and a study published in the New England Journal of Medicine streamlined those results, showing that chemotherapy would not benefit a certain group of patients, which is a large group of patients, patients over 50 years of age, with certain specific characteristics, such as being endocrine responsive, HER2-negative and without spread to axillary nodes. All that, in my opinion, means that we can now offer more and personalized treatment with same or similar overall outcomes by doing less, causing less side effects, and also reducing costs, so it's a win-win situation for patients and the society in general.

TARGETED ONCOLOGY: Looking at the advancements in the treatment landscape, what are some of the important advances we have seen in the surgical space?

Vorobiof: The first thing that comes to mind is node lymph nodes preservation. Lymph nodes preservation reduces lymphedema cases. Now routinely, in the past, axillary lymph nodes were removed from the armpit during breast cancer surgery to test for spread from the breast cancer. This sometimes, not always, caused added pain, numbness of the arm, and lymphedema. It caused lymphedema in up to 15% of the patients, so much so that when we had patients that were going to undergo mastectomies and radiation, we will be involving a lymphedema specialist from the beginning to help the patients with specific exercises and how to take care of the arm in that situation.

However, newer studies published and presented over the past few years have confirmed that most of those nodes can be preserved without compromising the long-term survival of the patient. One of these techniques is by doing a sentinel node mapping that allows surgeons to identify which lymph nodes are most likely affected by the breast cancer spread and remove all the dogs. By doing this targeted axillary surgery, you could potentially preserve the nodes that once tested positive for cancer, and that implies fewer complications and fewer side effects for our patients. Nowadays, the incidence of lymphedema has dropped to practically 5% when this technique is utilized. Improving patient's quality of life by being less aggressive in the surgical management is one of the big advancements in surgery.

TARGETED ONCOLOGY: What are the most important advancements we’ve seen in the breast cancer treatment landscape in terms of targeted therapies and other treatment approaches?

Vorobiof: These advancements are mainly new drugs and new combinations. In the last 5 years, we have had new drug combinations that make patients with hormonal-responsive breast cancer [have] more treatment [options] to become more effective. We know that patients with HR-positive disease often receive targeted therapy with anti-estrogen or anti-hormonal medications. For a few years now, we've known that those patients can do even better when hormone therapy is combined with new oral medications, which inhibit this so-called CDK4/6 pathway. This pathway is heavily involved in causing cancer cells in dividing more and faster. These days, there are a few different CDK4/6 inhibitor already approved by the FDA and available commercially to treat our patients. When combined with hormone therapy, the CDK4/6 inhibitors have shown a great improvement in the progression-free survival in patients with advanced stage IV breast cancer, so much so that it has become the standard of care in nearly all metastatic HR-positive breast cancer patients as their first-line treatment, knocking down the chemotherapy as a treatment for subsequent lines of treatment, and not as the initial treatment. Yes, it doesn't apply to all the patients, but it applies to a large number of patients, and that's good news.

Another development is the availability of a new generation of monoclonal antibodies, what's called biologicals, as single agents or conjugated compounds. The monoclonal antibodies, for example, anti-HER2 trastuzumab is the most commonly known and most used to treat HER2-positive breast cancer patients for 20 years, or so. It works by targeting the HER2 receptor, which is on the cell and in this cell because a part of the receptor is inside, preventing further cancer growth. Now, some breast cancers express too much HER2 protein, and that's, unfortunately, not a good prognostic factor because they trigger the cells to multiply rapidly, and that happens in approximately 18% to 20% of all the breast cancers that are diagnosed these days. Now, over the past 5 to 10 years, other monoclonal antibodies, also anti-HER2 and against other receptors, have been developed and are available. However, over the past few years, combinations of monoclonal antibodies and chemotherapy have been developed. One of them is called T-DM1, and it's approved for use in the treatment of HER2-positive breast cancer patients. Another one called sacituzumab govitecan has already been approved by FDA a couple of months ago. These antibody-drug combinations, you can call them a smart bomb [because they are] delivering chemotherapy directly to cancer cells by attaching to the HER2 receptors.

All these compounds have become a big game-changer in the treatment of different stages of breast cancer. In the past few years, there has also been a recent oral option as a targeted therapy, a different one. These are PARP inhibitors. They were used mainly to treat ovarian cancer. Today, these PARP inhibitors are being used also to treat breast cancer successfully as they block cancer cells so they cannot grow and divide and continue growing.

TARGETED ONCOLOGY: What is the biggest challenge that oncologists face now in the treatment of patients with breast cancer?

Vorobiof: The main challenge that we are having is the pandemic. This pandemic has created havoc, everywhere, and for sure, specifically in the treatment of cancer patients and immunocompromised patients. If we look at that situation as it is, and I'm sorry to say, some of these things, but it's the reality, it's that we have more limited use of resources, as resources have been channeled to treat the COVID-19 pandemic. We are mainly embarked in reducing possible contacts and subsequent infections in our patients with cancer. Over the past 6 months, there have been many recommendation statements around the world, how to deal with COVID-19 pandemic and with cancer patients. Different national and international societies have prepared guidelines as standards for clinical decision making during the pandemic. We had to learn these very quickly, and we had to educate our patients very quickly. There was a change in the attitude, a change in the in the way that we had to deal with our patients.

[The recommendations] include a few common aims. We need to understand that for us as clinicians, the optimal long-term clinical outcome for patients is extremely important. We need to lower the risk of infection, not just of the patient but also of the staff, because without the staff, we face more problems and more challenges. We have to protect our patients from treatments and related side effects, such as heavy immunosuppression. And all that, we have to do it while we are preserving resources within the health care system, as hospitals becomes strained by the health crisis.

Most of the guidelines have divided the groups of patients with breast cancer according to 3 priorities. Priority A, or high, is those patients which need to be treated immediately, and those patients that have a disease that may threaten their life. There are long lists of recommendations. Priority B, or medium, is for those patients that may not need immediate treatment, but we cannot postpone them until the end of this long-term pandemic. Somehow along the line you have to make a compromise and start reacting. Priority B is also divided or subclassified into B-high, B-middle, and B-low. Then we can feel more comfortable making decisions around those parameters. Priority C, or low priority, are those patients whose treatment can be delayed for a long, long time or other measures can be done for them.

Hopefully, when the pandemic is over, patients will be able to have all the treatments necessary, will not experience a negative result. Although there are many national and international guidelines available with these common points on how to manage breast cancer patients during the pandemic, each institution should also have their own policy and structures in place according to their own resources. Most importantly, patient recommendations should be closely evaluated on a case by case basis. We cannot put all the patients into 1 pot and say okay, you belong to this, move in or move out. We need to emphasize that we need to treat patients on a case by case. We need to focus on the health education of our patients. Things have changed. We are using now consultations from far away. We are not examining patients as much as we were examining before. Telehealth is playing a different role, so educating those patients that this is happening, providing empathy and understanding of the situation is extremely important. It's a big, big challenge for all the oncologists around the globe.

TARGETED ONCOLOGY: Considering all of these advances in breast cancer, the role of genomic testing has become important in the field. Do you think testing is being done enough at this time?

Vorobiof: I would like to focus on a specific a situation, which is BRCA testing. As you know, BRCA testing has been ready for many year, but we saw, I saw, and many of my colleagues saw that not too many patients are being tested and not all patients that require it are being tested. We embarked into a research program, which we did through our Belong.Life. Belong.Life is the largest global social media application for cancer patient management, and it's available free and anonymously for patients. This research abstract was accepted and published at the latest American Society of Clinical Oncology annual meeting. The aim was to look at physicians advice on BRCA testing in breast and ovarian cancer. The aim was to find if patients that undergo the BRCA testing was influenced by their physicians advice or not.

The US Preventive Services Task Force recommends that women with a personal and familiar history of breast cancer undergo BRCA testing so that risk assessment, prevention options, and treatment changes, if necessary, should be considered. We checked on 302 mainly USA-based members of the Belong application, and they answered an online survey for us, which contained demographic questions as well as their knowledge on the BRCA test, and if they had it, then as a result of their doctors intervention, recommendation, or not. Interestingly, 71% of the patients with breast cancer did the test, but of them, only 57% was based on their doctor's recommendation. The rest was based on information that was gathered from other sources, including family, friends, social media, internet, or other patients. The concern was when we look into the data that 32% of those that didn't have it because they didn't receive advice to do it, they fell under the recommendations of the US Preventive Task Force. We believe, therefore, that the doctors are not too well knowledgeable in genetic counseling or genetic testing. They don't have the time or the knowledge to recommend that to their patients, and patients that they are at high risk of being associated with the BRCA1/2 genes, which has long-term relevance in cancer screening, in risk-reducing approaches, and in new therapeutic modalities.

TARGETED ONCOLOGY: What advice would you like to share with community oncologists treating patients with breast cancer?

Vorobiof: I have strong advice for community oncologists. I ask them to look at those guidelines and to also refer those patients. They don't need to do it themselves. They can refer the patient to be done and to be counseled by a specific counselor, and therefore the patient will not miss out on any specific other treatments or approaches that they might need if they carry the genes.