Tag Archive for: enhertu

Antibody Drug Conjugates for Lung Cancer | Advances in Research

Antibody Drug Conjugates for Lung Cancer | Advances in Research from Patient Empowerment Network on Vimeo.

What are antibody drug conjugates, and how are these new agents changing lung cancer care? Lung cancer expert Dr. Thomas Marron defines antibody drug conjugates and explains how they work to treat lung cancer.

Dr. Thomas Marron is Director of the Early Phase Trials Unit at the Tisch Cancer Institute at Mount Sinai Hospital. Dr. Marron is also Professor of Medicine and Professor of Immunology and Immunotherapy at the Icahn School of Medicine at Mount Sinai. Learn more about Dr. Marron.

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Transcript:

Katherine Banwell:

What are antibody drug conjugates, and how do they treat lung cancer?   

Dr. Thomas Marron:

So, antibodies are proteins that have been manufactured. They’re a synthetic version of something that happens in our own body And they’re very specific for a very unique protein. And so, there are certain cancer proteins, there’s proteins on the surface of cancer that really aren’t expressed anywhere else in your body. And so, what we can do is we can develop these antibodies that basically are a heat-seeking missile. So, you inject them like chemotherapy, through an IV. But they’re a heat-sinking missile, and they go throughout your body, and they stick themselves to the cancer.  

And hopefully, they don’t stick anywhere else. And basically, antibody drug conjugate means the drug is conjugated to the antibody, meaning you basically have glued chemotherapy onto that antibody.  

And so, what it allows us to do is, instead of giving chemotherapy through the IV like we normally would, where that chemotherapy goes everywhere in your body, and that’s the main reason that you have toxicity.  

It doesn’t just go to the cancer, it also goes to your bone marrow, to your hair, to your intestines, has side effects. Antibody drug conjugates, the goal of them is to really deliver the chemotherapy directly to the tumor and spare the rest of your body, the toxicity from the chemotherapy that’s glued onto the antibody.

It’s important to note that they still do have side effects. So, some of that chemotherapy, for lack of a better term falls off the antibody or it might leak out of the tumor after it kills the tumor cells. And so, there is still the potential for toxicity, very similar to the toxicities that we see with chemotherapy.   

But so far, the data is very encouraging, both in lung cancer and other cancer types that antibody drug conjugates might be a superior formulation of chemotherapy, so better able to treat lung cancer. And we have a few drugs that’re actually probably going to be FDA-approved in the second line setting for non-small cell lung cancer. So, that’s for patients who have received standard first-line therapy and unfortunately, their cancer has progressed.   

And we actually already have one drug that was, it’s called Enhertu that was developed for breast cancer. And that’s now FDA-approved for lung cancer, for a rare subset of lung cancer patients who have an exon-20 HER2 mutation.  

And the patients I’ve treated with that drug do extremely well, and so I think it’s a very encouraging sign of what’s to come using more and more of these targeted chemotherapy regimens.  

Katherine Banwell:

Yeah. Well, that leads me to the next question, is there a patient type that ADCs are right for? 

Dr. Thomas Marron:

So, maybe is the question, answer. So, I don’t know because we don’t have good biomarkers right now to identify the patients that’re going to respond best to the drugs that’re in development, at least those ones that’re furthest along in development.  

And we’re always searching for biomarkers, which basically just means a test that we do on the patient’s biopsy or in their blood to tell us who’s going to respond to a therapy and who’s not. Unfortunately, right now we don’t have a good biomarker for these drugs.  

Hopefully as we do larger trials and we study biopsies and blood from the patients on those trials, we can identify the subset of patients that will do best with the therapy. Because we always want to make sure we’re getting patients the best therapy for them and we’re avoiding giving these therapies, because there are some toxicities to patients that aren’t going to respond to the therapy. So, it’s definitely a work in progress. 

An Overview of Current Gastric Cancer Treatment Options

An Overview of Current Gastric Cancer Treatment Options from Patient Empowerment Network on Vimeo.

Treatments for gastric cancer have expanded in recent years, providing new options for patients. Dr. Yelena Janjigian, a specialist and researcher, shares an overview of available gastric cancer therapies and outlines the different treatment classes.

Dr. Yelena Janjigian is Chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center. 

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Transcript:

Katherine:

Okay. I’d like to move onto current gastric cancer treatment options. Can you provide an overview of what’s available now?  

Dr. Janjigian:

Right. So, in patients with intermediate or early-stage tumors, really surgery is the main way to cure patients. Occasionally when we have an amazing response to chemotherapy or chemotherapy with immunotherapy or just immunotherapy, we can avoid surgery. But in most patients, surgery in early-stage disease is a gold standard for cure. Of course, it can be a very jarring thing to say to someone. “We have to take out. your stomach.” But patients do live without either fully their stomach removed or partially removed. And that’s the gold standard. We do additionally other treatments to help maximize chances of cure, but surgery is the main state. As I mentioned earlier, most of our patients, however, present with later stages where surgery is not feasible.  

And when I say it’s not feasible, we would only attempt an operation if we thought there was a possibility of removing the cancer completely. Leaving some of the tumor behind, even if it’s only 1 percent of the cancer behind, makes patients unwell. They may not be able to tolerate additional chemo, so we do not recommend doing suboptimal surgery unless cancer can be completely removed. So, in those patients, we always explain the situation.

And the disease is not potentially as curable, but it’s absolutely always treatable. And since the development of our immunotherapy options, really, we’ve changed the trajectory and the course of those cancers. We won’t know the stage or the final response to therapy until we’ve start it. But in those patients, usually a form of long-term therapy. Chronic treatment is very important.  

And usually it involves a combination of chemotherapy and some targeted agents, biologic agents, meaning that they were designed in the lab to target the cancer specifically. And usually, they involve some sort of immunotherapy.   

Katherine:

Excuse me. Can you go into some detail about the targeted therapies and immunotherapies that you use?  

Dr. Janjigian:

Sure. So, conventional chemotherapy works on any rapidly dividing cell. And these are chemotherapies that have been tried and true in the clinic for decades, right? And they work still in gastric. And in  particular they’re very important. And then over the last 10 years or so, we’ve started developing target agents in the lab that target the specific biologic tumor biomarkers. And when you think about tumor biomarkers, I would think about them as almost ZIP codes, right? How do you direct the cancer cell to die? 

And how do you inhibit the cancer cell for the thing that is uniquely what’s making it grow as opposed to normal cells, right? So, that’s the difference between chemotherapy because chemotherapy can affect any rapidly dividing normal cell and cancer cell, while biologic agents ideally only affect the target, cancer, the cell. So, that’s why it’s very appealing to do both to help maximize response and survival on treatment. So, the biologic therapies that are available in and already approved in our disease for stomach cancer are something called HER2 directed treatments.

And that’s been my focus in the lab. And then in my group has really spearheaded a lot of this research for HER2-positive tumors. In gastric cancer it occurs in up to 20 to 30 percent of tumors, but we have drugs such as trastuzumab or Herceptin, T-DXd, trastuzumab deruxtecan-nxki (Enhertu) or in HER2 that target these agents.  

And furthermore, our work here at Memorial Sloan Kettering demonstrated the combination therapies really for HER2-positive disease has helped improve outcomes in those patients. So, that’s biologic therapy. Other biologic therapies that’s approved in gastric cancer is something called VEGFR-2 inhibitor. These are drugs that target blood vessel formation around the tumor to help the chemotherapy drugs work well and better. Those drugs are called ramucirumab or Cyramza. And that’s used in a combination of chemotherapy in second-line treatment. And there’s other drugs such as regorafenib (Stivarga) and other inhibitors that maybe have some targetable activity in our disease. And last but not the least is immunotherapy. So, immunotherapy’s a completely different class of drugs.  

We think about immunotherapies, really the fundamental problem with cancer, right? The cancer issues that it started as a normal cell. So, at some point, it was a normal cell that then became and went awry and went rogue. And the body did not recognize that there was a problem. And the immune system did not eliminate that cancer cell. Before it started to metastasize and give us problems in their body, right? So, the fundamental question is why is the body’s immune system, why did it not recognize it as a abnormal cell?

Well, because it really acts and looks like a normal cell from the immune perspective. Our immune system is trained not to hurt us, right? And that’s why in patients with rheumatoid arthritis or other autoimmune disorders, what happens is the immune system goes awry. So, what the immune checkpoint blockade or immunotherapy for cancer does, is it helps take some of those brakes off our immune system and help our immune system recognize the cancer and give it permission to say, “Hey, you know what?  

You thought it was a normal cell. It’s not. It’s a cancer cell. Please help us eliminate it.” And that’s worked well because I think in for some of our patients, the immune system actually knows how to target and suppress the cancer much better than any of the fancy drugs we can design in the lab.

And that’s why in some patients, immune checkpoint blockade immunotherapy has been such a game changer if you do respond, your duration and durability of response is so much more better than anything that would go to just done on our own in the lab or with other chemotherapies. So, it really is a nice way to think about it. And the patients feel like they’re part of the solutions. It’s always nice for them to have that.  

But it’s been a real game changer for both HER2-positive and HER2-negative disease in combination with chemotherapy. I’ve had the pleasure of leading some of these studies. And it’s nice to be able to update the three or the four or the five-year survival rate from these studies in a disease where in the past most patients died within a year.   

Non-Small Cell Lung Cancer Treatment | Clinical Trials and Research Updates

Non-Small Cell Lung Cancer Treatment | Clinical Trials and Research Updates from Patient Empowerment Network on Vimeo.

What are the latest advances in lung cancer care? Lung cancer specialist Dr. Isabel Preeshagul shares highlights from recent conferences, promising clinical trial updates, and advice for people interested in joining clinical trials.

Dr. Isabel Preeshagul is a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center. Learn more about Dr. Preeshagul.

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Transcript:

Katherine Banwell:

What are you excited about right now in lung cancer research? 

Dr. Isabel Preeshagul:

I am excited and overwhelmed by the fact that we have so many approvals and so much exciting data that was just presented at ASCO and World Lung and ESMO that it’s next to impossible to keep up. And I’m happy that we have that problem, and I’m happy that the patients have – there’s a spotlight on lung cancer when we were in the shadows. And now, I think we have the spotlight.  

And all of these approvals, you know, with it being Lung Cancer Awareness Month as well, I think is just so important. Just to make sure that we get the knowledge of these new approvals out there though, that is another struggle. 

Katherine Banwell:

Well, are there any current clinical trials that look promising to you?  

Dr. Isabel Preeshagul:

Yeah, I think there are many clinical trials. In the induction setting, there was some data that was just presented on ALINA looking at adjuvant alectinib (Alecensa). We just had a – we have approval for adjuvant osimertinib (Tagrisso) and the ADAURA trial.  

But we are learning more and more that as these targeted therapies have approval in stage IV, we’re trialing them in stage III, and then we’re going to trial them in earlier stages and earlier settings. So, this has been the pattern of how drugs get approved. So, yes, there’s lots of exciting data coming through.  

Katherine Banwell:

That’s excellent. Can you talk about antibody drug conjugates and where they fit into lung cancer care? 

Dr. Isabel Preeshagul:

Yeah. That’s a great question. I don’t think anyone knows the answer as to where they fit in just yet. 

We have probably over 300 antibody drug conjugates that are in development right now. And one of the more common ones that we use is trastuzumab deruxtecan (Enhertu), or TDXD, which is used in patients that harbor HER2 alterations in the stage IV lung cancer setting. It is basically almost like a Trojan horse. So, you have this antibody.  

It’s typically IgG1, immunoglobulin. And then you have a linker, and then at the end of that linker is the warhead or the chemotherapy agent. So, the antibody comes in towards the cancer cell looking very innocent. It binds to the cancer cell. And, once it binds, then everyone inside the Trojan horse or this warhead rush into the cell and get to do its damage. So, it’s a totally different mechanism. We’re trying to outsmart some of the bypass mechanisms that cancer cells develop. And this may be the new wave, but stay tuned, more to come.  

Katherine Banwell:

Right. So, it’s promising.  How can patients find out more about current clinical trials? 

Dr. Isabel Preeshagul:

So, you can always ask your healthcare practitioner if there are any clinical trials at the institution that you’re at, but clinicaltrials.gov has all the clinical trials that are available nationally and internationally.  

You just type in your disease type. You can type in a couple keywords, EGFR maybe or ROS1 or stage IV, something along those lines, and then it should populate a list of clinical trials and what institutions have them open, if they’re still accruing or if they’re not, and a contact on that trial.  

Katherine Banwell:

If a patient is interested in a clinical trial, what kinds of questions should they be asking their healthcare about the trial? 

Dr. Isabel Preeshagul:

So, the first question to ask is, “Do we have any clinical trials that are appropriate for me?” If the answer is yes, “Are they appropriate for me now, or are they appropriate for me if what I’m on right now is not working?” 

So, trying to figure out where that will be, and if they are appropriate for you now, how can I get evaluated, and how can we get things underway? 

Katherine Banwell:

Yeah. What would you say to patients who are interested in participating in a clinical trial, but they’re nervous about it?

Dr. Isabel Preeshagul:

I think one thing that I love about being on a clinical trial is that there are more eyes are on you, because we are looking to get something approved, and we are just watching every single little granular detail. In a way, it’s almost like you’re being more micromanaged than if you were on standard of care because of just how many stops and checks there are, how many eyes are looking at your labs after the doctor and the nurse and the nurse practitioner, and the fellow take a look at everything. It’s 10 other people. So, it’s almost like it’s extra safe because of all of that. It’s exciting because you are hopefully getting tomorrow’s treatment today, right? 

You’re trailblazing the way for other people after you. So, I think it’s exciting, but, of course, it’s nerve-wracking. It’s something new. You don’t know if it’s going to work. But I have to believe that the way that clinical trials are designed now and the clinical trials that we choose to open here, we really hope are going to be pushing the space forward.  

Non-Small Cell Lung Cancer Treatment Options | Personalizing Therapy

Non-Small Cell Lung Cancer Treatment Options | Personalizing Therapy from Patient Empowerment Network on Vimeo.

How does the presence of biomarkers impact lung cancer treatment options? Lung cancer specialist Dr. Isabel Preeshagul discusses how test results may influence treatment options and aid in personalizing lung cancer therapy.

Dr. Isabel Preeshagul is a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center. Learn more about Dr. Preeshagul.

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Transcript:

Katherine Banwell:

How do biomarkers in lung cancer affect treatment options for lung cancer patients? 

Dr. Isabel Preeshagul:

So, it used to only be in stage IV, but now we are learning that biomarker testing is really important from the get-go because we have induction or neoadjuvant protocols that are looking at giving targeted therapy before patients go to surgery. 

We know that there’s FDA approval for patients to get targeted therapy after surgery, and there’s a survival advantage there. So, make sure that you have next-generation sequencing testing regardless of your stage. 

Katherine Banwell:

Okay. That’s good advice. So, we’ve heard how testing and a patient’s individual disease can lead to more targeted options. And you just mentioned targeted therapies. How do they work? 

Dr. Isabel Preeshagul:

So, there are many different targeted therapies that we have. Some of given as an infusion. For HER2, for example, we have TDXD, and we have T-DM1. TDXD is the only drug that’s FDA-approved in this setting. There are clinical trials looking at T-DM1. For EGFR Exon 20, we have another infusional drug called amivantamab-vmjw (Rybrevant). For EGFR Exon 19 and Exon 21, we have a pill called osimertinib (Tagrisso). For KRAS, there’s a pill. For most of the driver alterations, it’s a pill, but some of them it does require infusional therapy. But these are therapies that are targeted at the cells that harbor that mutation.  

Katherine Banwell:

Let’s turn to immunotherapy. What is it, and how does it work? 

Dr. Isabel Preeshagul:

So, immunotherapy is basically teaching your body to recognize cancer as foreign. So, when you have – I always kind of use this hand model. So, basically, a normal cell has, let’s say, three prongs. And then sometimes what happens is cancer will grow a marker called PD-L1 that makes it hide from the immune system. So, the body thinks that this is a normal cell. So, what immunotherapy does is it comes up and it sort of puts a cap on that PD-L1 so that the cell looks foreign again and the body can attack that cell and get rid of it. So, it’s almost like ramping up your immune system to recognize that marker and get rid of that cell.  

Katherine Banwell:

What is the regimen for immunotherapy, and how often is treatment administered? 

 Dr. Isabel Preeshagul:

So, immunotherapy is approved in the neoadjuvant setting, which means before chemotherapy. It’s approved after chemotherapy, and it’s approved in the stage IV setting. There are many different regimens and many different dosings and many different drugs. But it’s typically given in your veins, either once every three weeks or once every four weeks for a certain amount of time. If it’s given in a curative setting and it’s given indefinitely or until there’s disease progression or intolerance in the stage IV setting.  

Katherine Banwell:

Okay. Let’s touch upon the side effects of these types of treatment. You’ve mentioned that there are so many, but what are some of the major side effects, and how are they managed? 

Dr. Isabel Preeshagul:

Side effects of immunotherapy can include pneumonitis, which is inflammation of the lungs, any kind of endocrinopathy like issues with your thyroid, issues with your pancreas like diabetes.  

It can cause colitis, which is diarrhea, inflammation of the colon, hepatitis, inflammation of the liver. It can cause cerebritis, inflammation of the brain. It can cause arthritis or arthralgias, inflammation of the bones. And it can also cause rash and fatigue.  

Typically, if it’s the thyroid, it’s managed with thyroid replacement hormone or a drug that would calm down the thyroid if it’s overactive. Pneumonitis is steroids. Hepatitis is sometimes treated with steroids. Colitis, steroids typically. Steroids usually come somewhere in there, usually not with the endocrinopathies, but the other itis’s, it’s typically – we start with steroids and go up from there. And the goal is to really recognize these toxicities before they become a problem and just at the glimmer of them just starting.  

Katherine Banwell:

So, would you consider these treatments to be personalized medicine then? 

Dr. Isabel Preeshagul:

So, it’s personalized in the sense that if someone has a high PD-L1 expression, there may be some data to demonstrate that they may benefit from immunotherapy or have a response. If someone can’t tolerate chemotherapy or is not interested in chemotherapy or has other reasons that may preclude them from getting it, it might be reasonable. So, in that sense, it is considered personalized.  

Katherine Banwell:

How would you define personalized medicine? 

Dr. Isabel Preeshagul:

To me, personalized medicine takes into account the biologic makeup of a patient’s disease like if they have a mutation and what their PD-L1 status is, what the histologic makeup of it. What’s their stage? And then, on the other hand, what’s important to that patient? If they’re a tailor, you want to make sure you’re not giving them a medication that’s going to cause neuropathy, so they can’t use their hands.  

If they enjoy playing the harp or the piano, same thing. If their goal is to continue to run marathons, you may want to avoid something that’s going to cause inflammation of the lungs and risk them for pneumonitis. Tailoring to make sure that the treatment is part of their life but does not become their life.  

The Role of Antibody Drug Conjugates in Lung Cancer Care

The Role of Antibody Drug Conjugates in Lung Cancer Care from Patient Empowerment Network on Vimeo.

What are antibody drug conjugates (ADCs)? Expert Dr. Grace Dy defines this new class of therapy and explains how ADCs work to treat lung cancer.

Dr. Grace Dy is Chief of Thoracic Oncology and Professor of Oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York. Learn more about Dr. Grace Dy.

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Transcript:

Katherine Banwell:

What is the role of antibody drug conjugates in lung cancer care? 

Dr. Grace Dy:

So, the antibody drug conjugates are an exciting new class of therapy. In fact, it’s been developed for decades, but we had the first antibody drug conjugate that was just approved less than a year ago in lung cancer. And that’s the drug called trastuzumab deruxtecan (Enhertu). It seems like we’re always steps behind our breast cancer colleagues. 

You know, trastuzumab deruxtecan was first developed in breast cancer patients. But hey, we also find we can have some subset of patients who will derive benefit from that. But that’s just one example. There’s plenty of antibody drug conjugates that are being developed. 

So, what are antibody drug conjugates? So, as the name implies, it’s an antibody that is attached to a drug that is actually typically chemotherapy, but you can use any other drug. Generally, it’s a chemotherapy. So, you can think of it as a targeted way of delivering chemotherapy because the antibody is very specific to a certain protein. And generally, what we try to do is look for proteins that are more expressed in cancers than in normal tissues. And you try to target that and improve the therapeutic index by using a more potent chemotherapy and potentially increase efficacy that way.

How Is Metastatic Breast Cancer Treated?

How Is Metastatic Breast Cancer Treated? from Patient Empowerment Network on Vimeo

Breast cancer expert Dr. Adrienne Waks discusses treatment approaches for metastatic breast cancer and explains how research is evolving.

Dr. Adrienne Waks is the Associate Director of Clinical Research at Dana-Farber Cancer Institute. To learn more about Dr. Waks click, here.

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Transcript:

Katherine:

What about people who have metastatic disease? What treatment advances are available for them?  

Dr. Waks:

Yeah. You know, I think that’s an incredibly important question and a totally different set of discussions than we have with women with early stage breast cancer and unfortunately and unacceptably at this point for a woman diagnosed with metastatic breast cancer still typically that can become a life-threatening diagnosis. 

So, it’s exceptionally important that we rapidly improve the treatment options that we have for women with metastatic breast cancer. Maybe everybody says this every year, but I think that this year, 2022, has been a particularly exciting year in terms of advances that we’re making in the treatment of metastatic breast cancer, really of all subtypes. I would say the most exciting class of drugs or type of drugs that’s coming out in breast cancer and in all malignancies honestly, is called antibody drug conjugates, which is to say an antibody. So, a molecule that’s targeted to some particular approaching on a cancer cell surface and then is attached to or conjugated to a chemotherapy molecule.  

So, the antibody is like a smart delivery system directly to the cancer cell for what’s call a payload, basically like a sort of action molecule or the killer molecule, which is the chemotherapy. 

Those kinds of antibody drug conjugants have made a huge impact in recent years in improving outcomes for women really with all subtypes of breast cancer, so that drug class I think is a very exciting one to watch in general. In terms of specific recent developments in metastatic breast cancer, so probably the biggest blockbuster development over the past year and really over just the past three months is the understanding that we can break out a subtype of metastatic breast cancer that we really didn’t even talk about before which is called HER2-low breast cancer. So, before if you asked me in May of 2022, there really were only two types of HER2 readouts for a breast cancer tumor. 

There was a HER2-negative breast cancer tumor and there was a HER2-positive breast cancer tumor and as I already told you, the HER2-positive accounts for about 20 percent of breast cancers overall. The other 80 percent are HER2-negative. And so, historically, again you asked me three months ago I would have said if you’re HER2-positive and that 20 percent will give you these different HER2-directed treatments and if you’re not, we can’t use those. And what’s changed is that we’ve developed new antibody drug conjugants. So, drugs that are targeted against in this case the protein HER2 that seem to be so effective and work so well, that you don’t truly have to be HER2-positive.  

You can be HER2-low and still benefit from these treatments, which is to say your cancer has a little bit of HER2 protein on the surface of the breast cancer cells but not a lot. So, not enough to make it positive but enough to make it low in its designation. 

That’s actually a large proportion of breast cancer patients. It’s over 50 percent of breast cancer patients, so it’s significantly more than HER2-positive, so a large proportion of breast cancer patients actually fit into this new category called HER2-low and we now know from data that were presented in June of 2022 and then published in the New England Journal of Medicine, which is our biggest most high profile academic medical journal, we know that for patients who fall into that HER2-low category, again that’s more than 50 percent of breast cancer patients, that they can, if they have a metastatic breast cancer, benefit from this new antibody drug conjugate called trastuzumab deruxtecan (Enhertu).  

When it was compared to the existing chemo options we have for those patients which do have some efficacy but nonetheless, when trastuzumab deruxtecan was compared to the existing chemo options, it clearly looked better for patients with HER2-low breast cancer. So, that was not just an exciting advance in terms of new treatment options which we always love to be able to offer to patients but also in terms of breaking out this entirely new designation and subcategory that captures more than half of our metastatic breast cancer patients and helping us to offer them something new and hopefully will be a pathway for other drugs to be developed in this space and for this new subcategory. 

So, that was very exciting. I’ve been talking about it with patients all the time in the past just three months since those data came out.  

You know, a second antibody drug conjugate that has also been very exciting in recent months and recent years is called sacituzumab govitecan which Trodelvy is the brand name of that one. That’s an antibody drug conjugate that’s targeted against a different protein on the cell surface that’s targeted against the protein Trop-2, so that’s where the Trodelvy comes from. It’s targeting Trop-2. That’s an antibody drug conjugate that we’ve known for probably three or more years now can be very effective in triple-negative metastatic breast cancer. So, we’ve had that option for a number of years in metastatic triple-negative breast cancer. 

But again, just in the past few months have gotten good and exciting data that this Trodelvy or sacituzumab drug also works in estrogen-driven breast cancers.  

And so, it’s giving another option to patients with not just triple-negative but also estrogen-driven breast cancer. So, that was another very recent development just in the last three months or so. 

Katherine:

That’s really exciting. 

What Do You Need to Know About Metastatic Breast Cancer Genetic Testing?

What Do You Need to Know About Metastatic Breast Cancer Genetic Testing? from Patient Empowerment Network on Vimeo.

Why is it important to ask about metastatic breast cancer genetic testing? Find out how test results could reveal more about YOUR breast cancer and could help determine the most effective treatment approach.

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Transcript:

Why should you ask your doctor about metastatic breast cancer genetic testing?

The National Comprehensive Cancer Network – also known as the NCCN – recommends that every metastatic breast cancer patient undergo genetic testing. The test results can help predict how your cancer may behave and could indicate that one type of treatment is more effective than another.

This testing identifies specific gene mutations, proteins, chromosomal abnormalities, and/or other molecular changes that are unique to YOU and YOUR breast cancer.

There are two main types of genetic tests used in breast cancer:

  • Germline or hereditary genetic testing, which identifies inherited gene mutations in the body. These mutations are present from birth, can be shared among family members and be passed on to subsequent generations.
  • The second is somatic or tumor genetic testing, which identifies markers that are unique to the cancer itself. It is also commonly referred to as genomic testing, biomarker testing, or molecular profiling. Somatic mutations are NOT inherited or passed down from family member to family member.
  • Depending on your history, your doctor may order one–or both–of these types of tests.

So why do the test results matter?

  • If you have specific gene mutations – such as the BRCA1 or BRCA2 inherited gene mutations – it could indicate that a targeted treatment approach may be the most effective option. For example, there are two oral targeted therapies that are approved specifically for use in metastatic patients with BRCA1-positive or BRCA2-positive breast cancer.
  • Results of these tests may also help you to find a clinical trial that may be appropriate for your particular cancer.
  • Additionally, results from germline genetic testing may suggest that close family members should also be tested to determine their risk.

How can you insist on the best breast cancer care?

  • First, always speak up and ask questions. Remember, you have a voice in YOUR breast cancer care.
  • Ask your doctor if you have had–or will receive–genetic testing, including germline and somatic testing.
  • If you have already undergone genetic testing, bring a copy of your results to your current doctor, so they can understand your results and determine whether additional testing is needed.
  • Have a discussion with your healthcare team about the test results – including which markers were detected and how results may impact your care and treatment plan.
  • Ask whether your family members should meet with a genetic counselor or undergo testing to help gauge their risk of developing breast cancer.
  • And, finally, bring a friend or a loved one to your appointments to help you process and recall information.

To learn more about breast cancer and to access tools for self-advocacy, visit powerfulpatients.org/breastcancer

An Expert Review of Emerging Metastatic Breast Cancer Research

An Expert Review of Emerging Metastatic Breast Cancer Research from Patient Empowerment Network on Vimeo.

What’s the latest in metastatic breast cancer (MBC) research? Expert Dr. Sarah Sammons shares an overview of emerging treatment options and how they could be utilized in MBC care.

Dr. Sarah Sammons is an oncologist at Duke Cancer Institute and Assistant Professor of Medicine at Duke University School of Medicine. Learn more about Dr. Sammons here.

See More From INSIST! Metastatic Breast Cancer

Related Resources:

What Could Metastatic Breast Cancer Genetic Testing Advances Mean for You?

Metastatic BC Research: How Can You Advocate for the Latest Treatment?

Metastatic BC Research: How Can You Advocate for the Latest Treatment?

Why Should Metastatic Breast Cancer Patients Consider a Clinical Trial?


Transcript:

Katherine:

When it comes to metastatic breast cancer research and emerging treatment options, what are you excited about specifically?

Dr. Sammons:

That’s a really good question. I think, right now, I’m very interested in a class of drugs called antibody drug conjugates.

What antibody drug conjugates are – they take a monoclonal antibody, which is – most patients have heard of Herceptin. So, Herceptin is an antibody which goes in and targets HER2. But that antibody is actually linked to a payload of chemotherapy cells. But instead of just – regular chemotherapy we inject that chemotherapy into the veins, it goes all throughout the body, it can be fairly toxic.

Antibody drug conjugates specifically find the cells that have that biomarker, like HER2, or TROP2, or HER3, and they find that cell, and they don’t release their chemotherapy until they’re taken up by that cell. So, it’s more a targeted, focused chemotherapy.

There is an antibody drug conjugate in HER2-positive breast cancer called Enhertu, or trastuzumab deruxtecan, which is – has been shown to have excellent efficacy in very heavily pre-treated HER2-postitive breast cancer.

It’s moving into earlier lines of therapy. The drug is so effective in HER2-positive breast cancer, we’re also looking at it in something called HER2-low breast cancer. So, breast cancers that we never thought before would respond to HER2 targeted therapy is – it appears that even if they express a little of HER2, this drug might have efficacy. So, that’s in clinical trials, and that’s really exciting.

What’s also great, is about 60 percent of women with hormone receptor-positive breast cancer are HER2-low. So, that could be a really great drug option in the future for those patients.

There’s another antibody drug conjugate called sacituzumab govitecan, which is approved in triple-negative breast cancer, and was shown to improve overall survival, which you always want at the end of the day – a drug that is well-tolerated and helps patients live longer.

That drug is approved in triple-negative breast cancer, but we’re now looking at it in hormone receptor-positive breast cancer.

There are also a variety of other antibody drug conjugates in clinical trials. One that’s looking at HER3, a few others that are looking at HER2, and also TROP2.

So, I’m definitely excited about antibody drug conjugates.

I’m also very excited about the field of immunotherapy in general. Immunotherapy has sort of lagged behind in breast cancer compared to some other tumor types like lung cancer and melanoma. But in triple-negative breast cancer, we finally have approval for two types of immunotherapy, but only if they have a certain biomarker.

Right now, immunotherapy only helps patients with metastatic triple-negative breast cancer if they express something called PDL1. So, we have FDA approval for two different immunotherapies for PDL1-positive triple-negative breast cancer. And there are many different strategies ongoing in clinical trials with different types of immunotherapy that try to harness the patient’s immune system to fight the cancer, instead of just giving regular chemotherapy. It’s really trying to help the patient’s immune response help fight the cancer. 

When Is a Full Mastectomy Appropriate for Metastatic Breast Cancer Patients?

When Is a Full Mastectomy Appropriate for Metastatic Breast Cancer Patients? from Patient Empowerment Network on Vimeo

Dr. Stephanie Valente discusses mastectomy for metastatic breast cancer patients, including common misconceptions around breast cancer surgery.

Dr. Stephanie Valente is the Director of the Breast Surgery Fellowship Program at Cleveland Clinic. More about this expert here.

See More From INSIST! Metastatic Breast Cancer


Transcript:

Dr. Valente:                

So, there are a lot of reasons that a woman undergoes a mastectomy. The first one is choice. So, anytime somebody is diagnosed with breast cancer, they actually have the choice of whether or not they want to remove their whole breast. So, even if their cancer is small, they do have the option of removing the whole breast. If the cancer is smaller, they might have the option to save the breast, which is called a lumpectomy.

Sometimes cancer is found, and it’s a little bit more advanced where saving the breast is not an option. So, the cancer is larger than a lumpectomy would allow. And sometimes that’s what’s called the extent of disease. So, the amount of breast tissue that’s involved requires a majority of the portion of the breast to be removed.

So, just because a woman has breast cancer that’s made its way out of the breast, into the lymph nodes, or beyond – so, metastatic cancer – doesn’t necessarily mean that she needs a mastectomy. So, just because you’ve got metastatic cancer doesn’t necessarily mean that the breast needs to be completely removed.

So, I think that one of the biggest misconceptions is that the more aggressive somebody is with their surgery, the better their chances with survival.

And again, taking a step back and saying you can choose a more aggressive surgery, but a more aggressive surgery doesn’t necessarily mean it gets you out of chemotherapy or it gets you out of radiation therapy. Those things are recommended, independent of a woman’s choice for the type of surgery that she may or may not pick.

Metastatic Breast Cancer: Accessing the Best Treatment For YOU

Metastatic Breast Cancer: Accessing the Best Treatment For YOU from Patient Empowerment Network on Vimeo.

How could genetic testing results impact your metastatic breast cancer treatment options? In this INSIST! Breast Cancer webinar, Dr. Julie Gralow discusses essential testing, the latest targeted therapies and emerging breast cancer research.

Dr. Julie Gralow is the Jill Bennett Endowed Professor of Breast Medical Oncology at the University of Washington, Fred Hutchinson Cancer Research Center, and the Seattle Cancer Care Alliance.

Download Program Resource Guide


Transcript:

Katherine:

Welcome to Insist Breast Cancer, a program focused on empowering patients to take an active role and insist on better care. Today, we’ll discuss the latest advances in metastatic breast cancer, including the role of genetic testing and how this may affect treatment options. I’m Katherine Banwell, your host for today’s program, and joining me is Dr. Julie Gralow. Welcome, Dr. Gralow. Would you introduce yourself?

Dr. Gralow:   

Hi, thanks, Katherine. I’m Dr. Julie Gralow. I’m the Jill Bennett Endowed Professor of Breast Medical Oncology at the University of Washington, Fred Hutchinson Cancer Research Center, and the Seattle Cancer Care Alliance.

Katherine:    

Excellent, thank you. Before we begin the discussion, a reminder that this program is not a substitute for seeking medical advice. Please refer to your own healthcare team. Well, Dr. Gralow, let’s start by helping people understand how breast cancer is staged. Could we go through those stages?

Dr. Gralow:     

The staging of breast cancer has traditionally been by something we call anatomic staging, which has the tumor size, the number of local lymph nodes involved, and whether it has metastasized beyond the lymph nodes. So, that’s TNM – tumor, nodes, metastases. And so, that’s the classic staging, and based on combinations of those things, you can be a Stage 0 through Stage 4. Stage 0 is reserved for ductal carcinoma in situ, which is a noninvasive breast cancer that can’t generally spread beyond the breast, so that’s Stage 0, and then we go up for invasive cancer.

Interestingly, just a couple years ago, the big group that oversees the staging of cancers decided that in breast cancer, that TNM – the size, the lymph nodes, and the location beyond the lymph nodes – is not good enough anymore, so they came up with a proposal for what we call a clinical prognostic stage, which is a companion to the traditional TNM staging.

What they were getting at here was it’s not just how big your cancer is, how many lymph nodes, or whatever, it’s also at the biology of your cancer. So, this new clinical prognostic stage takes into account the estrogen and progesterone receptor of your cancer, the HER2 receptor at the grade, which is a degree of aggressiveness, and then, if your tumor qualifies, one of the newer genomic testing profiles that we use in earlier-stage breast cancer, such as the Oncotype DX 21-gene recurrence score or the MammaPrint 70-gene assay.

So, all of that goes into account now, and the whole point here is that the estrogen receptor, the HER2, the grade, and some of these genomics may actually make more difference than how many lymph nodes you have, where the cancer is, and how big it is, so it’s not just the size, but also the biology of the cancer that we’re trying to include in the new staging systems.

Katherine:    

In this program, Dr. Gralow, we ’re focusing on metastatic breast cancer. Would you explain when breast cancer is considered to have metastasized?

Dr. Gralow:  

That’s a great question because technically, if the lymph nodes in the armpit – the axillary area – are involved, that does represent spread beyond the breast, but if it stays in the local lymph node areas, it’s not technically called a metastatic or Stage 4 breast cancer. So, metastatic breast cancer would have traveled beyond the breast and those local lymph nodes, and some common sites would be to the bone, to the lungs, to the liver, less commonly – at least, up front – to the brain, and it could also travel to other lymph node groups beyond those just in the armpit and the local chest wall area as well.

Katherine:   

What about subtypes? How are they determined?

Dr. Gralow:   

The main way that we subtype breast cancer right now is based on the expression of estrogen and progesterone receptor, the two hormone receptors, and the HER2 receptor, the human epidermal growth factor receptor. So, to date, those are the most important features when we subtype, and so, a tumor can either express estrogen and progesterone receptor or not, and it can overexpress or amplify HER2 or not, and if you think that through, you can come up with four different major subtypes, in a way, based on estrogen receptor positive or negative and HER2 positive or negative.

When all three of those are negative, we call that triple negative breast cancer, and that’s about 18-20% of all breast cancers as diagnosed in the U.S. And then, when all three are positive, we sometimes call it triple positive, and the reason that we subtype is because we know that those different subsets act differently and that we have different drugs to treat them with, and we’ve got great drugs in the categories of hormone receptor positive and HER2 positive, and increasingly, some recently hope in a new drug approval or two in triple negative breast cancer as well.

Katherine:     

For a patient to get diagnosed, what are the essential tests?

Dr. Gralow:  

So, we’re talking about metastatic breast cancer here, and in the U.S., maybe up to 10% or slightly less of breast cancer is technically Stage 4 or metastatic at diagnosis. That means at the time we first found it in the breast, it had already spread beyond. So, an important thing that we’ll do with a newly diagnosed breast cancer is especially if there are a lot of lymph nodes are involved or the patient has symptoms that might say there’s something in the bone, liver, or lung is staging.

So, we’ll use scans – maybe a CAT scan, bone scan, or PET scan – and we will look at whether the disease has gone beyond the breast and the lymph nodes, and if so, where. So, maybe 8-10% of breast cancer diagnosed in the U.S. already has some evidence that it has spread beyond the breast, but the most common way that metastatic breast cancer happens is that a patient was diagnosed possibly years and years ago, treated in the early-stage setting, and now it comes back, and that is the most common presentation for metastatic breast cancer, and sometimes that can be due to symptoms.

As I said, if it comes back in the bone, maybe that’s bone pain. If it’s in the lung, it’s a cough. There are symptoms. Sometimes, it’s because we’ve done a blood test or something and we find some changes there.

And so, when a breast cancer has recurred, it’s really important to document that it’s really breast cancer coming back, first of all, and so, if we can, we generally want a biopsy, and we want to stick a needle in it if it’s safe to do, and look and verify that it looks like breast cancer, and also, it’s really important that we repeat all those receptors that we talked about from the beginning because it can change.

So, a cancer up front 10 years ago could have been positive for estrogen receptor, but the only cells that survived – mutated, changed – were estrogen receptor negative, so what comes back could be different. So, it’s really critical to get that biopsy, repeat the estrogen/progesterone receptor and HER2, and also, in an ideal world, now that it’s 2020 and we’re moving more toward genomics, to do a full genomic profile and look for other changes and mutations that could drive our therapeutic options.

So, staging, knowing where the cancer is, getting a good baseline by understanding where it is and how big it is so that we can follow it and hopefully see that it’s responding to treatment, and then, repeating all of the biology components so that we know what the best options are for treatment are really critical.

Katherine:  

Right. How can patients advocate for a precise breast cancer diagnosis, and why is that important?

Dr. Gralow:    

Well, all those things I just mentioned are key. Knowing exactly where it is so that we can monitor it – for example, if the cancer has come back in the bones, we would add what we call a bone modifying agent, a drug like zoledronic acid or denosumab – Zometa or – which can suppress bone destruction from the cancer, but if it’s not in the bone, we wouldn’t add that.

And, we want to have a good look everywhere so that we can see if it’s responding because sometimes, the tumor can respond differently in one area than another. Also, I think it’s really important to know what your treatment options are by doing that biopsy, getting a full panel, and looking at potentially hundreds of genes that could be mutated, deleted, or amplified so that we know what our treatment options are.

And, we’re not going to use all the treatment options up front, so it’s helpful for knowing that if this treatment doesn’t work or is too toxic, what are the second-line or third-line options? So, we make sure that there’s what we call good staging up front so we know where the cancer is, and then we make sure that we’ve looked at it as best we can in 2020 with all the genomics.

That would give us the best chance of being tailored – individualized – to the tumor. Sometimes, if we can’t biopsy it, like with a needle that would go into a liver spot, then increasingly, we’re looking at what we call liquid biopsies, and that can be drawing the blood and seeing if we can find parts of the tumor, whether it be the DNA or the RNA that’s floating around in the blood, and sometimes we can get that information out of the blood as well.

Katherine: 

All right. Dr. Gralow, when you meet with patients, what are some of the more common misconceptions that you hear related to diagnosis?

Dr. Gralow:  

Well, I think people do confuse – especially at an early diagnosis – that the metastases, the travel to the local lymph nodes, is not the same as a metastatic breast cancer, so we spend some time talking about how it’s still curable and not considered a distant metastasis if the lymph nodes are in the armpit or up above the collarbone, and so, that’s something that we spend some time talking about.

This whole term of “metastatic recurrence” – unfortunately, when you start looking online and get your information from Dr. Google, you read right away that it’s no longer curable, and in 2020, yes, that’s true. That’s probably the most specific statement that we can make. We are not going with curative intent, which means we treat for a defined amount of time, and then all the disease goes away, and we stop treatment, and then you go on with your life, and it never comes back. That would be cure.

But, I think it’s really important to point out that much of metastatic breast cancer can be highly treatable, and what we hope to do – and certainly, at least a subset of metastatic breast cancer – we want to convert it more to what we would call a chronic disease, and so, think of it more like hypertension, high blood pressure, or diabetes. These are diseases that we generally don’t cure with treatment, but that we can control with drug therapy, which sometimes has to be adjusted, and if we don’t control it, we can get some bad complications.

So, that’s not all metastatic breast cancer, unfortunately – we can’t convert all of it do something where we can use a therapy for a long time that keeps it in check and where you have a pretty good quality of life – but we’re hoping that more and more, we’re getting targeted therapies and more specific treatments to patients so that we can convert more patients to a more chronic kind of situation.

Katherine:

So, it’s something that patients live with.

Dr. Gralow:  

Right.

Katherine:  

Many people are confused about genetic testing. They often think that it relates to ancestry or physical traits like hair and eye color. What’s the role of genetic testing in breast cancer?

Dr. Gralow:    

Well, you can do genetic testing of the patient’s inheritance, which is how most people think of genetic testing, and that’s actually really important and increasingly important in metastatic breast cancer to do your own inheritance. Have you inherited a gene that was associated with how your cancer developed? Because now, we actually have a class of drugs called PARP inhibitors that are approved for tumors that have a BRCA1 or BRCA2 mutation with them. Most of those mutations were inherited, but not all. Sometimes they can develop as well.

So, now, when my patient – if she didn’t previously have genetic testing for an inherited risk for breast cancer either coming from mom or dad’s side of the family, a lot of people do have that up front, especially if they’re younger at diagnosis or they have a lot of family members with breast cancer. If she didn’t have that genetic testing done previously, at the time of the metastatic occurrence, I’m going to recommend that that be done because knowing if the cancer is associated with one of these DNA repair genes – BRCA1, BRCA2, some other genes – we have a new treatment option, which is an oral pill that actually is highly effective if the tumor has a mutation in one of these.

But, we can also – so, that’s genetic testing of the patient’s own DNA, but we can also do what we call genetic testing – or genomic testing, if you will – of the genes of the cancer. What were the changes in the DNA at the gene level that caused a normal breast cell over time to develop into a cancer cell that’s now growing without responding to our body’s checks and balances? So, what were those mutations, deletions, or amplifications in the tumor itself?

So, we’ve got the patient’s genetics, we’ve got the tumor’s genetics, and both of those come into play when we’re making our best treatment recommendations and trying to understand what the right approach is.

Katherine:       

How is testing administered?

Dr. Gralow: 

So, for our inherited testing, those gene changes can be found in every cell in the body, so we can do that from a simple blood test where we just look at the blood cells. We can actually do it with our sputum and with a cheek swab, even. You can get enough of the DNA from the inside of the mouth to do that.

For a tumor’s genetics, we need some of the tumor, so that’s either done with a biopsy into the metastatic site or, as I mentioned before, increasingly, we’re exploring the potential for a liquid biopsy – so, drawing some blood and then trying to find pieces of the tumor that are shed into the blood.

Katherine:      

What advances have there been in testing?

Dr. Gralow: 

Well, it used to be – just going back a couple of years ago – that we didn’t do a lot of this genetic testing or genomic profiling of the tumor because we didn’t have many – the term is an “actionable mutation.” So, if we found something, would we do something with it? Did we have a drug we could use to do it? But, more and more and more, even in breast cancer, we’re finding actionable mutations that would drive therapy.

For example, in estrogen receptor positive breast cancer, we have a new class of targeted therapies called PI 3-kinase inhibitors – a drug called alpelisib or Piqray was approved in the last couple of years in that category – and it only is effective in estrogen receptor positive breast cancer that has a mutation in the PI 3-kinase gene. So, that would be something we’re looking for in the tumor’s genes, and actually, we need to know that there’s a mutation to even get the drug approved for treatment because it doesn’t work if you don’t have that mutation.

Increasingly, we’re finding some changes that can happen in the estrogen receptor gene and the HER2 gene, interestingly, so that you can have estrogen receptor expressed on your tumor, but over time, that tumor might develop an estrogen receptor mutation so that it stops responding to certain drugs that target the estrogen receptor.

And so, that’s called an ESR1. That’s the name of the estrogen receptor gene – an ESR1 mutation – and that would tell me probably not going to respond as well to a drug in the class we call aromatase inhibitors, but might respond better to a drug in the class that we call the selective estrogen receptor degraders like fulvestrant or Faslodex, is the name of a drug in that class.

We’re also finding that you can have what we call activating mutations in HER2, and they can be present whether the tumor overexpresses HER2 or not, and we’ve got some ongoing clinical trials looking at if the tumor doesn’t have extra HER2 on its surface – so, it doesn’t have extra HER2 protein, but at the gene level, it’s got an activated HER2 gene – we can use certain types of HER2 therapy to treat it, and we’re testing that right now in clinical trials.

So, could we even use some HER2 drugs even though technically, the tumor would be classified as HER2 negative? So, fascinating increasing information that we’re understanding, and I also mentioned before we can inherit mutations in genes such as BRCA1 and 2, but fascinatingly, the tumor can acquire those mutations. Even if we didn’t inherit a mutation, we can see mutations in the BRCA1 and 2 gene – we call those somatic as opposed to germline mutations. So, “germline” means it’s in every cell in your body, but “somatic” means the tumor somehow acquired this over time.

And so, we’ve done – we just presented some very early results of a trial, and we’re expanding this trial, looking at if you didn’t inherit a BRCA1 or 2 mutation, so technically, you don’t qualify for a PARP inhibitor, but if the tumor acquired a mutation and we can prove that with testing the tumor’s DNA, then we have seen responses from these PARP inhibitors, so that opens up another whole class of treatments, and there are other DNA repair genes that actually may be qualified as well that we can inherit or that can be acquired by the tumor.

So, more and more, we’re doing this genomic profiling, and it is leading to results that would give us possible treatment options.

Katherine:  

Dr. Gralow, the goal of this program is to provide the confidence and tool for patients to advocate for the essential tests to get best care personalized to them. Are there specific tests that patients should make sure they have?

Dr. Gralow:  

Well, there are a lot of assays out there to do this genomic profiling or genetic testing of the tumor, so I don’t promote any one. Various institutions do it and do it well, various companies do it, but I think every metastatic patient should have the tumor looked at in this kind of profiling.

I also think every metastatic patient should advocate for having a biopsy of their cancer, and if a biopsy cannot be done safely in the recurrence, then see if they could get a liquid biopsy – have blood drawn to find it. So, I think that patients should be asking about this. Sometimes, insurance won’t always cover it, and so, my job as a treating physician is to advocate for that, to do an appeal.

More and more, because we have so many actionable mutations in breast cancer now, I’m not having insurance decline, but occasionally, it does, and then it’s our job as the healthcare providers to make the case that yes, this will impact the patient, and yes, it should be covered by insurance.

Katherine:  

You’ve been referring to a number of terms. Patients may have heard the BRCA or “braca” that relate to breast cancer in genetics. Would you give us an overview of common mutations in breast cancer?

Dr. Gralow:    

So, of the mutations that we can inherit, the first two that were discovered were BRCA1 and BRCA2, and for all breast cancer – not just metastatic, but all breast cancer – we think that maybe 5-10% of breast cancer is the direct result of the inheritance of a strong gene that gives you a high – not 100%, but a high likelihood of developing breast cancer.

So, for BRCA1 and 2, these two genes are associated predominantly with breast and ovarian cancer, and if you live out your normal lifespan, you could have up to a 75-80% chance of getting one of those two cancers, and breast cancer being more common. Also, some association with some other cancers including, interestingly, prostate cancer, which we’re learning more about.

So, BRCA1 and 2 are the most common, and they tend to be found – because they have such a high association with the risk of breast and ovarian cancer, they tend to be found in families that have a lot of other breast cancers, and also breast and ovarian cancer presenting at a younger age. So, you’ve inherited a gene that leads to a high predisposition, and the cancer occurs earlier.

So, whereas the average age of diagnosis of breast cancer in the U.S. is 61-62 most commonly, in a patient who’s inherited a BRCA1 or 2 gene mutation, it’s closer to 40-42 – so, a lot younger. And then, there are a variety of other genes that can be inherited that are either much less common or have a weaker link. So, for example, there are genes called CHEK2 or PALB2, ATM, P53 – I just mention that because some of the listeners will potentially have one of those mutations or have heard it. Those are either rarer or they’re associated with a weaker chance of getting cancer.

So, those might be more commonly found in a family that doesn’t have a lot of cancer in it because a carrier – the mother or the father – and their other relatives would have maybe only a 30% chance of getting breast cancer in some cases. So, there would be a lot of carriers who don’t get cancer.

So, as I mentioned earlier, I think it’s really important – especially right now in metastatic breast cancer – that pretty much everybody, even if you didn’t have a strong family history, even if you weren’t diagnosed at a young age, get tested because if we find one of these inherited mutations, we now have some additional treatment options, especially right now, approved for BRCA1 or 2, but clinical trials going on for many of these other genes.

Katherine: 

How do these mutations affect disease progression and prognosis?

Dr. Gralow:          

So, most of the genes I’ve mentioned – in their normal state, they’re critical, actually. They’re called DNA repair genes, and their job in our life is when we accidentally make a mistake when we’re replicating our DNA and two cells are dividing, if there’s a mistake in the DNA, they go in and repair it. And, we’ve got all kinds of mechanisms to try to prevent mutations from happening as cells divide, and BRCA1 and 2 are a key part of that, and so, they’re fixing it.

So, if you inherit a mutation in one of those genes, you still have some ability to repair any routine mistakes that are being made, but over time, you have less ability, and then, if you get a cancer that has a deficiency in BRCA1 or 2, those cancers can be more sensitive to certain kinds of chemotherapy that affects DNA repair.

So, for example a class of chemotherapy agents called the platinum drugs – carboplatin and cisplatin – may be more effective in BRCA1- or 2-mutated cancers, also more generally in triple negative breast cancer because they can be more similar to BRCA1-mutated cancers in a lot of ways.

So, to go back to your original question, once a cancer has developed in a patient who has a BRCA1 or 2 mutation, we treat that cancer for what it is. So, it might have developed estrogen – have estrogen receptor on the surface or HER2, so we treat it as the subtype that developed, and actually, the chance of cure is just the same for BRCA1-associated breast cancer as it would be for one that doesn’t have a BRCA.

But, the chance of getting a second breast cancer – a totally new breast cancer – would be higher unless you chose to remove both of your breasts and the bulk of your breast tissue. So, decisions like surgery – if you had a known BRCA1 mutation, we’d treat the cancer you have now aggressively and for cure, but when you talk about your surgery options, we’d say doing more aggressive surgery, like removing both of your breasts – that’s not gonna improve your chance of surviving the cancer you have now, but it will markedly reduce the chance of getting a second breast cancer.

So, you could consider that as an option for surgery – not to improve your chance of this cancer, but to reduce the chance of another breast cancer. So, your surgery decisions might be impacted by knowing your BRCA1 or 2 mutation. And then, clearly, if you had metastatic breast cancer, knowing if you had the option of a PARP inhibitor, one of the drugs in that class could be – you could have a different treatment option for drug therapy.

Katherine: 

Well, Dr. Gralow, what other factors should be taken into consideration with a treatment route?

Dr. Gralow:   

I always like to think of the treatment decision as relying on three factors, and the first relates to the tumor factor, the cancer factor.

So, we talked a lot about the biology, the estrogen receptor, the HER2, the genomic profiling. So, that’s critical, but there are two other components that we need to really strongly consider when trying to devise the right treatment regimen. One of those is patient factors, and not just the patient’s genetics, but are they pre- or post-menopausal?

What is the age? Where are they in life? Are they young with young kids? Are they working, and is that an important priority for them? Are they older and with grandchildren, and they don’t need to work? What is it that would be critical? What are the patient’s priorities here, and what are their fears, what are the things they would – what would be really important as we plan a regimen? And so, the patient factors which would be patient priorities and where they are in life right now.

And then, there’s factors related to the treatment itself, which would include not just how effective it is, but – and, this is really important when trying to decide regimens – what are the side effects of a regimen? For some patients, hair loss is a big deal, and we can put it off as long as possible – maybe choosing the first couple regimens don’t cause hair loss sometimes.

But, for other people, that doesn’t matter to them. For some, we have oral – some regimens, and that could keep them out of the infusion room, and others actually – I’ve had patients who actually like coming into the infusion room regularly so that they can review the side effects and get the reassurance provided by it. So, we’ve got different route of administration of the drugs, different side effects. If you already had, for example, a neuropathy – a numbness/tingling of fingers and toes – from treatment that you might have gotten for early-stage disease, we’d probably want to avoid drugs where that’s their major side effect in the metastatic setting and that would increase that even further.

We’ve got some drugs that cause a lot of toxicity to our GI system – nausea, vomiting, or diarrhea – and other drugs that don’t. And so, understanding what symptoms the patient already has and actually tailoring the treatment based on some of the side effects of the drug could also be done, as well as how they’re administered. So, again, patient factors, tumor factors, and then, factors related to the treatment itself all come into play when we make decisions.

Katherine:    

There have been so many advances in breast cancer research. What are you excited about in research right now?

Dr. Gralow: 

Well, every single drug that’s been approved, every single new regimen that’s been approved in breast cancer is the direct result of clinical trials, and this is a major part of my career, is to help patients get access to clinical trials and run important clinical trials that could lead to new discoveries – is this regimen better? What’s the toxicity?

Because until we have a cure for breast cancer, we need to do better, and we need to research better treatment options. So, doing trials, having access to clinical trials where you can participate, help move the science forward is key.

I think where we’re moving with breast cancer is the more we’re understanding the patient and the tumor, the more we’re realizing every single breast cancer is different, actually, and whereas when I started my training 20-plus years ago, breast cancer was breast cancer – we weren’t even using HER2 yet, we were just learning how to use estrogen receptor, and we kind of treated everything the same – now, we’re subsetting, and subsetting, and subsetting. Even in triple negative breast cancer now, which is about 18-20% of breast cancer, we’re subsetting.

Does that triple negative breast cancer have PD-L1, which is associated with being able to get immunotherapy drugs? Does it express androgen receptor? Because sometimes, even a breast cancer that doesn’t have estrogen or progesterone receptor can express the androgen receptor, like prostate cancer, and we can use some prostate cancer drugs. So, even triple negative breast cancer we’re subsetting and subsetting, and could that triple negative breast cancer be associated with a BRCA1 or 2 mutation, and then we can use the PARP inhibitors?

So, I’m actually really excited about that we’re learning more and more, and subsetting, and not treating breast cancer as one size fits all, and if we can better tailor the treatments to the patient and the tumor, that we are going to get to the point where I can tell my patients yes, we can get cures in metastatic breast cancer.

Katherine:    

For patients who may be hesitant to speak up – to advocate for themselves in the process – I’m gonna start again. For patients who may be hesitant to speak out for themselves and advocate for their own care and treatment, what advice do you have?

Dr. Gralow:   

You have a whole team who’s behind you, and I’m the MD on the team, but I’ve got a nurse practitioner, and a nurse, and a scheduler, and a social worker, and a nutritionist, and a physical therapy team, and financial counselors. I’ve got a whole team who works with me. And so, a patient might be hesitant to speak up during the actual appointment with their physician. It’s a short amount of time. I would recommend come into it with written-down questions because things go fast. You don’t get a lot of time with your doctor.

Things go fast, but don’t come in with 25 questions, either. Pick your top few that you want to get taken care of this visit because if you come in with 25 or 30, you’re gonna lose the answers to most of them. Maybe bring somebody with you who’s an advocate and a listener for you who could be taking notes, so you can process and you don’t have to write it down, or ask if you can record it. It’s really important if you’re newly diagnosed or maybe there’s a progression and you’re going on a new treatment. That’s okay too.

But, I would also say you have a whole team behind you, so sometimes, if you don’t have time or if you’re hesitant to speak up in your doctor’s visit, you can ask the nurse, or maybe you can ask the social worker for help, even. See if there’s support groups around.

Interestingly, we’ve got a peer-to-peer network where patients can request to talk to somebody else who’s matched to them by some tumor features, and their stage, and things like that. Maybe finding somebody else who’s gone through something similar, and somebody independent to talk to instead of relying on your family.

It can also be really helpful to talk to a therapist or a psychologist about your fears, and sometimes, you want to be strong for your family, strong for your children and all, but you need a safe space with somebody that you can just express your fears and your anger if that’s what’s going on, or your depression or anxiety to while you’re trying to hold a strong face for others in your family. So, I would encourage patients to look at who is the whole team and talk to the other members of the team as well, and sometimes, they can help advocate.

Also, find somebody who might be able to come to your appointments with you, somebody who will help you advocate or remind you – “Didn’t you want to ask this question?” – or be another set of ears that you can process it with afterwards.

Katherine:     

Dr. Gralow, we’ve covered a lot of useful information today for patients. Thank you so much for joining us.

Dr. Gralow:    

Thank you, Katherine.

Katherine:       

And, thank you to all of our partners. To learn more about breast cancer and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell.