Road to a Cure - Dr. Sara Hurvitz
This is the second stop in our series that will release a new interview on the concept of a CURE every Monday until the beginning of the San Antonio Breast Cancer Symposium in early December. What has struck me the most about this series is that each of these special interviews can feel like an intimate conversation with your smartest friend who also happens to be an oncologist researcher.
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That's exactly what we try to do here at the podcast and this interview will not disappoint. Co-hosts Victoria Goldberg and Kate Pfitzer sit down with the Medical Director of the Clinical Researcher Unit of the Jonsson Comprehensive Cancer Center and the Director of the Breast Cancer Clinical Trials Program at UCLA, Dr. Sara Hurvitz.
Dr. Hurvitz has won numerous awards over the past few years, among them the Marni Levine Memorial Breast Cancer Research Award 2008 through 2015. She has an active clinical practice specializing in the treatment of women with breast cancer. She is involved in designing, implementing and leading multiple national and international clinical trials testing new targeted therapies and also leads the preclinical evaluation of novel breast cancer targets in the Translation Oncology Research Laboratory at UCLA.
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This special series, Road to a Cure, has been produced by Victoria Goldberg, Paula Jayne, Ellen Landsberger, and Kate Pfitzer.
Join us as we make over 10 stops all over the U.S. (with one stop in Europe) on this Road to a Cure - every Monday until the start of the San Antonio Breast Cancer Symposium in December!
Mentioned in this Episode
HER2+
Clinical Study: DESTINY-Breast03 [NCT03529110]
DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03]
ESMO 2021: DESTINY-Breast03 Trial of T-DXd Versus T-DM1 in HER2-Positive Breast Cancer
FDA Grants Breakthrough Therapy Designation to Trastuzumab Deruxtecan for HER2+ mBC
Novel HER2-Targeted Therapies Pose Sequencing Challenges
Low HER2
Excerpt from the interview
“We know that HER2 is expressed at some level on many, many cells in our body that are normal heart cells and bone marrow cells. And it's an normal gene in our body. And it's expressed normally. It’s important in the development of the fetuses, , heart cardiac system. It is present at some level on most cells, if not all in our body. Breast cancers can have varying levels of expression. The only breast cancers that benefits from the drug Herceptin or trastuzumab are those that have clear over-expression 3+ expression of that antigen HER2 on the cell surface in normal cells. You may have 20,000 receptors per cell in a normal cell, a HER2+ 3+ cancer cell it's on the order of 2 million receptors.
So that is logarithmic difference, there is a drug that was FDA approved almost two years ago.now called trust trastuzemab deruxtecan or Tdx-D, which is an antibody. It’s Herceptin, linked to chemo, high number of chemo molecules per antibody, and it delivers the chemo to the HER2 on cancer cells.
This is a unique drug because once it's taken up into the HER2 positive cancer cell and the chemo is released, the chemo is membrane permeable. It's allowed to leave the cancer cell, which is different from another antibody drug conjugate TDM-1, where it can't leave the cancer cell. And when it leaves that cancer cell, it can kill nearby cancer cells that have no HER2 expression or low HER2 expression.
So this is called the bystander effect of Tdx-D and they reported that some patients with low her two expression, meaning there's a little bit or a mild amount of her two on the cancer cell, but patient doesn't have a HER2+ breast cancer. Around 40% of patients, treated with this drug withHER2 low breast cancer, had their disease shrink or disappear.
So those were very intriguing. It's not that HER2 low breast cancer is a subtype. We don't have any evidence that it behaves any differently from HER2 zero breast cancer. It is just that the way this drug works, it might be able to deliver this chemo close enough to the tumor that it has activity.
And there are other drugs like Tdx-D that are being developed that similarly release the payload near HER2, and may have anti-tumor activity. The downside of having a drug like this, that isn't specific to HER2 over-expressing is you're getting chemo released around the cancer cell, not in it directly.
And you may have more toxicity. You can have low white counts, you can have diarrhea or nausea or hair thinning, other toxicities that you don't see when it’s really targeted. So more data is going to be coming out in that drug. If it shown to be really effective in HER2 low, based on the phase three trial, it may be available to our patients, but there are ongoing studies now that are enrolling patients that are classified as HER2 low.
The other thing would just mention. If you get your tumor tested at one lab on day one and it's HER2 zero, you could have it re biopsied and tested in another lab and they'll call it HER2 one. Plus the high level of HER2 expression varies, and different labs may interpret her two totally differently.
It's just, pathologists aren’t good enough at being completely consistent each time. So if you want entry to a trial and you're HER2 0, you could always retest the tumor and see, usually there is variations from time to time. “
Clinical Trials
DESTINY-Breast06[NCT04494425] trial is a phase III trial for people diagnosed with metastatic hormone-receptor-positive breast cancer with low HER2 levels that has been previously treated with at least two hormonal therapy medicines.
In this study, HER2-low breast cancer means the cancer has a score of 1+ or 2+ on an immunohistochemistry (IHC) HER test and/or a negative result on a in situ hybridization (ISH) HER2 test.
HER2 Mutations ERBB2
Excerpt from the interview
“There's a difference in gene amplification and gene mutation. So remember back to high school or college biology, everybody gets a set of genes from mom and a set of genes from dad. We hav 23 chromosomes from mom, 23 from dad. And we have a gene from mom and a gene from dad for everything. So two copies. So what happens sometimes that one of the genes in the tumor instead of having two copies, the cell makes way too many copies of that gene and that's called amplification. And then the gene gets transcribed to RNA and then the RNA is read and translated into a protein that's expressed.
So when you have amplification of the HER2 gene, you have more than two copies, you've got sometimes 10-20 different copies of HER2. And that makes the cell crank out that HER2 protein, which is then expressed on the cell. That type of breast cancer was first identified in 1987 by my boss Dr. Dennis Slamon as being associated with the worst outcome. And that's known as HER2+ breast cancer. And it means the gene was amplified and the proteins overexpressed, contrast that to HER2 mutation. I would say between 15 and 20% of breast cancer isHER2+. Now a mutation in a gene is when there's something about the gene that's funky. There aren’t too many copies. It's just broken. There is a problem with the gene itself.
So the protein that's generated from that faulty gene is funky. And when there's a HER2 mutation, it causes a funny, HER2 protein and that HER2 protein can turn itself on. It gets activated on its own. It's called constitutively activated. So its engine is always running. There is no off switch and that is rare in breast cancer that only occurs in probably less than 3% of all breast cancer.
It's been more associated with invasive lobular breast cancer and later line. In that type of breast cancer, we don't have good evidence that drugs like. Herceptin or Perjeta that target the outside of the protein are really effective, but there are drugs that get into the inside of the receptor. There’re pills like neratinib that can block the inside of the receptor.
And there is some really promising early evidence that that's an effective strategy. I actually have just put a patient on this trial called SUMMIT, looking at this. And for the first time tumor markers are plummeting with this treatment because we discovered there was a HER2 mutation.”
Clinical Trials
SUMMIT (NCT01953926) is a phase II ‘basket' study investigating the use of the irreversible pan-HER tyrosine kinase inhibitor neratinib, in combination with the estrogen degrader fulvestrant, for the treatment of patients with advanced hormone-positive breast cancers harboring ERBB2 mutations.
ER+
Excerpt from the interview
“At ESMO 2021 MONALEESA-2 was big news.
It was overshadowed by the Tdx-D data, but this study looking at CDK4/6 inhibitor Ribociclib is the first clinical trial of a CDK4/6 inhibitor in the first-line setting, combined with an aromatase inhibitor that shows an improved overall survival with Ribociclib. The median overall survival from this study was over 60 months.
There was more than a one year improvement by adding Ribociclib. So patients live onaverage a year longer by going on Ribociclib in the frontline setting, so it's the first study of a CDK4/6 that has met that endpoint in that particular combination. And I think it's great data and it is moving the needle forward.”
ESMO 2021 - MONALEESA-2: RIBOCICLIB EXTENDS OS ON HR-POSITIVE/HER2-NEGATIVE ADVANCED BREAST CANCER
Clinical Trials
MONALEESA-2
Efficacy—KISQALI + AI in Premenopausal
At the ESMO Congress 2021, OS data from the MONALEESA-2 trial (LBA17_PR) were presented. The combination of ribociclib plus letrozole showed a significant OS benefit versus placebo plus letrozole (median 63.9 months versus 51.4 months, respectively; hazard ratio 0.76; 95% confidence interval 0.63–0.93; p=0.004) and met the boundary of statistical significance. This is the first trial in HR-positive/HER2-negative MBC to demonstrate an impressive median OS exceeding 5 years. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% for placebo.
As such, the MONALEESA-2 trial is the first to demonstrate a statistically significant and clinically meaningful OS benefit with the combination of a CDK4/6 inhibitor (i.e. ribociclib) plus an AI as first-line treatment in postmenopausal patients with endocrine-sensitive HR-positive/HER2-negative ABC (Ann Oncol 2018;29:1541-1547).
Mentioned in this Series
The Future of Metastatic Breast Cancer Treatment Is Bright (HealthCentral, 2020) Simple summary of research updates / reasons for hope, by subtype
Sledge Jr. (2016) Curing Metastatic Breast Cancer
Susan G. Komen Breast Cancer Statistics
