The following is an interview between Dr. Chandler Park, a hematologist, oncologist, and Doximity Fellow; and Dr. Jame Abraham, a Professor of Medicine and Director of Breast Oncology Program at Cleveland Clinic. The interview has been edited for length and clarity.
Dr. Chandler Park: Dr. Abraham, congratulations on being appointed the Department Chair of the Hematology/Medical Oncology Department at Cleveland Clinic in 2019.
2019 has been one of the best years ever for innovative treatments to help our breast cancer patients. Every major breast cancer subtype (ER/PR positive, HER2 receptor positive, and Triple Negative) has had practice-changing updates in 2019.
Dr. Jame Abraham: Thank you Dr. Park. It is always a pleasure to talk to you.
Dr. Park: The first area I would like to talk about is our breast cancer patients with triple negative breast cancer. In March 2019, the FDA approved the first immunotherapy treatment regimen for our patients with breast cancer. What are your thoughts on this study?
Dr. Abraham: Dr. Park, it is a landmark study. This is the first study that showed an improvement in overall survival and progression free survival with immunotherapy in breast cancer. The benefit was limited to patients with PDL-1 (immune cells 1%) positive with the SPF 142 antibody. A seven month improvement in overall survival was seen in patients who are treated with atezolizumab. The overall survival was about 25 months. Overall, this treatment of immunotherapy with nab-paclitaxel was well tolerated with no safety signals.
Dr. Park: Would you consider immunotherapy with nab-paclitaxel for all first line triple negative metastatic breast cancer patients (i.e. with PDL-1 >1%, etc)?
Dr. Abraham: My treatment algorithm for metastatic triple negative patients now is as follows:
- All patients will be tested for PDL-1 and if they are positive, they will be treated with nabpaclitaxel and atezolizumab. This is about 40% of all triple negative patients.
- All patients will be tested for BRCA germline testing. If they are positive for BRCA, they will receive a PARP inhibitor. This will be about 10% of patients.
- All patients will undergo next generation sequencing (NGS). This will allow us to select the patients for targeted therapy on or off clinical trials.
- Rest may be considered for clinical trials or standard chemotherapy.
Dr. Park: It is interesting that you mention NGS for triple negative breast cancer patients. Recently, we have had many more second opinions from oncologists with patients having triple negative breast cancer patients in my national molecular tumor board meetings.
Now in terms of the early stage triple negative breast cancers. We had some exciting news at the 2019 ESMO meeting in Barcelona, Spain.
I found it very interesting that "high risk" patients in the study such as Stage 3 and patients with PD-L1 positive breast cancers (stage 2 or stage 3) had a much higher pathologic complete response (pCR). What did you think about this practice-changing study?
Dr. Abraham: Immunotherapy is evolving as a new treatment option for triple negative, locally-advanced breast cancer. The KEYNOTE-522 is a potentially practice-changing study. In this trial, patients with triple negative, stage 2, and 3 were treated with carboplatin, paclitaxel, and anthracycline/cyclophoshamide regimen with pembrolizumab, and had a 65% pathological complete response compared to 51% for non-immunotherapy arm. That is really an impressive complete pathological response. In the first pre-planned interim analysis, there was an improvement in event-free survival for patients who received pembrolizumab-containing regimen. I think this will change the treatment paradigm in neoadjuvant triple negative breast cancer.
Dr. Park: I was in New York with the Doximity team when that landmark study first came out in October 2019. I was very excited about the game-changing potential for this neoadjuvant immunotherapy regimen for our patients with triple negative breast cancer. Dr. Nate Gross noticed my enthusiasm and commented he could tell I wished I was in Barcelona (for the 2019 ESMO meeting) so I could talk to the lead authors of that study.
Now, let’s talk about our patients with BRCA 1/2 mutated metastatic breast cancer patients in 2019. PARP inhibitors such as Olaparib (OlympiAD trial) and Talazoparib (EMBRACA trial) are now considered the standard of care vs. chemotherapy for our metastatic BRCA mutated cancer patients. How do you manage triple negative breast cancer patients with BRCA 1/2 mutations?
Dr. Abraham: All patients with triple negative metastatic breast cancer will undergo germline testing and if they are positive for BRCA, I will treat them with a PARP inhibitor. I will not consider them for chemo upfront. The progression-free survival was better in patients who received PARP inhibitors, and most importantly, the quality of life was much better in patients who were treated with a PARP inhibitor.
Dr. Park: Now on to our ER/PR positive breast cancer patients. For our metastatic ER/PR positive breast cancer patients we had a new FDA approved regimen that selects out patients with the PIK3CA mutation.
What did you think about this practice changing second line treatment after CDK 4/6 (palbociclib, ribociclib, or abemaciclib) with an aromatase Inhibitor?
Also, how do you treat the hyperglycemia that occurs with our patients based on this treatment?
Dr. Abraham: Dr. Park, you are right, it is a practice-changing study. I test all ER positive patients for PI3K mutation by next generation sequencing or any other method. If they have PI3K mutation, and they progress on an aromatase inhibitor or aromatase inhibitor plus CDK 4/6 inhibitor, then they will receive alpelisib.
Hyperglycemia is one of the most common side effects. I check the blood counts and intervene promptly with metformin as the trial recommended and explained in the package insert.
Dr. Park: How about for our early stage ER/PR breast cancer patients? Based on the NSABP B42 study and a recent update at the 2019 San Antonio Breast Cancer Symposium (SABCS), what are your thoughts on aromatase inhibitor for five years vs 10 years?
Dr. Abraham: NSABP B42 study showed that there is an improvement in breast cancer free interval for patients who received extended adjuvant therapy with an AI. Disease free survival was 76% in the letrozole group versus 71% for the placebo group p-value of 0.01.
Dr. Park: For which patients would you consider 10 years of treatment?
Dr. Abraham: So I will recommend extended adjuvant therapy for clinically high risk patients who are tolerating the AI well and have well-managed bone health.
In very low risk patients, those who have joint pain or with significant osteoporosis, I will stop after five years. This will be a shared decision making with the patient.
Dr. Park: Moving on to the HER2-positive metastatic breast cancer space. SABCS had a couple practice-changing studies. Thank you for your outstanding update. I found the HER2CLIMB to be very fascinating because of the brain metastases subgroup. I can see this regimen initially moving in the third line setting after TDM-1/Kadcyla (currently second line treatment for metastatic HER2 breast cancer patients).
Moreover, I am very excited about the potential for this regimen for patients with leptomeningeal HER2 metastatic breast cancer in the future. What did you think about this study?
Dr. Abraham: The data with Tucatinib is very exciting. As you mentioned, its impact on brain metastases has tremendous implications. There is an improvement in disease-free survival and overall survival in these heavily treated patients. This is clearly a practice-changing study. The treatment is well-tolerated. I am sure more studies will be designed to move this drug to earlier lines of therapy or even in the adjuvant setting.
Dr. Park: The other study that I found very interesting was the trastuzumab derextecan (DS 8201) in previously treated HER2 positive breast cancer. What did you think of this study?
Dr. Abraham: This will definitely change practice. As you know, the FDA recently approved DS 8201 for treatment of HER2 positive metastatic breast cancer. In heavily-treated patients, who were exposed to herceptin/pertuzumab and TDM-1, DS 8201 improved response rate and survival. Clinicians need to be cognizant about pulmonary toxicity, its early diagnosis, and management.
Dr. Park: Yes, I agree about the pulmonary toxicity. Up to 13% of the patients treated with the FDA approved DS 8201 medication developed interstitial lung disease. Dr. Ian Krop (one of the lead investigators of this study) recommended getting a high resolution CT chest, pulmonary function test, and a pulmonologist consult for patients with new onset dyspnea while on this medication. If there is any concern, Dr. Krop recommended giving a steroid dose for interstitial lung disease right away.
Our Doximity team really appreciate your expert analysis of the practice changing updates in 2019. Do you have any last thoughts about the 2019 Breast Cancer update?
Dr. Abraham: This is one of the most exciting San Antonio meetings in recent years, where several practice-changing studies were discussed as mentioned above and as I mentioned in my write up which was published previously.
I thank the patients and advocates for continuing to inspire us to work hard in finding better treatments for breast cancer.
Dr. Park: Thank you very much Dr. Abraham. Looking forward to seeing you again in 2020.
Dr. Chandler Park is a practicing hematologist and medical oncologist. He’s trained at Cleveland Clinic, Indiana University, West Virginia University, and University of Pittsburgh. During his training, he served on various academic committees, including medical school admissions, residency selection, and residency review. He’s a clinical professor at the University of Kentucky College of Medicine, faculty on the American Society of Clinical Oncology (ASCO) CME committee, and a 2019-2020 Doximity Conference Fellow.
Illustration by April Brust