The Oncologist: The late-breaking clinical trials session featured the phase III OlympiA trial of adjuvant olaparib versus placebo in patients with high-risk, human epidermal growth factor receptor 2 (HER2)-negative, BRCA1/2 mutation-positive early breast cancer. What are your thoughts on this trial?
Dr. Kaklamani: The results were impressive. In this high-risk population—patients with early-stage HER2-negative breast cancer and germline BRCA1/2 mutations—results showed a significant improvement in disease-free survival with adjuvant olaparib. The side effect profile was minimal; this is a well-tolerated medication. I expect these results to be practice changing. I'm already screening patients for germline BRCA1/2 mutations to put them on olaparib if they qualify for it based on the OlympiA trial.
The Oncologist: Do you think these results will encourage genetic testing?
Dr. Kaklamani: I hope so. Genetic testing is extremely important. In the metastatic setting, we should be screening every patient with HER2-negative breast cancer for germline BRCA1/2 mutations. In the adjuvant setting, we should probably be doing something similar. In 2019, the American Society of Breast Surgeons published guidelines suggesting that we should be screening every single breast cancer patient. We haven't adopted that widely yet, but based on the OlympiA trial, I think the high-risk patients should be screened.
The Oncologist: The oral abstracts session for metastatic breast cancer featured several updates from phase III trials of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hormone receptor (HR)-positive, HER2-negative disease. What are the key take-home messages from these trials?
Dr. Kaklamani: With the latest trial updates from PALOMA-3, MONALEESA-3, and DAWNA-1, we see what we expected to see: consistent benefits in terms of overall survival (palbociclib, ribociclib) and progression-free survival (dalpiciclib) with CDK4/6 inhibitors in the metastatic setting. The degree of overall survival benefit, with hazard ratios in the range of 0.64–0.71, is clinically meaningful to our patients. Also, these are well tolerated medications, with no major safety signals.
Next is the question of sequencing. People are asking, “do I need to use this first-line or second-line?” We don't yet have the data to answer. That said, I think it's extremely important for people to recognize that we have to use a CDK4/6 inhibitor at some point during metastatic disease. I personally use CKD4/6 inhibitors in the first-line setting, unless there's a contraindication.
The Oncologist: In addition to overall survival, the MONALEESA-3 trial included the endpoint of second PFS (PFS2), defined as the time from randomization to disease progression or death while patients were receiving subsequent cancer therapy. What does that endpoint mean clinically?
Dr. Kaklamani: Basically, the PFS2 endpoint shows us that there is an ongoing benefit beyond disease progression. In the past, there has been a concern in patients receiving a CDK4/6 inhibitor that once we stopped the CDK4/6 inhibitor, there was going to be a rebound effect, and that that rebound effect would cause more aggressive disease. We don't have any data to suggest that is the case.
The Oncologist: An update from the SOLAR-1 trial in patients with PIK3CA-mutated, HR-positive, HER2-negative MBC who achieved disease control with alpelisib plus fulvestrant showed a potential for long-term benefit across patient subgroups. Is this what you are seeing in clinical practice?
Dr. Kaklamani: Yes, more than 70% of patients achieved long-term disease control on the SOLAR-1 trial. This is impressive, and this is what we see in practice as well; a large number of patients with PIK3CA mutations have a long disease-free interval with alpelisib.
The Oncologist: Another theme from the oral abstract session involved mechanisms of resistance to CDK4/6 inhibitors and novel treatment options in the post-CDK4/6 inhibitor setting. Where do you think this area of research is going?
Dr. Kaklamani: Most of the oncology trials right now are drug A versus drug B, or drug combination A versus drug combination B. We don't have drug A followed by drug B versus drug B followed by drug A. Those trials would have a lot of variables: the dropout rate would be high, and the time to complete the trial would be longer. As a result, head-to-head trials have been mostly prohibited in the past.
Lacking head-to-head data, typically what we do in practice is use our most effective drug first, and then we go to our second-most effective and third-most effective drug and so forth. In the metastatic ER-positive setting, we do the same thing. We start with a first-line CDK4/6 inhibitor in most cases. Then if a patient is PIK3CA-mutation positive, we will use alpelisib, and if not, we may use everolimus. At the end of the day, we don't have the data to guide these sequencing decisions, and I don't think we ever will.
I take the following approach. If a drug is not very toxic—and CDK4/6 inhibitors are not very toxic—I don't see a major reason why we should withhold it from our first-line patients, because some of these first-line patients may not ever receive a second-line therapy, even though that's likely a small number. Overall, I think it's important to offer our most effective drug first-line, and then move on to our second- and third-line choices.
The Oncologist: In several presentations, researchers shared observational data describing the effects of the COVID-19 pandemic on breast cancer care, with some evidence of diagnostic delays. What has your experience been?
Dr. Kaklamani: Yes, we experienced that as well. Patients were either too concerned to come in for mammograms or mammography centers were closed for a few months last year. Patients went on with their lives. Even when centers reopened, some patients were still not comfortable coming in and getting a mammogram. This did cause a delay in diagnosis. We don't know how clinically relevant that will be—we are going to have to wait a long time to figure this out—but there definitely was delay in diagnosis.
As far as patients receiving chemotherapy for breast cancer, we did not see any detrimental effects in terms of risk of COVID-19 infection. We didn't have many patients like that, but we didn't see many detrimental effects. Having said that, we're always encouraging our patients to get vaccinated. We still don't have a lot of data, and we don't want to put patients at risk when they don't have to be at risk.
In our own research, we are currently looking at the interaction between chemotherapy and post-vaccination antibody levels in patients with cancer. We know that it is important that patients get vaccinated prior to receiving any treatment, so that the vaccine is effective and also so that they don't run into any issues with treatment delays. In our facility, if a patient has COVID-19, we have to wait at least 10 days before we treat them for their safety and also for the safety of other patients in the treatment room. It is important to keep that in mind as something that could potentially delay treatment, and we don't know how this delay might affect their long-term prognosis.
Author notes
Highlights from the 2021 ASCO Annual Meeting
