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De-escalation of Therapy in HER2+ Breast Cancer Patients

We are seeing higher efforts at de-escalation in HER2+ breast cancer. For example, there was recent approval of TDM1 for patients after neoadjuvant therapy with ataxin-based anti-HER2 therapy that still have residual cancer in the breast. Even if minimal, those patients do better if treated with TDM1 for a year compared to patients that continue Herceptin for a year.

Carlos Arteaga, MD
Past President- American Association for Cancer Research (AACR)
The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology
Professor and Director
Simmons Comprehensive Cancer Center
UT-Southwestern Medical School
Dallas, TX

I think that’s one example of de-escalation. At first, investigators were testing anti-HER2 therapy pertuzumab with endocrine therapy and ER+ breast cancer that is also HER2+ in the absence of chemotherapy. Those studies will take longer to see the outcomes where chemotherapy is obviated. In local therapy, I think again, there is de-escalation in terms of avoiding radiation therapy in patients with DCIS or a very small stage one, low risk of recurrence ER+ breast cancer. I am less of an expert in that area, but again, that is another space where we are probably overtreating too many patients with too much therapy for too long.

De-escalation – or at least the clinical investigation of de-escalation – could make sense if it provides better tolerance and less side effects; not at the risk of a worse outcome, though.

Understanding the Mechanism of Resistance

Regarding the investigation of resistance or tumor escape, I think the area where there’s a higher level of activity is in ER+ breast cancer. Perhaps as a result of the efficacy of CDK46 inhibitors – which we know from first line metastatic recurrence – the addition of a CDK4 inhibitor to an AI (aromatase inhibitor) can give patients a progression for survival median of close to 2 years. To me, that’s impressive. But on the other hand, all those tumors eventually progress. They probably are having to take a major evolutionary step to bypass what is a very effective treatment. And there I think we’re starting to learn about some mechanisms of resistance.

For example, RB mutations in tumors that progressed after CDK4 inhibitors, though that’s only a minority. I am sure there is a whole suite of genomic and expression alterations that are associated, maybe causally, to that resistance. We have the tools to investigate that, so the other reason to do that is because a number of those patients may have a targeted therapy that can be offered to them. They don’t have that many options after they progress on CDK46 inhibitors. They can be treated with tamoxifen and with a number of other options, but none of them are going to be curative. So that is a space where we have the tools to re-interrogate those tumors and look at why they are progressing. How have they changed from the original tumor? We are going to hear a lot about that. Some of the insights are coming from extracting plasma from tumors, ctDNA. Again, that doesn’t mean we should not biopsy those metastatic recurrences when it can be done safely. But in those that can’t be done safely, sometimes analysis of a tumor’s DNA in the plasma can give us some insight.

Breast Cancer Study Updates

The NALA study, looking at neratinib plus capecitabine versus lapatinib plus capecitabine, suggests that we may have a drug that is superior to lapatinib and the control of brain metastases in patients with HER2+ breast cancer.  

The SOPHIA study – margetuximab plus chemotherapy versus trastuzumab (Herceptin) plus capecitabine in patients with HER2+ metastatic breast cancer after prior anti–HER2-targeted therapies – is a study that uses an antibody that may do something that Herceptin doesn’t do: to potentially control tumors that have lower than HER2 overexpression. That is important because patients that do not have HER2 overexpression or amplification that’s defined are not patients that we would expect to benefit from trastuzumab. Perhaps the best demonstration of that is the NSABP-B41 study which compared, again, Herceptin versus no Herceptin in HER2+ patients and in tumors that were below that strict definition of HER2 overexpression or amplification. So there’s a possibility that those tumors, which basically are now HER2 negative, may have a drug that can work against them. I think it’s important.

Addressing and Understanding Gaps in Breast Cancer Treatment

We have the tools now to study these tumors, against which we have very effective therapy but in the metastatic setting, we cannot cure. And remember that some patients with early breast cancer still recur with metastatic disease. A minority, but some do.

So, I think that as an investigator and a provider, I remind myself that we do have the tools to study those cancers: cancers that recur late, or recur, or that are in the metastatic setting and responding to some of these treatments are continuously evolving.

Breast cancer that is happening now but was diagnosed 7, 8, 9, 10 years ago may not look the same. It may harbor some vulnerabilities that can be discovered. That can be interrogated with current genomic tools and may identify a treatment option for those patients today. I think we are not doing enough of that interrogation for a number of reasons. One is the perception of cost, another one is the perception from providers that those things really don’t help. They may not help enough today, but one day they will and become standard of care so we need to start now. I think the idea that tumors evolve, that tumors late are not the same as upfront, and that information we have from many years ago may not be relevant anymore to that cancer is something we probably need to remind ourselves every day when we see patients with advanced disease.


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