Abandoning Old Paradigms: Embracing Molecular Targeting in Breast Cancer Treatments

Published: Thursday, Apr 26, 2012
Dr. Pat Whitworth, Jr

A Conversation With Pat Whitworth, Jr, MD

Pat Whitworth, Jr, MD, is the director of the Nashville Breast Center and a clinical associate professor of surgery at Vanderbilt University in Tennessee. He is currently involved in clinical breast cancer trials that evaluate pretreatment and on-treatment molecular profiles to target neoadjuvant regimens for breast cancer.

Our editors met with Whitworth at the Miami Breast Cancer Conference to discuss how breast cancer treatment has evolved from a “kitchen sink” approach with chemotherapy to a new paradigm that targets chemosensitivity.

OBTN: Can you describe how molecular profiling has affected how you treat patients with breast cancer in your practice?

Dr Whitworth, Jr: A lot of things have happened over the course of the past 10 to 20 years. There was a period of time when we had to debate about whether patients who were node-negative and estrogen receptor (ER)-positive even needed tamoxifen or endocrine therapy. The NSABP B-14 study showed us that indeed there was a benefit for those patients. That same question came up later about chemotherapy: Would chemotherapy improve the outcomes for node-negative and ER-positive patients? Frankly, we were excited to learn that we could improve outcomes for those patients with systemic adjuvant chemotherapy. But there’s a curse with the blessing. At that time, we weren’t able to target that treatment. So, for many years, we grew up giving chemotherapy to all of those patients, primarily based on their level of risk for recurrence. We didn’t use that same criterion for treatment with tamoxifen or endocrine therapy. If a patient was ER-positive and had any risk, we treated them with endocrine therapy. If the patient was ER-negative and high-risk, we didn’t add endocrine therapy because we knew it was targeted to ER-positive patients.

The same thing was true with HER2. We learned in 2005 that Herceptin could really improve outcomes in patients who expressed HER2 and was beneficial even in nodenegative patients. We didn’t generalize that to everybody (ie, patients who didn’t have HER2 overexpression); we were targeting that treatment, but we weren’t able to target chemotherapy to those patients who had chemosensitive tumors. The emotional history that we had with treating these patients was really based on their risk for recurrence. If there was a high risk for recurrence, we gave them chemotherapy. It was just all about risk. That’s why node status was critically important in cases with an apparently low-risk primary tumor; positive lymph node status would be critical in helping us make treatment decisions.

So, endocrine treatment and anti-HER2 treatment are based on targeted biological sensitivity; but chemotherapy is just based on overall risk, not chemosensitivity?

In 2006, we learned that we could in fact target chemosensitivity. The analysis of the B20 study using the Oncotype DX 21-gene recurrence score showed that patients who had a low score had no benefit whatsoever, and patients who had a high score had a lot of benefit from chemotherapy. That was a huge change in our understanding. However, translating that change in understanding to a change in practice is a different matter because we grew up with a very strong emotional attachment to this notion of a “kitchen sink” approach for someone at high risk. If we saw a patient with a lot of positive nodes or a high-risk tumor, we were conditioned to think, “This patient needs chemotherapy. Her risk is high. We know chemotherapy helps with high risk.” And that’s what we did—treated the patient with chemotherapy. Even though we understood targeting with ER and HER2, it still was very difficult to let go of that notion and embrace individualized chemosensitivity targeting.

There is a difference between understanding the new information about targeting chemotherapy only to patients who have chemosensitivity versus applying that in practice. When we began to understand that chemosensitivity can be measured and can be identified, and absence of chemosensitivity can be identified with a low recurrence score, it was still difficult not to use the approach that we have always used to treat the patient with everything we’ve got. I think the fact that we could understand targeting based on ER status and based on HER2 status enabled us to abandon the old paradigm based on risk, and move to a new paradigm based on targeting real chemosensitivity.

Would you say that most oncologists have overcome this hurdle and have started offering treatments other than chemotherapy?

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Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
Community Practice Connections: Oncology Best Practice™ Targeting Cell Cycle Progression: The Latest Advances on CDK4/6 Inhibition in Metastatic Breast CancerOct 31, 20181.0
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