Around the Practice: ctDNA in Treatment Decisions and Monitoring - Episode 7

Scenario 2: Use of ctDNA to Monitor High-Risk TNBC

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Moving on to the second patient scenario, panelists elucidate the value of ctDNA in patients with triple-negative breast cancer.


John H. Strickler, MD:I’d like to discuss a breast cancer case, and I’ll go ahead and provide the patient scenario and rely on the two of you to provide commentary here. This is a 43-year-old woman who presented after finding a mass in her left breast on self-examination. Mammography showed a 4.4-cm mass in the left outer quadrant of her left breast. CT scan of the chest, abdomen, and pelvis demonstrated the primary mass in the left breast and no other suspicious sites. Breast biopsy demonstrated ductal carcinoma in situ with pathology showing it to be ER [estrogen receptor] negative, PR [progesterone receptor] negative, and HER2 [human epidermal growth factor receptor 2] negative as well as BRCA wild type. The patient opted for breast-conserving surgery and received neoadjuvant chemotherapy plus pembrolizumab. After neoadjuvant therapy, the patient underwent breast-conserving surgery. Surgical pathology revealed T2N0 disease. She then received adjuvant pembrolizumab. Dr Bardia, what are your impressions of this scenario?

Aditya Bardia, MD, MPH: This is a common scenario we see in the clinic. The KEYNOTE-522 trial [NCT03036488] demonstrated that the addition of immunotherapy to standard neoadjuvant chemotherapy for patients with stage II or stage III triple-negative breast cancer is associated with not only improvement in pathological complete response rate but also improvement in event-free survival. So it’s now an FDA-recommended therapy for patients with triple-negative breast cancer. This patient received the right therapy, which would be chemotherapy plus neoadjuvant immunotherapy, but you don’t have 100% pCR [pathological complete response]. There is a subset of patients who have residual disease, as seen with this patient. As for the KEYNOTE-522 trial, you discontinue the adjuvant immunotherapy in patients with residual disease. It was this subgroup where you see a separation of the curves between no therapy vs adjuvant immunotherapy. Just because this patient had residual disease after neoadjuvant chemotherapy plus immunotherapy does not mean you should use adjuvant immunotherapy. If anything, that’s the setting where it shouldn’t be used, so I would recommend the use of adjuvant pembrolizumab for this patient. This is also a subgroup at higher risk of recurrence. Multiple studies, including a recent meta-analysis, demonstrated that patients who have residual disease have a higher risk of recurrence compared with patients with pathological complete response. [Although] adjuvant pembrolizumab is the current standard of care, this is a setting where there are ongoing studies to see whether we can further improve the outcome of patients who have residual disease with newer therapies, antibody-drug conjugates, and combination therapy. If there’s a clinical trial, I would strongly recommend consideration of a clinical trial for this patient who has residual disease.

John H. Strickler, MD:Dr Dietrich, what is your approach to monitoring a patient with triple-negative breast cancer receiving pembrolizumab?

Martin Dietrich, MD, PhD: To recap, it is obviously a high-risk disease with very limited chemotherapy sensitivity on pembrolizumab. One of the questions here, and this has not really been answered in the literature: The patient is on adjuvant pembrolizumab, so do they require regular clinical monitoring? The other question is, would this patient be a candidate for adjuvant chemotherapy as well? We don’t have that in combination, but it would be a reasonable discussion to think about adjuvant capecitabine or olaparib if the patient had a BRCA mutation. I always get suspicious when I see triple-negative breast cancer in a 43-year-old. I would like to look not only at the pathology but also the assay that was utilized to look at BRCA1 and BRCA2. When it comes to monitoring, there’s very little being done. Most patients are typically being analyzed clinically for adverse effects of therapy. They’re getting labs, but there’s limited information regarding the monitoring techniques by distant imaging or tumor markers. We do the regular local mammograms at an increased frequency. Clinical examinations I typically do every 3 months. Mammograms are typically on the affected side every 6 months, but it’s difficult to monitor disease that has been surgically resected. We don’t have some of the monitoring challenges we see in a metastatic setting; pseudoprogression here [is] an issue in the neoadjuvant setting. Although in the combination of chemotherapy plus immunotherapy, pseudoprogression is a less common phenomenon. In Florida, the pseudoprogression in our skin cancer patients [happens] frequently, and it’s more of a real-time measurement. There is some mitigation of inflammatory response when given together with chemotherapy.

That’s one of the biggest questions. How do you monitor these patients and how would you be able to influence their care? This might be a patient at [a] high risk of disease where in a compromise, if you’re not exposing a patient to radiation or other imaging modalities, MRD [minimal residual disease] technologies might be very helpful. I would also talk to the patient about the surrogate nature of neoadjuvant therapy. This is the reason why we’ve moved most of our chemotherapy into the neoadjuvant space to document chemosensitivity as a prognostic marker. Again, the conundrum here is whether we can translate the clearly prognostic nature of the assay into a predictive intervention, and this is where clinical trials are key to see whether an augmentation of additional therapy may be helpful. Conversely, and I think Dr Bardia already alluded to this, for patients [who] would have had a much better response or pathological complete response, whether a corroborating MRD negativity would be able to help us deescalate therapy and save the additional year of immunotherapy in an attempt to not only avoid unnecessary toxicities but also attempt to save costs. There’s a dimension of MRD monitoring that is not the primary focus of our investigation but has its use in a setting where we use immunotherapy indiscriminately.

Transcript edited for clarity.