Q & A With A Community Oncologist: Denise A. Yardley, MD

Denise A. Yardley, MD

Denise A. Yardley, MD

Q: On what basis do you choose from the available neoadjuvant treatments for a patient with triple-negative breast cancer?

Q: How do you make that decision about which schedule to use for patients with TNBC?

Q: What is the role of platinum agents and non-taxane microtubule inhibitors in TNBC?

A: Triple-negative breast cancer (TNBC), while it accounts for only 15% to 20% of breast cancers in the US, does account for a disproportionate share of the morbidity and mortality due to its aggressive behavior, higher incidence in younger women, and lack of effective targeted therapies. Based on the fact that these are very high-grade lesions, and they express a basal-like phenotype, when you evaluate them by gene microarray expressions, these are tumors for which I typically use the most active agents in breast cancer. This would typically involve a combination chemotherapy program that usually incorporates administration of anthracycline and taxanes either concurrently or sequentially to offer the chance of having a higher pCR rate at the time of surgery. There are a variety of schedules as well; some are dose dense; some involve a weekly schedule. But I think incorporating the 2 groups of active agents with the anthracyclines and taxanes has been shown to yield the best responses at the time of surgery.A: I would say considerations include the physiologic age of the patient; their other comorbid conditions; and whether a dosedense schedule, requiring a return visit to receive growth-factor support the next day, is feasible. A patient receiving a concurrent schedule would need a lot of stamina to be able to undergo the chemotherapy.A: I think we have a lot of data that support the role of the platinum agents as a single agent in some patients with aggressive triple-negative disease or BRCA-like disease. The use of platinum chemotherapy is really based on similarities of the BRCAassociated breast cancers and the sporadic TNBCs, in addition to the single-agent activity of the platinums. There is great interest now in adding these platinum analogs to our neoadjuvant chemotherapies. Most recently, 2 trials were presented: the CALGB 40603 by Sikov and colleagues,¹and then our European colleagues with GeparSixto evaluated a weekly carboplatin schedule.²Both of these studies suggested that the addition of neoadjuvant carboplatin to treatment significantly increased pCR rate in this setting.

There is still no defined role for a biologic or targeted agent in the preoperative setting despite knowledge of a plethora of these regulated pathways, but it does seem that the platinums have emerged as adding some benefit. We know these platinum salts bind directly to the DNA, and they result in this formation of DNA platinum adducts that crosslink and impair cell division.

The question remains as to whether platinums have an impact as a single agent; they resulted in an excellent pathologic response when added to a chemotherapy program with a taxane at the time of surgery, but we still do not know whether they impact overall disease-free survival and overall survival (OS)—these data are not yet mature. But use of platinums does seem to increase the eradication of disease at the time of surgery. However, toxicity is also increased, and so some patients certainly have more dose reductions and even some of them have missed a treatment due to the increased toxicity by adding another chemotherapeutic agent.

Q: How do the results from the 301 study affect treatment selection in metastatic TNBC?

Several trials are planned to evaluate the platinums further. One interesting study was the I-SPY2 study,³presented at the San Antonio Breast Cancer Symposium in December. This study evaluated the addition of veliparib/carboplatin to weekly paclitaxel followed by 4 cycles of doxorubicin/cyclophosphamide- (AC- ) based standard neoadjuvant therapy for high-risk breast cancer. The estimated pCR rate was 52% with the veliparib/carboplatin addition to paclitaxel followed by AC versus 26% with chemotherapy alone, with a 95% probability that this regimen is superior to the control. A large 3-armed trial is now under way that hopefully will confirm these initial results.A: In the EMBRACE trial,⁴eribulin was shown to demonstrate an advantage in terms of disease control and overall survival in a very heavily pretreated group of advanced breast cancer patients. Now, that trial certainly was compared with a standard of care where most patients received vinorelbine, gemcitabine, or capecitabine, and it was superior in that particular trial with an overall survival advantage of 10½ to 13 months.

Study 301,⁵examined whether eribulin would be effective for less heavily pretreated patients and included a standardized control arm, capecitabine. Half of the approximately 1000 patients had received only 1 prior regimen for advanced disease. The coprimary endpoints were overall survival and progression-free survival (PFS). While, the primary endpoint of this trial was not met, there clearly was a trend for an OS advantage. We could certainly say from that trial that eribulin appears to be just as active and effective as another efficacious drug, ie, capecitabine. So it is clearly equivalent, in efficacy, to one of our best drugs. I think the question becomes, with this trend in OS, whether we can identify the population in the metastatic setting that may derive more or preferential benefit, and subgroup analysis suggests that there was an advantage in the TNBC group with eribulin therapy.

Q: How do you go about arriving at and defining a personalized treatment approach for patients?

I think the other interesting aspect that has come from that trial is regarding the global health and overall quality of life—this has certainly improved over time but is more pronounced in the eribulin-treated patients—even cognitive function improved significantly in the patients treated with eribulin.A: My personalized approach for patients with triple-negative advanced disease, is first to do a rebiopsy. Even though I know they have a history of TNBC, I reevaluate for any discordance between previously known HER2-negative expression; in the metastatic setting there is a 20% to 25% discordance rate with HER2 expression based on primary tumor status, and there may even be changes in estrogen and progesterone receptor expression. I do look for—depending on the patient—androgen receptor expression. Those patients tend to have a history and course that is similar to that of patients with hormone-positive disease, and several trials are evaluating treatments that affect the androgen receptors, for example, enzalutamide and bicalutamide.

I also conduct molecular profiling of these tumors to look for molecular aberrations for which there may be drugs in clinical development. The signals evolving in the triple-negative population may lend me then to focus on a clinical trial. There are some interesting data with immune therapies and the PD-1/PD-L1 drugs that suggest patients with TNBC may benefit. So I try to start building an armamentarium of possible clinical trial choices for the patient that they may be eligible for at that point or down the road, as well as going through my standard chemotherapy treatment options. I talk to the patient about setting out the plan to try to determine all possible avenues to target this tumor, both investigational and conventional.

With regard to selecting chemotherapy, there is a large firstline international trial right now, the tnAcity trial,⁶which is comparing nab-paclitaxel in combination with either gemcitabine or carboplatin with the combination of gemcitabine and carboplatin as first-line therapy in metastatic TNBC. In patients with very symptomatic aggressive relapses or with lots of visceral disease or de novo stage IV disease presentations, my approach is to consider these patients as candidates for doublet chemotherapy. By contrast, for a patient who has a less aggressive relapse, I may consider using sequential single agents.

It is encouraging that we have, in the treatment of all breast cancer patients, become closer to being able to deliver a personalized treatment approach based on breast cancer phenotypes and incorporating molecular features of the tumor partnered with the patient considerations of treatment goals, treatment schedule, mode of treatment administration, quality of life, and toxicities.

References

1. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dosedense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). Paper presented at: 36th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; Abstract S5-01.
2. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.Lancet Oncol. 2014 Apr 30. pii: S1470- 2045(14)70160-3. doi: 10.1016/S1470-2045(14)70160-70163.
3. Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Paper presented at: 36th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S5-02.
4. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.Lancet. 2011 Mar 12;377(9769):914-23. doi: 10.1016/S0140-6736(11)60070-6.
5. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. 2012 San Antonio Breast Cancer Symposium. Abstract S6-6. Presented December 7, 2012.
6. ClinicalTrials.gov. Evaluate risk/benefit of nab paclitaxel in combination with gemcitabine and carboplatin compared to gemcitabine and carboplatin in triple negative metastatic breast cancer (tnAcity). http://clinicaltrials.gov/ct2/show/ record/NCT01881230. Accessed May 12, 2014.