Paving the Path Ahead in HR-Positive, HER2-Negative Breast Cancer: Reflections From SABCS 2020

Paving the Path Ahead in HR-Positive, HER2-Negative Breast Cancer: Reflections From SABCS 2020

Question

What were the most important practice-changing insights to come out of the 2020 San Antonio Breast Cancer Symposium (SABCS)?

Answer

The practice-changing results that we were waiting for were from the RxPONDER trial.¹ It is exciting to have the opportunity to determine how we can tailor chemotherapy and endocrine therapy in lymph node-positive, endocrine receptor [ER]-positive breast cancer.

I was also excited by a session discussing health equity.² These abstracts were not necessarily big scientific breakthroughs, but it was refreshing to see the American Association for Cancer Research taking a stand on the issue at this time in the history of our country. The organization highlighted issues around health equity in medicine and put them center stage.

Another presentation that caught my interest was an update on the RSClin 21-gene recurrence score.³ The abstract showed that a tool incorporating clinical and pathological factors could estimate risk for distant recurrence and adjuvant chemotherapy benefit for patients with early breast cancer with hormone receptor [HR]-positive, HER2-negative, node-negative disease. For better or for worse, there is still some art in how to interpret the 21-gene recurrence score, and when looking at statistics, it can occasionally be hard to decide if the potential toxicities of chemotherapy are worth it. To have a more nuanced decision support tool is important for patients. That additional information is helpful, and I am pleased to see that Genomic Health has already updated its website and made it available for clinicians.

Question

In the RxPONDER trial, researchers determined that postmenopausal women with HR–positive, HER2-negative, early-stage breast cancer with 1 to 3 positive lymph nodes and a recurrence score of 0 to 25 can safely omit adjuvant chemotherapy, by contrast with the premenopausal subpopulation, which would benefit from chemotherapy.¹ Was this result seen in premenopausal women because of the chemotherapy-induced impact of suppression of ovarian function, or could it be that young patients with breast cancer just have different biology?

Answer

Unfortunately, answering that question is going to require a different clinical trial. I don’t know whether there is time to do that or if it is financially feasible. This may be an unanswered question that lingers. I would love to see SWOG tackle that question.

The numbers do line up, which makes you wonder if the benefit of chemotherapy in premenopausal women is just the benefit of ovarian suppression from chemotherapy. We know from the SOFT/TEXT trial⁴ that the benefit of ovarian suppression hovers in about the same percent benefit range that we saw for premenopausal women. The absolute benefit of chemotherapy in the RxPONDER trial was 5.2%.

We also know that approximately half of the patients in RxPONDER received docetaxel/cyclophosphamide chemotherapy, which is not the most ovarian suppressive chemotherapeutic regimen. The other half received an anthracycline-containing regimen, which offers more ovarian suppression. There may be an opportunity, by regimen, to explore further chemotherapy benefit and ovarian suppression benefit.

We do not yet know the extent of the data available on premenopausal women who went on to receive ovarian suppression, which premenopausal women had return of menstrual function and in what time interval, and who received aromatase inhibitors vs tamoxifen. There are many unanswered questions in the premenopausal population. Hopefully, as we move forward, future publications and subset analysis will give us some additional information.

In the interim, I think that if a premenopausal woman with lymph node-positive breast cancer wants to feel that she is receiving care with maximal benefit, the RxPONDER trial tells us that chemotherapy is the right decision.

Question

The results of the PENELOPE-B study did not support the addition of 1 year of palbociclib to standard adjuvant endocrine therapy for patients with HR-positive, HER2-negative primary breast cancer.¹ What do these results tell us about the role of CDK4/6 inhibitors in this disease setting?

Answer

The PENELOPE-B study included a slightly lower-risk population (where risk was defined by response to neoadjuvant treatment rather than by stage) than we saw in some of the other clinical trials looking at CDK4/6 inhibition in the adjuvant setting. Response to neoadjuvant treatment in hormone receptor-positive breast cancer may not be the best predictor for future risk. There is a good chance that a patient has to be at a high enough risk for cancer recurrence for these medicines to offer benefit.

Compliance is another factor. On the trials of palbociclib that we have seen in the adjuvant setting, we have seen high rates of discontinuation. In PALLAS, for example, there was a 42% discontinuation rate largely driven by neutropenia. On the monarchE study, the discontinuation rate was approximately 16%. In order for a drug to work, a patient has to be able to tolerate it.⁶

We know that this was a concern in the design of studies of ribociclib, which have yet to be reported in this setting. The ribociclib trial started at a lower dose of 400 mg instead of 600 mg, the approved dose in the metastatic setting. We will see how these different factors come together as the data mature.

Question

Updated results from the monarchE trial showed that the addition of abemaciclib to standard adjuvant endocrine therapy continued to delay invasive disease for patients with node-positive, HR-positive, HER2-negative, high-risk early breast cancer. This seems to conflict with what was seen in PENELOPE-B. Do you suspect that the monarchE results will remain positive with longer follow-up?

Answer

Cross-trial comparison is always dangerous ground to tread on. We have seen differing results in the metastatic setting. Overall survival benefit in the metastatic setting has been reported for abemaciclib and ribociclib, but not palbociclib. We continue to question if the slightly different impact on CDK4 as opposed to CDK6 with these different drugs drives their impact on outcomes for metastatic or early-stage breast cancer.

I would love to see these drugs improve early-stage disease so that we have less metastatic breast cancer, but monarchE is still too early in follow-up, with approximately 25% of patients having finished 2 years of therapy, to be practice-changing.

A criticism of these studies is that they are just delaying metastatic presentation. We know that in the metastatic setting, patients stay on CDK4/6 inhibitors for about 2.5 years on average. We wouldn’t expect—with only 25% having finished therapy—to be seeing metastatic disease progression show up yet in monarchE. We will need longer follow-up.

Question

In the CONTESSA trial, tesetaxel plus a reduced dose of capecitabine led to delayed disease progression in patients with previously treated HER2-negative, HR-positive metastatic breast cancer, but the chemotherapy combination arm had more treatment discontinuations due to adverse events and patients died more frequently in this arm vs the capecitabine arm.7 Do the benefits observed with tesetaxel outweigh the risks of adding a novel therapy?

Answer

The CONTESSA trial received some negative feedback in trial design and in outcome. That is both rightly and wrongly deserved. It is rightly deserved because there was a lot of toxicity and the improvement in outcome was small. It was wrongly deserved in that I know that in the design of the trial, the investigators were hoping to compare standard-dose capecitabine, and early data supported the hypothesis that capecitabine and tesetaxel may have a synergistic effect. The hope was that reduced-dose capecitabine in combination with tesetaxel would create a 1 plus 1 equals 3 effect. But ultimately, it led to the side effects that we saw reported.

If they had used a non-standard control arm or non-combination approach and had a negative trial result, we would criticize the trial for the opposite reason. It is a bit of a double-edged sword.

The CONTESSA trial opens up the possibility of giving a patient a treatment that may be right for them. It is not a huge improvement, but there certainly are patients who strongly prefer oral therapy. There are patients who prefer a certain side effect profile over a different side effect profile. When speaking with patients about selecting a therapy that optimally meets their goals, the more options that we have, the better for the patient.

Furthermore, I think that an oral taxane is exciting for the future of breast cancer in many different ways. An oral taxane that doesn’t require a significant amount of steroid could give us more options to combine with immunotherapy, or with tucatinib in HER2-positive disease, which could create another all-oral option. The possibilities of what an oral taxane could do in combination with medicines other than capecitabine or as a monotherapy would be interesting.