Leisha A. Emens, MD, PhD

Using the Data From ESMO Congress 2019 in Practice: Breast Cancer

Question

There was a “controversy session” during the European Society of Medical Oncology (ESMO) Congress 2019 called, “Is there a role for the addition of platinum-based chemotherapy to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC)?” — What are your thoughts on this question?

Answer

Adding platinum-based chemotherapy is an option for patients with triple-negative breast cancer, as it increases the rate of pathological complete response. However, there has not been a clear improvement in event-free survival rates, and adding platinum-based chemotherapy also comes at the expense of greater hematologic toxicity. I consider adding a platinum to standard AC (doxorubicin and cyclophosphamide) and paclitaxel if a patient has a BRCA mutation or if they have particularly high-risk features such as multiple positive nodes, high-grade disease, lymphovascular invasion, a larger tumor, and/or a high Ki-67.

Question

CDK4/6 inhibitors: What do you think the role of these drugs will be in breast cancer, now that there appears to be an overall survival benefit in certain patient subgroups with these types of therapies?

Answer

There are 3 different CDK4/6 inhibitors that the US Food and Drug Administration has approved for the treatment of metastatic breast cancer.

Palbociclib in combination with an aromatase inhibitor is approved for the first-line therapy of postmenopausal women with metastatic ER-positive, HER2-negative breast cancer. It is also approved in combination with fulvestrant for women of any menopausal status with metastatic ER-positive, HER2-negative breast cancer who have progressed on endocrine therapy. The FDA more recently expanded these indications to include male patients.

Abemaciclib is approved in combination with an aromatase inhibitor for the first-line therapy of women with metastatic ER-positive, HER2-negative breast cancer, and in combination with fulvestrant for women with metastatic ER-positive, HER2-negative breast cancer. It is also approved as a single agent for women with metastatic ER-positive, HER2-negative breast cancer who have progressed on prior endocrine therapy and chemotherapy.

Ribociclib is approved for women with ER-positive, HER2-negative metastatic breast cancer in combination with an aromatase inhibitor for first-line treatment, and in combination with fulvestrant for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer that has not yet been treated, or [who have] progressed on endocrine therapy.

These drugs have transformed the management of metastatic ER-positive, HER2-negative breast cancer, and there are increasing data supporting a survival benefit in some patients treated with CDK4/6 agents. A major question currently being addressed in clinical trials evaluating these agents in metastatic disease [addresses] what the value is of continuing CDK4/6 inhibition beyond disease progression.

Given data suggesting an overall survival benefit, the added value of these agents when incorporated into the management of early stage ER-positive, HER2-negative breast cancer in the adjuvant or neoadjuvant settings is of high interest and an area of active clinical investigation. There are some data that [suggest that] CDK4/6 agents may promote immune activation, and combining these agents with immune checkpoint blockade is also being evaluated in clinical trials.

Question

A study presented at the meeting¹ found that PARP inhibition conferred a progression-free survival (PFS) benefit, but no overall survival (OS) benefit, in BRCA-mutated (BRCAm) breast cancer. How do you think these findings will impact adoption of this class of drugs?

Answer

PARP inhibitors are an important treatment option for metastatic germline BRCA-mutated ER-positive, HER2-negative breast cancer, and triple-negative breast cancer. The finding that PARP inhibition may confer a PFS benefit, but perhaps not an OS benefit, may impact when physicians utilize them.

There are some data from the OlympiAD trial to suggest that there may be an overall survival benefit in the first-line setting with PARP inhibitors similar to immunotherapy, but the patient numbers from this exploratory analysis are small.

Given the data supporting the use of atezolizumab with nab-paclitaxel to treat metastatic triple-negative breast cancer that is PD-L1-immune cell–positive in the first-line setting, a major question is how to sequence immunotherapy and PARP inhibition in a germline BRCA-mutated patient with metastatic PD-L1 IC+ triple-negative breast cancer.

Give the mechanism of action of the 2 classes of agents and the current data, in my opinion there is a higher potential OS benefit with the use of first-line immunotherapy than with a first-line PARP inhibitor.

In a patient with metastatic triple-negative breast cancer who is germline BRCA-mutated with PD-L1 IC+ disease, I would tend to use atezolizumab with nab-paclitaxel first-line and a PARP inhibitor as a later line of therapy. Given the growing data supporting an OS benefit with CDK4/6 inhibition for patients with germline BRCA-mutated ER-positive, HER2-negative breast cancer, I would also tend to use CDK4/6 inhibitor-based therapy first, reserving therapy with PARP inhibition for later lines of treatment.

Question

What are your thoughts or predictions about PARP inhibition in homologous recombination-deficient (HRD) patients with advanced breast cancers?

Answer

This is a really interesting area of research and an area that we need to pay close attention to. Platinum agents and PARP inhibitors are both generally thought to be most likely to have clinical activity in patients with germline BRCA mutations, BRCA-deficiency or “BRCAness”, or other mutations in DNA repair (homologous recombination deficiency).

Results from the TNT trial suggested that patients with advanced triple-negative breast cancer and a high level of homologous recombination deficiency did not have a significantly higher response rate with carboplatin relative to docetaxel, whereas patients with germline BRCA-mutated disease had a response rate twice as high with carboplatin than with docetaxel. This finding suggests that there is likely a spectrum of biology underlying various types of DNA repair deficiencies. In contrast, there are some clinical data that some patients with homologous recombination deficiency do have a clinical benefit from PARP inhibition. At this point, the data are evolving and, again, this is an area that bears watching. I suspect there will be some patients with homologous recombination-deficient advanced breast cancer who will benefit from PARP inhibition.

Question

What will be the long-term implications of the results of TAILORx, in your view?

Answer

The TAILORx trial² rigorously evaluated the 21-gene Oncotype DX recurrence score as an effective way to understand tumor biology and give the most optimal therapy to women with early hormone-dependent, HER-negative, lymph node-negative breast cancer. The TAILORx data allow us to identify patients who will not benefit from chemotherapy, and spare them unnecessary toxicity. Occasionally, data from TAILORx will prompt us to give chemotherapy to a patient when we otherwise may not use it based on historical clinical risk criteria.

Data from TAILORx clearly showed that women with hormone-dependent, HER2-negative, lymph node-negative breast cancer and a low- to intermediate- recurrence score can be treated with endocrine therapy alone and spared chemotherapy, whereas, those with a high recurrence score (>26) clearly benefit from chemotherapy in addition to endocrine therapy. These data thus support sparing 70% of this group of women the side effects and inconvenience of chemotherapy, reserving its use only for the 30% of high-risk women who might benefit.

Recently, a closer look at these data suggested that the subgroup of women younger than 50 years with intermediate recurrence scores (16-25) can benefit from chemotherapy. Part of the way chemotherapy is effective in premenopausal women is by inducing menopause. Extrapolating from these data, it is possible that combining ovarian suppression with an aromatase inhibitor may be as effective as chemotherapy in this group of patients younger than 50 years of age with an intermediate recurrence score. Thus, it is probably reasonable to spare these patients the toxicities of chemotherapy and use combined ovarian suppression with an aromatase inhibitor.

Additional analyses reveal that considering clinical risk factors (tumor size and grade) to complement the recurrence score can provide a better assessment of prognosis, but does not provide information to predict clinical benefit from adjuvant chemotherapy. As these data continue to be applied in the clinic, evaluating real-world data from electronic medical records may provide additional data to guide us in the treatment of early hormone-dependent, HER2-negative, lymph node-negative breast cancer.