Denise Yardley, MD

Question

What are your key takeaways from the TAILORx trial results presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting?

Answer

Results of TAILORx presented at the ASCO 2018 meeting help us identify a group of women with early stage breast cancer who will not benefit from or need adjuvant chemotherapy in addition to the recommended antiestrogen therapy.¹ Specifically, the investigators studied patients with hormone receptor (HR)-positive, HER2-negative, lymph node negative early breast cancer whose OncotypeDx recurrence score (RS) was considered low intermediate — defined as RS between 11 and 25. We already knew that those with very low RS could safely be treated in the adjuvant setting with endocrine therapy alone, whereas those with high RS scores, greater than 31, would benefit from chemotherapy.² We struggled about the decision, though, when the RS was intermediate and many physicians believed, in the absence of prospective data, that it might be prudent to offer chemotherapy in addition to endocrine therapy in that setting. However, the current results from the TAILORx study showed that outcomes were roughly equivalent for those who received endocrine therapy alone compared with those who received both chemotherapy and endocrine therapy. As clinicians, we can now feel comfortable informing patients with low intermediate Oncotype RS that there is no evidence that chemotherapy will offer greater benefit than endocrine therapy alone. There is a caveat for patients younger than 50 who had RS between 16 and 25; for them, it appears that the addition of chemotherapy to endocrine therapy provided some benefit: when RS was between 16 and 20, the benefit was a 2% reduction in disease recurrence, whereas for RS of 20 to 25, the benefit was about 7%. These data provide younger patients with solid information on which to base their decisions about whether to undergo chemotherapy and how much benefit they can expect to obtain.

Overall, this study is important in our efforts to de-escalate therapy for many women — up to 70% — with HR-positive, HER2-negative, lymph node̶negative early breast cancer. The data also help us identify those 30% for whom the addition of chemotherapy will provide substantial benefit.

Question

Which data from the MONARCH trials (MONARCH 1 and MONARCH 2) do you find to be most relevant and/or compelling for clinicians who treat patients with breast cancer?

Answer

The MONARCH 1³ trial looked at abemaciclib (one of the three currently available CDK4/6 inhibitors) as monotherapy in patients with advanced HR-positive, HER2-negative breast cancer who had previously been treated with chemotherapy.³ Abemaciclib differs from palbociclib and ribociclib in that it is dosed continuously and has a slightly different toxicity profile.⁴ For example, abemaciclib is associated with less neutropenia compared with the other two agents, but somewhat more gastrointestinal toxicity. It is also the only agent for which there is evidence of activity when used as a single agent. Clinically, that is important because some patients may miss the opportunity to receive a CDK4/6 inhibitor with endocrine therapy as a first- or second-line option in combination with endocrine therapy. However, even as a later-line regimen, abemaciclib may be considered as monotherapy.

The MONARCH 2^5,6 and MONARCH 3⁷ trials, which combined abemiciclib with fulvestrant and with an aromatase inhibitor, respectively, showed striking improvements in progression-free survival (PFS) in eligible patients.

As clinicians, we sometimes struggle with the question of whether all patients with advanced HR-positive, HER2-negative breast cancer should be treated with a CDK4/6 inhibitor or whether there are some patients who might do well with endocrine therapy alone. Although CDK4/6 inhibitors are not chemotherapy, they are not without toxicities or challenges. These agents require close monitoring and are associated with neutropenia and gastrointestinal effects.

Findings from the MONARCH trials suggested that although abemaciclib was very active in patients with visceral disease, those with more indolent disease (ie, when relapse occurs after a long disease-free interval and/or is characterized by bone-only disease) might be candidates for endocrine therapy alone.

Question

What is your perspective on the SANDPIPER results presented at the 2018 ASCO Annual Meeting?

Answer

The SANDPIPER trial was essentially a proof of concept that the PI3 kinase pathway, which confers resistance in up to 40% of patients with HR-positive breast cancer, may be effectively targeted in patients with a fairly common tumor mutation, PIK3CA.⁸ Baselga and colleagues showed that taselisib, an alpha-specific PI3 kinase inhibitor, combined with fulvestrant, decreased worsening of disease by 30%, and improved PFS by about 2 months. This is the first evidence that the PI3K pathway can be effectively targeted and can improve outcomes. The benefits in this trial, however, came at a high price in terms of toxicities, such as diarrhea (60%) and hyperglycemia (40%). Of note, between 15% and 17% of patients discontinued therapy due to adverse effects.

Although taselisib is an alpha-specific agent, it still exerts some delta and gamma effects, which may account for the off-target effects (ie, toxicity) seen with the regimen. In the future, we look forward to development of agents that are more precisely alpha-specific or strategies that may render PI3 kinase inhibition less toxic.

Question

Were there any other breast cancer studies reported at the 2018 ASCO Annual Meeting that you found to be of particular interest/importance? Are there any ongoing studies that you think will yield important results for practitioners?

Answer

There was a small signal-finding trial⁹ of a PARP inhibitor in development, talazoparib,¹⁰ that was given to patients with early BRCA-mutated breast cancer as an oral neoadjuvant regimen without chemotherapy. Results were provocative in that after 6 cycles, about 50% of patients achieved a pathologic complete response with daily oral talazoparib and without chemotherapy. The regimen was associated with some toxicities, including bone marrow suppression that required dose reductions or transfusions. Nevertheless, this study was another promising proof of concept about the use of a single, very targeted agent for this population of breast cancer patients with BRCA mutation.

The RESPECT¹¹ and PERSEPHONE¹² trials paralleled the theme of de-escalating therapy in patients with HER2-positive breast cancer. The RESPECT trial,¹¹ which looked at elderly patients between 70 and 80 years of age, demonstrated excellent (> 90%) 3-year disease-free survival (DFS) with trastuzumab alone or in combination with chemotherapy. In real life practice, clinicians will encounter patients who are unfit for chemotherapy, refuse it, or want to discontinue it. This trial gives us a degree of comfort that trastuzumab alone will still provide significant benefit in those situations.

Similarly, the PERSEPHONE trial¹² examined the question of duration of adjuvant trastuzumab therapy: 6 months vs 12 months. Although the results were not necessarily practice changing, outcomes were noninferior after 6 months compared with 12 months. The longer, full year regimen appeared to be superior in those with HR-negative breast cancer, in those who received taxanes without anthracyclines, and in those who received neoadjuvant chemotherapy. As practitioners, we should encourage those patients to persist with the full year of adjuvant trastuzumab treatment. However, for the overall population, we now understand that the diminution in DFS with 6 months of treatment (vs 1 year) is about 2% to 3%, which may be acceptable to some patients, especially if they experience significant toxicity, encounter cost issues due to their health insurance coverage, or encounter other challenges that make continued treatment difficult.

In conclusion, although many studies of targeted therapies in breast cancer fail, there are successes and each helps us come closer to the goal of offering regimens that omit chemotherapy or delay it without sacrificing efficacy.