Roisin Connolly, 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

Findings from the TAILORx study are relevant to women with hormone receptor (HR)-positive, HER2-negative breast cancer and negative axillary lymph nodes.¹ The overall goal of the study was to determine which patients with early HR-positive breast cancer might be able to forgo adjuvant chemotherapy. The study, which included pre-, peri-, and postmenopausal women, tested whether endocrine therapy alone would be noninferior to endocrine therapy following chemotherapy in a specific subset of patients: those women with intermediate Oncotype recurrence scores (RS), defined as scores from 11 to 25. A previously reported analysis by the TAILORx study group had already shown that regardless of age, those patients with a low Oncotype RS (10 or lower) had excellent long-term outcomes with endocrine therapy alone and thus could be spared chemotherapy.2

The primary endpoint of this portion of the TAILORx trial was invasive disease-free survival (DFS). The overall results of the trial at the 9-year time point showed that outcomes (invasive disease-free survival) in both groups (endocrine therapy with or without chemotherapy) were similar: 83.3% (endocrine therapy only) and 84.3% (endocrine plus chemotherapy). Clinically, these results mean that we can tailor therapy and spare patients with intermediate Oncotype RS from having to undergo adjuvant chemotherapy for early breast cancer.

A separate analysis was performed in a younger group of patients, those women 50 years of age or younger. It appears that those younger patients with scores at the higher end, RS of 16 to 25, may benefit, albeit modestly, from the addition of chemotherapy to endocrine therapy.

Although many practitioners already omit adjuvant chemotherapy for women over 50 with HR-positive, HER2-negative, node-negative early breast cancer if they have low to intermediate Oncotype RS, these results are reassuringly confirmatory. We need to be more cautious in those women younger than 50 who have RS at the higher range of the intermediate category. A value at the higher end of the Oncotype score, even while technically in the intermediate range, warrants a conversation with the patient about the potential for a small benefit with adjuvant chemotherapy.

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 series of trials are investigating abemaciclib, one of the three CDK4/6 agents now available for clinical use for patients with HR-positive advanced breast cancer. What is consistent among all of these studies, across all lines of treatment (including the other agents, palbociclib and ribociclib), regardless of menopausal status or endocrine backbone, is that progression-free survival (PFS) is improved with the addition of the CDK4/6 inhibitor to endocrine therapy. Clinicians may now offer eligible patients the opportunity to extend time on endocrine therapy (ie, by adding a CDK4/6 inhibitor) and thus delay the need for chemotherapy.

Specifically, the MONARCH 2 study included both pre- and postmenopausal women.³ Previous studies primarily focused on use of abemaciclib in postmenopausal women. Clinicians needed to know whether the data extrapolate to the premenopausal setting. Findings demonstrated that the regimen of abemaciclib plus fulvestrant improved PFS in the overall population (all age groups) from 9 to 16 months; in the younger group (ie, pre- and perimenopausal patients), the PFS improved to 10.5 months in the fulvestrant alone group; median PFS was not reached in the group that received fulvestrant plus abemaciclib.⁴ Moreover, the overall response rate with the combination regimen in those with measurable disease was about 60%. Often, we believe that such response rates are only achievable with chemotherapy, but this study proves otherwise. The clinical implication is that we can consider this approach in premenopausal patients.

Although all three available CDK4/6 inhibitors are quite similar in terms of observed efficacy to date, varying toxicity profiles may be considered when selecting therapy for individual patients. Some agents may cause more neutropenia, which requires close monitoring of blood counts, and may result in drug delays or dose reductions. Other agents, such as abemaciclib, can cause more diarrhea, which may be managed with loperamide to minimize impact on quality of life for patients.

Question

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

Answer

SANDPIPER was a phase 3 study looking at fulvestrant with or without the PIK3 kinase inhibitor taselisib in patients with locally advanced or metastatic PIK3CA-mutant disease, which is a specific subpopulation of those with HR-positive, HER2-negative breast cancer.⁵ For the last several years, there has been a great deal of interest in targeting the PI3K/mTOR pathway as a strategy for overcoming hormone resistance in breast cancer. Development and approval of the mTOR inhibitor everolimus plus exemestane on the basis of the BOLERO trial is an example of a regimen that is intended to exploit that pathway and thus extend duration of endocrine therapy through prolongation of PFS.⁶

In the SANDPIPER trial, investigators used taselisib, a PI3K inhibitor in women with a specific mutation (ie, PIK3CA). Patients had to have had at least one prior therapy and “hormone-resistant disease,” defined as disease progression while on or after receiving an aromatase inhibitor. Although the study met its primary endpoint, PFS, the difference of 2 months with the addition of taselisib was quite small, and there are questions about whether the results are clinically meaningful. The results of ongoing trials with these and similar agents will help define their role further in advanced breast cancer.

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

The theme of de-escalating treatment was discussed at an ASCO 2018 poster discussion session where the key question being addressed was, “Are we overtreating some patients? And, if we are, how can we know which patients would do well with less aggressive therapy?” I presented results from the TBCRC026 study where we looked at giving a chemotherapy-free regimen of only trastuzumab plus pertuzumab neoadjuvantly in patients with ER-negative, HER2-positive early breast cancer.⁷ We wanted to identify biomarkers of response so that we might spare some patients the addition of neoadjuvant chemotherapy in the future. Previous research demonstrated high responses with dual HER2-directed therapy plus chemotherapy in the preoperative setting, and in those with HR-negative, HER2-positive breast cancer, rates of pathologic complete response (pCR) as high as approximately 70% were seen.^8,9 Based on the NeoSphere⁸ and ADAPT studies,¹⁰ we know that about 30% of those patients with ER-negative, HER2-positive disease can have a pCR with dual HER2-directed therapy alone (no chemotherapy). If we could predict upfront that the response to dual HER2-directed therapy would be robust, we could potentially omit chemotherapy for those patients. We used a positron emission tomography (PET) scan as an imaging biomarker; those who showed a significant decline in standardized uptake value (SUV) at 2 weeks after starting pertuzumab and trastuzumab were more likely to achieve a pCR. These results will be used to design a next step study, which will bring us closer to identifying those patients who may be spared chemotherapy.

This theme of treatment de-escalation is an important one, currently being explored by breast surgeons (eg, elimination of radical mastectomy, minimizing axillary surgery) and radiation oncologists (eg, partial breast irradiation), as well as by medical oncologists (eg, avoiding use of chemotherapy). The goal of therapy de-escalation is to maintain excellent outcomes with less toxicity and impact on patient quality of life.