Certain patients with luminal early breast cancer and up to 3 involved lymph nodes can be treated with adjuvant endocrine therapy alone, according to the primary outcome analysis of the ADAPT HR+/HER2- trial  (NCT01779206), presented at the 2020 San Antonio Breast Cancer Symposium [1]. Physician’s Weekly interviewed study presenter Nadia Harbeck, MD, PhD, from the University of Munich in Germany, for her perspectives on these new findings.

In the intent-to-treat population of the ADAPT trial (n=2,290), luminal early breast cancer patients who were candidates for adjuvant chemotherapy received preoperative standard endocrine therapy followed by adjuvant endocrine therapy alone. Patients were grouped by recurrence score and Ki67 immunohistochemistry expression levels, which served as a surrogate marker for endocrine response. Patients with a maximum number of 3 involved lymph nodes were included. In the group with a low recurrence score between 0 and 11 (n=868), the median age was 57 years, of whom 34.6%  were premenopausal. Those with a recurrence score between 12 and 25 (n=1,422) who showed an endocrine response (defined as the surgical sample staining 10% or less for Ki67 following endocrine therapy), the median age was 58 years, of whom 26.3% were premenopausal.

The primary endpoint of ADAPT was invasive disease-free survival (DFS) at 5 years. Key secondary endpoints included distant DFS, and overall survival (OS).

With a median follow-up of 60 months, the primary endpoint was met, indicating that higher risk patients (recurrence scores of 12 to 25) who responded to preoperative endocrine therapy did not have a worse 5-year invasive DFS outcome than low risk patients (recurrence scores of 0 to 11), even though they did not receive adjuvant chemotherapy (93.9% vs 92.6%, respectively). Likewise secondary endpoints were met; the 5-year distant disease-free survival rates were 96.3% versus 95.6%, respectively and 5-year OS rates were 98.0% versus 97.3%, respectively.

One subgroup, however, did have a worse outcome without chemotherapy. Namely, those patients with 3 involved lymph nodes and a recurrence score of 12 to 25 who responded to preoperative endocrine therapy had a lower 5-year distant DFS (75.9% compared with 96.3%).

In conclusion, the results presented by Prof. Harbeck showed that endocrine therapy response should be considered along with the recurrence score when deciding whether adjuvant chemotherapy is necessary in hormone receptor-positive, HER2-negative early breast cancer. However, patients can be treated by endocrine therapy alone if they have:

  • 0 to 3 involved lymph nodes and a recurrence score of 0 to 11
  • 0 to 2 involved lymph nodes and a recurrence score of 12 to 25, in whom an endocrine response is observed after short preoperative endocrine therapy.

Physician’s Weekly interviewed Prof Harbeck for her perspective:

What were the take-home messages from the new ADAPT data?

“In ADAPT, we postulated that patients with endocrine response and an intermediate-risk recurrence score would have the same good outcome as patients who had a very low recurrence score to begin with. The trial reached its primary endpoint and we had a 93% 5-year invasive disease-free survival rate in both arms. We defined  endocrine response as 10% or lower positivity for Ki-67 in the surgical specimen after 3 weeks of endocrine therapy prior to surgery. The rationale was derived from the good data from Mitch Dowsett’s POETIC trial (NCT02338310) in addition to Matt Ellis’s work [2,3]. Happily, the trial was positive and the take-home message for the clinician is that we can avoid chemotherapy in luminal early breast cancer patients with up to 3 involved lymph nodes and a recurrence score of either 0-11 or 12-25 with an endocrine response.”

What is the benefit from the patient perspective?

“For the patients, I think the data presented at the San Antonio Breast Cancer Symposium was a great step forward because there were several trials on gene expression essays, and how to avoid overtreatment by chemotherapy. And what ADAPT did was slightly different from the other trials, because we looked either at very low-risk, by a gene expression essay, meaning recurrence score 0-11, or we included the information by endocrine response after a short pre-operative therapy. Patients can certainly understand the clear benefit of being treated safely by endocrine therapy alone without forgoing any benefits of chemotherapy. We can now tell the patient that we know if they have a tumor that is endocrine responsive after only 3 weeks of therapy, then after their surgery, endocrine therapy alone will still work in these tumors. There is no additional burden for the patient, and potentially sparing them from overtreatment. The novelty here is that we have previously neglected incorporating information about endocrine responsiveness directly from the tumor into the treatment plan for the patient, but this approach from ADAPT works really well in the clinic.”

What is the value of stratification by Ki67 positivity?

“Ki-67 is a proliferation marker with a somewhat bad name because the standardization of the methodology has been difficult to perfect. Thanks to a recent international effort, the technology has improved and it can now be routinely used in clinical practice [2,4]. Although inter-observer concordance is excellent at the higher and lower % ranges for positivity, the intermediate ranges of Ki-67 can still be difficult to standardize, but it is good enough now to use for prognostication. What I think is most interesting is the very high-risk Ki-67 cohort, because we know from the PlanB  study that if Ki-67 stains more than 40% of the tumor, that there is a good concordance with high-risk oncotype results [5].”

Which patients can be treated by endocrine therapy alone?

“At the San Antonio meeting, we also saw data from the RxPONDER study (NCT01272037), looking at patients with up to 3 involved lymph nodes. Those results indicated that post-menopausal luminal early breast cancer patients could forgo chemotherapy safely if they had a recurrence score less than 26, and in the pre-menopausal setting, they saw benefit for chemotherapy in the range of about 5%, albeit somewhat lower if the recurrence score was only 0-13. So there is a little bit of a discordance with the ADAPT data. My take on that is that endocrine responsiveness may not play such a large role in the post-menopausal setting. In pre-menopausal patients, we only have around 45% who have adequate endocrine response to tamoxifen treatment. RxPONDER included that other 55% of the patients that did not respond adequately to endocrine therapy; maybe that is why they see this apparent chemotherapy benefit. I think we can tell patients that they can safely forgo adjuvant chemotherapy independent of their age, as long as they have a recurrence score between 0-11 and a maximum 3 involved lymph nodes. Patients who have a recurrence score between 12 and 25 can forgo chemotherapy if they do not have more than 2 involved lymph nodes. I think the physicians should discuss these slight discrepancies with the patients for decision-making. But I do not think that every premenopausal patient will need adjuvant chemotherapy, according to the ADAPT study findings.”

“At the San Antonio meeting we also presented neoadjuvant chemotherapy  part of the ADAPT study, and we saw that there is only adequate response in patients with a high-risk recurrence score of >25. One unmet need is that it is not yet entirely clear what to do with intermediate-risk luminal breast cancer patients, and whether they always need chemotherapy. To address that gap, for example, we are running the West German Study Group is running the phase 3 ADAPTcycle trial (NCT04055493) where we randomized CDK4/6 inhibitor-based therapy versus chemotherapy in those patients with a chemotherapy indication but are not at very high risk.  The aim is to investigate whether the intermediate-risk patient group identified during the screening phase derives additional benefit from treatment with ribociclib in combination with endocrine therapy compared to chemotherapy (followed by adjuvant endocrine therapy). We are looking forward to those results.”

 

References

  1. Harbeck N, et al. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score <26 and Ki67 response after preoperative endocrine therapy: First efficacy results from the ADAPT HR+/HER2- trial (n=4,690). Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS4-04.
  2. Smith I, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1443-1454.
  3. Ellis MJ, et al. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. 2017 Apr 1;35(10):1061-1069.
  4. Viale G, et al. Ki-67 (30-9) scoring and differentiation of Luminal A- and Luminal B-like breast cancer subtypes. Breast Cancer Res Treat. 2019 Nov;178(2):451-458.
  5. Nitz U, et al. West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer. J Clin Oncol. 2019 Apr 1;37(10):799-808.