October 4, 2016
Agendia Responds to “Clinical Insights on MINDACT”
Dear Dr. Febbo,
I recently received an email from you, in which you provided your unsolicited “Clinical Insights on MINDACT”. I have been a practicing medical oncologist for nearly 30 years, the last 20 of which have been devoted exclusively to the management of breast cancer. It may interest you to know that I am also the Chief Medical Officer of Agendia, and therefore uniquely qualified, both as a clinician and as an expert in the genomics of breast cancer to comment on your “insights”. Although you are certainly entitled to your opinion of the data, I feel compelled to point out some of the most important results of the MINDACT trial that you have chosen to omit from your email to physicians.
MINDACT primary and secondary objectives
First and foremost, despite the misleading language in your email, the MINDACT trial did indeed meet its primary and secondary objectives, unequivocally establishing level 1A evidence for the clinical utility of the MammaPrint 70-gene assay. With this prospective, randomized controlled data from the largest trial of its kind published in a peer-reviewed journal, MammaPrint now stands alone as the only breast cancer recurrence assay to achieve this highest level of evidence for a molecular assay. Outcomes from the primary test group in MINDACT showed that patients that were considered clinically high risk (which included 48% 1-3LN+), but determined to be genomically Low Risk by MammaPrint, had a distant metastasis free survival (DMFS) at 5 years of 94.7% without chemotherapy.1
MINDACT chemotherapy benefit prediction
When comparing chemotherapy efficacy amongst these discordant patients, in an intention-to-treat analysis, there was no statistically significant difference in DMFS between those randomized to chemotherapy vs no chemotherapy. The small numerical difference of 1.5% did not meet statistical significance, but even if real, is below the threshold of benefit for which most women would accept chemotherapy. As you well know, compared to DMFS, other endpoints such as DFS and OS are not indicative of the utility of a molecular assay designed to predict risk of metastatic disease.2 These positive results were acknowledged and supported by the following statement from the accompanying editorial authored by Clifford Hudis, M.D. and Maura Dickler, M.D., “The genomic test can reassign some classically high-risk patients with early-stage breast cancer to a lower-risk cohort in whom any plausible chemotherapy benefit would be modest”. Sub analyses were performed on HR+/HER2-/LN0 patients, as well as LN+ patients, which also showed no statistically significant difference in DMFS between patients treated with chemotherapy vs no chemotherapy in MammaPrint Low Risk patients.
For physicians who regularly treat breast cancer patients, the decision to utilize chemotherapy is one of the most challenging decisions that we face. In the presence of high risk clinical features that would otherwise indicate the need for chemotherapy to prevent metastatic recurrence, only the HIGHEST level of evidence can provide the confidence that withholding treatment for these patients is safe. MammaPrint has achieved this through MINDACT, showing no clinically meaningful benefit of chemotherapy in MammaPrint Low Risk patients. As the only assay that has specifically sought out to answer this question, it is the only assay that has consistently proven its ability to identify these patients, and safely spare patients from overtreatment.
As you are well aware, in contrast to the positive results published of the MINDACT trial, the TAILORx study has failed, up to now, to report on its primary objective of the randomized Oncotype Dx RS 11-25. 3 The lack of randomized data forthcoming from TAILORx has not escaped the notice of key opinion leaders. The comments from the accompanying editorial (also authored by Dr. Clifford Hudis), regarding the limited observational data from TAILORx, are in stark contrast to his comments about MINDACT, and raise valid concerns for physicians currently using the 21-gene assay, “For the many physicians already using the test [Oncotype Dx], the gap between this cutoff point of 10 and the higher “standard” cutoff point of 18 may be a concern…If chemotherapy is effective in this newly defined intermediate-risk group (score, 11 to 25), then examination of the subgroup of patients with scores of 11 to 17 will be critical, since there will be two conflicting guides to their treatment that need to be reconciled: the cutoff point used in this trial and the previously available cutoff point that is associated with the commercial test.” This statement is supported by the National Cancer Institute’s website, citing the limitations of the September 2015 publication of the observational arm of the TAILORx trial; “Although this study clearly identifies patients who do not benefit from adjuvant chemotherapy, only 16 percent of those enrolled had a recurrence score of 10 or less. Nearly 70 percent of enrollees had a mid-range score of 11 to 25, and the results to date do not provide information about whether this subset of women can be spared chemotherapy.”4
It seems likely, then, that in view of the continued lack of prospective data from TAILORx in patients with an RS= 11-17 (who nevertheless are currently advised that there is no need for chemotherapy), Genomic Health and its investigators have apparently chosen to aggregate non-randomized data from other sources to attempt to maintain support for the 21 gene assay. Data has been cited from a retrospective SEER registry (Level 4c evidence) as well as from the Plan B trial, the latter in which all patients with a RS>11 received chemotherapy without randomization. Since all three studies used different RS levels for “low risk”, the only consistent observation is that there are still no data supporting any clinical decision regarding chemotherapy for the intermediate risk group of patients, which represents up to 67% of patients tested with the new risk cut-offs of 11-25. With no clear and consistent prospective evidence available regarding the risk of distant relapse above the Oncotype Dx RS=10, de-escalation of treatment using the 21-gene assay remains a risky and uncertain task for the majority patients undergoing Oncotype Dx testing. This suggests that the thousands of physicians and patients who rely on Oncotype Dx with RS scores of 11-25 may not choose the appropriate curative therapy.
Questions that require answers about the Oncotype Dx
Taking advantage of your initiative to “educate” physicians with your clinical insights, I ask that you please provide your additional insights regarding the following questions pertaining to the Oncotype Dx assay which still remain unanswered:
- What is the exact cutoff in the Oncotype Dx Recurrence Score that determines if a patient is at low risk of recurrence? Is it 10? 11? 18? or 25? Several publications reference Oncotype Dx RS “Low Scores” where patients are believed to have a low risk of recurrence and for whom chemotherapy should not be added to the treatment, but the ambiguity of the threshold for “Low Scores” creates confusion. In this regard, genomic information provided by the Oncotype Dx test is contributing no precision to “Precision Medicine”, and requires that physicians return to reliance upon only clinical-pathological criteria.
- What is the evidence regarding the clinical utility of the Oncotype Dx for patients with RS 11-25? From recent publications, over 67% of all Oncotype Dx results fall into this “intermediate/Indeterminate” range of RS 11-25. The predictive claim that is so heavily marketed by GHI appears to apply only to the minority of patients whose results fall below RS 11 or above RS 31.
As you know, women diagnosed with breast cancer rely on their physicians to make evidence based, definitive treatment decisions. MammaPrint provides definitive and consistent results for these women during their most critical time of need. As clearly stated by Dr. Hudis and Dr. Dickler in their editorial accompanying the MINDACT data, “On the basis of the MINDACT study, clinicians may consider ordering the 70-gene signature for patients in line for chemotherapy who hope to forgo it on the basis of a possibly low genomic risk.” I hope the clinical insights of these breast cancer experts, and their vote of confidence, clarifies the benefits that MammaPrint can give breast cancer patients everywhere.
William Audeh, M.D.
Chief Medical Officer, Agendia
- Cardoso F., et al. N Engl J Med 2016; 375:717-729 August 25, 2016
- Hudis C., et al. J Clin Oncol. 2007 May 20;25(15):2127-32.
- Sparano, J. et al. N Engl J Med. 2015 Nov 19;373(21):2005-14
- NCI Website: https://www.cancer.gov/types/breast/research/tailorx-low-risk