Full Interview with Agendia’s CMO on MammaPrint 70-gene Signature Test

Full Interview with Agendia’s CMO on MammaPrint 70-gene Signature Test

Breast Cancer News, in an email exchange, interviewed Dr. William Audeh, chief medical officer of Agendia and a breast medical oncologist with nearly 30 years of clinical practice experience, to know more about Agendia’s MammaPrint 70-gene Breast Cancer recurrence assay in patients with early stage breast cancer.

An in-depth article on this interview, which includes the major findings from the MINDACT Phase 3 trial that assessed whether women with low genetic risk of recurrence could safely forego chemotherapy, can be found here.

Here is the interview in full:

Q: The Phase 3 study investigating the utility of the 70-gene signature test (MammaPrint) in selecting early stage breast cancer patients for adjuvant chemotherapy, found that nearly 46% percent of breast cancer patients currently treated with chemotherapy based on their clinical assessment may safely avoid such treatment because their tumors were low risk by genomic assessment, a considerable benefit to people with early stage breast cancer. Since the publication of the MINDACT trial results, the prognostic test for risk of breast cancer recurrence has been widely adopted in Europe and the US. Have you had feedback on its use, and is that feedback meeting your expectations? Are there places where you would like to see it used, but for whatever reasons (economic, simple availability) it has not yet come into practice?

A: The MINDACT trial accurately predicts that there is no meaningful benefit of chemotherapy in MammaPrint Low Risk patients, despite a clinically High Risk assessment. This was the primary endpoint of this positive trial. Since the risk of distant metastasis guides the decision for potentially curative therapy, noting no difference in DMFS (Distant Metastasis Free Survival) in women with a Low Risk MammaPrint test result, randomized to chemotherapy versus no chemotherapy, has given patients and their physicians the confidence to make the decision to forego treatment. Industry key opinion leaders have stated that these findings are “Huge”. Dr. Jose Baselga, Physician-in- Chief of Memorial Sloan Kettering in NY and AACR Past President, called the study of nearly 7,000 women a “tour de force” and said that the results were “practice changing,” in that they provide evidence that nearly half (46%) of women who are currently prescribed chemotherapy following surgery do not need it and can therefore be spared its damaging side effects, including impaired fertility. Dr. Cliff Hudis, who co-authored the NJEM publication editorial, stated “the MINDACT trial shows how a well-coordinated and highly collaborative multinational team of investigators can efficiently conduct a potentially practice-changing study. This is a research model that will be even more critical as we advance toward precision medicine.”

We are seeing use of the MammaPrint test increasing worldwide. Women are more savvy than ever before, advocate on their own behalf, and use the internet and social media to educate themselves. They are requesting the test from their doctors. Additionally, we are working with regions where the test is not readily available to help patients gain access.

Q: Is there a particular group of breast cancer patients this test best served, best described as best outcomes for particular patients? How might you counsel a woman with clinically high-risk breast cancer who’s been found to be at low risk though MammaPrint, and trying to decide whether to go ahead with chemo or not? What points would you recommend she and her physician consider, and how would you reassure her should she want to go with MammaPrint’s findings, but is uncertain.

A: MammaPrint is appropriate for use on women of ALL ages (not just post-menopausal). The test is primarily useful for Stage l or ll invasive breast carcinoma, LN [lymph node] negative or up to 3 positive LN, ER positive; in the case of HER2 positive or triple negative, those patients with Stage I tumors may also benefit from genomic profiling.

Patients who are clinically High Risk but MammaPrint Low Risk, benefit, as they might safely avoid chemo; those who are clinically Low Risk but MammaPrint High Risk, have additional data (independent of clinical-pathological factors) to help them and their doctors determine the best course of treatment.

Since the results are binary, there are no intermediate results. Based on the MINDACT trial, the MammaPrint test is perfect for patients in line for chemo who hope to forego it, given a low genomic result.

One of the most important questions, when determining if chemotherapy is the right course of action, is how likely will the cancer come back or spread to other parts of the body, or metastasize. If a woman is clinically High Risk and MammaPrint Low Risk, we would point out that the MINDACT data showed a possible reduction of metastasis of 1.5% for patients who had chemotherapy as compared to those who did not receive chemotherapy. Dr. Cliff Hudis states that “a difference of 1.5 percentage points, if real, might mean more to one patient than to another.” This number did not meet statistical significance, and is below the threshold of benefit that most women would accept to justify the toxicity of chemotherapy. Many women would find the risks of chemotherapy, such as neuropathy, cognitive dysfunction (chemo brain), hair loss, infertility, leukemia and congestive heart failure, outweigh the small potential benefit of chemotherapy.

Q: Why is this test better than other genomic tests? Can you describe for us why it has superior and more trustworthy results, and what it exactly means in saying the test takes “individual biologic characteristics” of a tumor into account? This is, essentially, precision preventive medicine of a sort, isn’t it? 

A:

  • MammaPrint is currently the only FDA cleared test for risk of recurrence of breast cancer within five years of diagnosis in women of all ages, both premenopausal and postmenopausal.
  • It is indicated for use on tumors that are ER+/-, HER2 +/-, all tumor sizes up to 5cm, up to 3 positive LN, and is unaffected in patients with metabolic syndrome or its components (obesity, diabetes, HTN).
  • The MammaPrint test was created independently of endocrine therapy treatment for 5 years (this therapy treatment reduces the risk of recurrence by approximately 50%). Many patients do not realize that their risk of recurrence statistics from some of the other tests depends on them taking Tamoxifen or another type of aromatase inhibitor for five years or more.
  • MammaPrint provides a binary result, genomic High or Low risk, with no confusing intermediates. [The PROMIS study, in fact, was a prospective trial that evaluated the clinical impact of the 70-gene test (MammaPrint) on patients who were previously given an indeterminate/intermediate result with the 21-gene test (Oncotype). The use of the MammaPrint resulted in a 76% change in treatment decision, thus preventing overtreatment and undertreatment in patients who had an indeterminate result with the 21-gene test. The PROMIS data also identified both High and Low risk MammaPrint patients in each of the intermediate range results, 18-30, from the 21-gene test].
  • MammaPrint contains the 70 significant prognostic genes, identified after assessing the entire human genome of 25,000 genes. Each of these genes falls into one of the 7 pathways involved in the process of breast cancer metastasis. That means more genes, encompassing all the pathways, provide more in-depth information about the genomic anatomy of the tumor, which in turn provides more useful data to help determine a treatment plan.

Just like a thumbprint, every tumor is different. “Individual biologic characteristics” refers to the specific genes in a tumor which helps to identify what is driving the growth. This type of genomic testing helps design a personalized medical treatment plan tailored to each patient’s specific needs. By using both the MammaPrint test (which determines the risk of recurrence for metastatic disease) and the BluePrint test (which identifies the molecular subtype, or genes that are driving the growth), the doctor will have the tools necessary to create a treatment plan specifically for the patient.

Q: The MINDACT trial assessed the average risk of recurrence at 5 years in early stage breast cancer patients, and in the subgroup of patients with hormone receptor positive, HER2 negative, lymph node (and up to 3 positive nodes) negative breast cancer. What other subgroups of patients were enrolled? Were those subgroups independently analyzed to understand if patients there may also forego chemotherapy if deemed at low genetic risk?

A: The primary test population, clinical high/genomic low for the MINDACT trial consisted of: 58% >2cm; 93% Grade I or ii; 48% LN+ 1-3; 98% Hormone receptor+

Patients enrolled in the MINDACT trial ranged in age from 18 to 70, had tumors up to 5 cm in size, Grade 1-3, up to 3 positive LN, and were ER +/– and HER2 +/- . This data is being further evaluated for additional conclusions.

BluePrint, the molecular subtyping laboratory-developed test developed and performed exclusively by Agendia, was compared to traditional pathological subtyping using the MINDACT patients’ data. In this evaluation, BluePrint reclassified 16% more patients to Luminal A, 38% of HER2+ patients were reclassified to Luminal, and 54% of Luminal B patients were reclassified to Luminal A. BluePrint identified 24 out of 531 (5%) as Luminal rather than Basal as identified through standard pathological testing. Outcomes for these reclassifications are excellent.

Q: The trial was designed to follow patients for a minimum of 10 years after randomization. Is a follow-up analysis by 2021 likely to be published?

Yes. Based on when the patients enrolled in the trial, some have already been followed for nine years; however, they will be re-evaluated to provide 10-year data. It is important to emphasize that the primary objective of the trial of the chemotherapy question was answered in the 5-year cutoff (Based on Oxford overview).

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