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Agendia Adds to Data Supporting Breast Cancer Assay in Guiding Long-Term Endocrine Therapy Use

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NEW YORK – Data from a retrospective trial on the ability of Agendia's MammaPrint test to assess the risk of long-term breast cancer recurrence suggests that oncologists might able to use the assay to identify post-menopausal patients who may have an excellent prognosis with limited tamoxifen therapy.

Based on the study results, presented recently by collaborators from the Netherlands Cancer Institute at the European Society for Medical Oncology's Virtual Congress, Agendia speculated that with more evidence oncologists might eventually be able to use the test to identify low-risk patients who can entirely forego tamoxifen treatment.  

Tamoxifen is the oldest and most-prescribed selective estrogen receptor modulators approved by the US Food and Drug Administration to treat post-menopausal women diagnosed with estrogen receptor (ER)-positive, early-stage breast cancer post-surgery to minimize recurrence. However, the drug can lead to serious side effects, and breast cancer patients at particularly low risk of long-term recurrence may not need it.

Agendia's FDA-cleared MammaPrint assay analyzes the expression of 70 breast cancer recurrence-associated genes from a patient's recently resected tumor using Agilent's oligonucleotide microarray platform.

Assigning tumor subtype based on the biomarkers identified in the tissue, MammaPrint's algorithm then produces a risk score (high, low, and ultralow) that the firm says can help doctors decide which patients can avoid chemotherapy.

Agendia's previously published Stockholm tamoxifen trial (STO-3) initially showed that MammaPrint can identify patients at ultralow risk of late recurrence, or patients who may benefit from less endocrine-based treatment than is advised by the breast cancer community.

In the study presented earlier this month at ESMO, a team led by Sabine Linn, senior author and senior staff member in the medical oncology department at The Netherlands Cancer Institute, collected formalin-fixed paraffin-embedded (FFPE) samples from 736 breast cancer patients. Of those, 482 samples were ER-positive, HER-2-negative stage I to III cancer patients, and 346 had enough material afterward for RNA isolation and MammaPrint analysis. The team successfully established MammaPrint scores for 135 patients from the cohort.

While noting that both the ESMO and STO-3 studies both identified patients at ultralow risk of late recurrence, William Audeh, CMO of Agendia, pointed out that the new study's patients had a shorter duration of endocrine therapy than the STO-3 trial. Most patients either received no endocrine therapy or therapy for a single year, while the STO-3 trial had some patients who underwent two to five years of endocrine therapy.

"Finding the same excellent outcome in the ultralow group with even less therapy than the STO-3 trial further confirms the importance of identifying these ultralow patients," Audeh said in an email.

Linn said that she believes that the most important result of the relatively small study was that of the 16 node-negative, ultralow-risk patients, none developed a recurrence with a median follow-up of eight years. Linn and Audeh agreed that the latest results confirm data from the larger randomized STO-3 trial.

"As with the [STO-3] trial in 2017, this trial did confirm that those patients who fell into the ultralow category as defined by the MammaPrint Index had an excellent 10-year prognosis," Audeh said. "Although this study has somewhat less follow-up, it shows that ultralow-risk patients did well with relatively low or no treatment."

Because the size of the enrolled breast cancer patient cohort was smaller and patients varied in terms of disease stage, Audeh acknowledged that the trial lacks a definitive answer about the utility of the ultralow index in lymph node-positive patients. However, he highlighted that data from the lymph node-negative patient cohort is complete enough to demonstrate that the results correlated with the 2017 study.

Linn also acknowledged that a major limitation of the study involved extracting high-quality RNA from old FFPE samples from breast cancer patients who participated in the original randomized trial from 1982 to 1994.

"Hospitals are only obliged to keep patient materials for up to 15 years in the Netherlands, [and so] it was a challenge to recollect enough tumor material and [perform] long-term follow up for these patients," Linn said in an email. "We only obtained a 70-gene signature result in 28 percent of cases, and this limited the statistical power of our study."

Agendia has received a CE mark and FDA 510(k) clearance to market MammaPrint as a prognostic test to determine if a cancer patient has sufficiently low recurrence risk, information that oncologists may use to decide how aggressively to treat a patient (i.e. with or without chemotherapy). However, Audeh said that more evidence is needed before oncologists can confidently use MammaPrint to identify which patients may entirely forgo endocrine therapy.

"However, we can say that if [the patient] is embarking on anti-estrogen therapy and has an ultralow index, the data supports the decision to stop early, since these studies show that MammaPrint ultralow-risk women did extremely well with less than the standard five years of endocrine therapy," Audeh explained.

Audeh pointed to breast cancer patients who might have deleterious side effects to standard anti-estrogen therapy over the course of treatment. Since some patients have trouble completing the full five years of therapy, the firm believes that a certain portion might be able to cease treatment and still achieve an excellent prognosis.

"It's best if these patients [can continue], but knowing that they're ultra-low might make it comfortable for the physician to tell them to stop early if they have rough side effects, as this gives extra reassurance that the woman will do very well," Audeh said.

Future research

The researchers now plan to follow patients even longer, for up to 20 years, and collect more evidence on how patients with ultralow MammaPrint results fare with or without long-term endocrine treatment.

Agendia is not the only diagnostic firm focused on refining late recurrence risk assessments and treatment strategies for early-stage breast cancer patients. Genomic Health is currently collecting clinical data on the ability of its Oncotype Dx breast cancer test to predict endocrine therapy response. Biotheranostics is similarly advancing its Breast Cancer Index test to predict benefit from extended endocrine therapy in patients with early-stage, ER-positive tumors.

Meanwhile, two Medicare Administrative Contractors recently denied Myriad Genetics expanded coverage of its EndoPredict assay to assess the benefit of extended endocrine therapy for breast cancer patients.

While Agendia's two retrospective studies focused on tamoxifen, the breast cancer oncology community has more recently turned to aromatase inhibitors, which are relatively more effective at reducing estrogen levels and recurrence risk. Audeh believes that the risk-based use of aromatase-inhibitor treatment may not differ much from tamoxifen.

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