OPTIMA: Prosigna Test Finds Which Patients With Breast Cancer Can Skip Chemotherapy

The OPTIMA trial presented during the American Society of Clinical Oncology (ASCO) Annual Meeting represents a landmark advance in the management of early breast cancer, addressing a question that has challenged clinicians and patients for decades: Which patients with clinically high-risk, hormone receptor–positive breast cancer truly benefit from adjuvant chemotherapy, and which can safely avoid it? Iain MacPherson, MD, PhD, FRCP, professor of breast oncology at the University of Glasgow and a study coauthor, explains some of the important results and what they mean going forward in this interview with The American Journal of Managed Care® (AJMC®).

Using the Prosigna genomic test (Veracyte), this phase 3 trial (ISRCTN42400492) demonstrated that approximately two-thirds of women who would historically have received chemotherapy can safely forgo the treatment without a meaningful increase in the risk of cancer recurrence. This finding has significant implications for reducing patients’ exposure to the well-known toxicities associated with chemotherapy while maintaining equivalent oncologic outcomes. A preliminary estimate suggests that for every 3 Prosigna tests administered, chemotherapy is avoided in 2 patients, pointing toward a highly favorable economic profile.

This transcript of an interview with MacPherson is lightly edited.

AJMC: What problem was OPTIMA designed to solve, and why do the results matter for patients with early breast cancer?

MacPherson: Optima is really a landmark clinical trial in early breast cancer, and that’s because it’s set out to solve a problem that clinicians and patients have been [dealing] with for decades, and that’s the question: Which patients with clinical high-risk hormone-sensitive breast cancer benefit from a course of adjuvant or preventive chemotherapy following surgery, and similarly, which patients might be able to safely avoid that course of chemotherapy—and all that comes with chemotherapy—in terms of the various toxicities?

So, we set out to address this in OPTIMA. We’ve been able to show that using a test called Prosigna, we can identify about two-thirds of women who, up until now, would have received chemotherapy who can safely avoid receiving that treatment with no associated or no meaningful increase in risk of the cancer returning. Importantly, we have also recruited patient populations that have not been represented in previous clinical trials in this area, and specifically, that’s patients really at the highest clinical risk of recurrence by virtue of their cancer stage. These are patients with, for example, more than 4 involved auxiliary lymph nodes; prospective evidence has been lacking for this patient group.

The other important thing about OPTIMA is that we looked at premenopausal women; results with tests like Prosigna in premenopausal women have been very mixed so far, and currently, guidelines generally would recommend against test use in premenopausal women with high clinical risk. This group was included in OPTIMA. We’ve shown that our results apply equally to both postmenopausal and premenopausal patients.

AJMC: Nearly 70% of patients in the per-protocol population had low scores for risk of recurrence. What does that tell us about how many patients may be overtreated under current standard approaches?

MacPherson: In OPTIMA, we found that nearly 70%, or over two-thirds of patients who would ordinarily have received chemotherapy, had a low Prosigna risk-of-recurrence score in their tumor, and therefore were able to avoid chemotherapy. And we showed by following up with these patients very carefully that at 5 years, the end point we looked at, invasive breast cancer–free survival, was no different, according to whether or not chemotherapy had been given. So, the implication is that we can now apply these data, we can allow two-thirds of women who would have received chemotherapy to safely avoid that treatment, and the various toxicities, both physical, emotional, social, time, and financial that come hand-in-hand with a course of chemotherapy. On the other hand, for the one-third of patients now who do have a high Prosigna risk-of-recurrence score, we have even greater confidence that that treatment is actually making a difference—and a much larger difference than we would have quoted based on historical data applied to the whole population.

AJMC: OPTIMA included premenopausal patients, who are historically underrepresented in this field. Why was it important to include this group?

MacPherson: It was important for OPTIMA to include premenopausal patients, and in particular to mandate a specific type of hormonal treatment. Within OPTIMA, premenopausal patients were required to receive a type of hormonal treatment called ovarian function suppression, and that would be given in addition to oral medications, such as tamoxifen or an aromatase inhibitor. The reason for that is that prior trials in this area have really failed to show that gene expression tests can identify a group of premenopausal women who do not benefit from chemotherapy, but the problem is these prior trials were really confounded by the fact that chemotherapy itself induces, at least temporarily, ovarian suppression in most premenopausal women who receive it. So, these prior clinical trials, which did not include ovarian function suppression, essentially were comparing tamoxifen in patients avoiding chemotherapy with tamoxifen plus chemotherapy plus chemotherapy-induced ovarian suppression. If the benefit that was seen in these trials was all to do with ovarian suppression, well, we can achieve that medically with drugs. We don’t need to give chemotherapy to do that. So…we think this is a key reason why we find that a test such as Prosigna works just as well in the premenopausal as postmenopausal population: We’ve controlled for or eliminated that confounding factor of chemotherapy-induced ovarian suppression.

I would just note, as well, that since the OPTIMA [trial was] conceived, ovarian function suppression really has become standard of care for this patient population. So, in fact, that would be part of their treatment now. That wasn’t the case when some prior trials of other gene expression assays were conducted.

AJMC: For a managed care audience thinking about coverage and formulary decisions, what is the economic argument for making Prosigna gene expression testing broadly available?

MacPherson: Our primary objective of OPTIMA was to study the health economics of a test-directed approach, and I would certainly hope that the design of OPTIMA is very helpful for health care systems, for payers, and being able to evaluate the evidence. We differ a little bit from previous studies in that, within OPTIMA, the randomization was either to a control arm, chemotherapy followed by endocrine therapy, or to a test-directed arm, the test being Prosigna; then, chemotherapy was given to patients with a high Prosigna risk of recurrence score. Chemotherapy followed by endocrine therapy, the same as the control arm, but for two-thirds of patients with a low score, chemotherapy was avoided. They moved straight to endocrine therapy.

So, what we’re actually doing with that design is comparing what happens when you do things without the test vs bringing the test in—and that comparison has been lacking previously. I think this will be very helpful to bodies making decisions about health economics and resource allocation. Now, the health economic analysis of OPTIMA was not presented during ASCO. That work is ongoing, and we would hope to present that at a major oncology conference later this year. Notwithstanding that, we can make a back-of-the-envelope calculation here. We know approximately how much a Prosigna test may cost providers; we know how much a course of chemotherapy and everything that goes with those costs, and we’ve shown that the outcomes are equivalent. Importantly, so that means for every 3 Prosigna tests we do, we will avoid giving chemotherapy to 2 patients, and that would suggest that the health economics will be very favorable. But the analysis will be presented later this year.

Reference

Stein RC, Makris A, MacPherson IR, et al; OPTIMA Investigators and Trial Management Group. First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer. J Clin Oncol. 2026;44(suppl 16):500. doi:10.1200/JCO.2026.44.16_suppl.500