NEW YORK – Oncologists used Reveal Genomics' predictive assay, HER2DX, to alter neoadjuvant and adjuvant treatment plans for nearly half of their early-stage HER2-positive breast cancer patients, three-quarters of whom saw a de-escalation in their treatment, a real-world study has shown.
The observational study included nearly 300 patients with newly diagnosed stage I to stage III HER2-positive breast cancer treated at 12 hospitals across Spain. The researchers used a questionnaire to measure the treating oncologists' confidence in HER2DX, 27-gene expression test and whether they changed their treatment plan based on the results. Each oncologist completed a questionnaire to document their initial treatment plan and their level of confidence in their initial approach prior to seeing the results, and then, they answered the same questions after seeing the HER2DX results.
Treatment de-escalation is a growing area of interest in breast cancer. Particularly for patients with early-stage or low-risk breast cancer, there are several tests that can guide treatment de-escalation decisions. In recent years, tests and prediction models from Exact Sciences, Agendia, and several academic research groups have shown promise in de-intensifying breast cancer treatment involving radiation therapy, endocrine therapy, CDK4/6 inhibitors, and other approaches.
Typically, physicians consider several systemic options for patients with early-stage breast cancer, weighing whether to give both neoadjuvant and adjuvant treatment, whether patients should receive single-agent or multi-agent chemotherapies along with HER2 targeted therapies, and the duration of these regimens.
The real-world study results, published in ESMO Real World Data and Digital Oncology earlier this month, showed that oncologists altered treatment plans for half of the breast cancer patients included in the analysis based on the HER2DX results and that physicians' confidence in their treatment plans improved after using the test.
"We've done substantial validation of HER2DX over the last four years, but now was the moment to show that we could do a prospective trial to test how the physicians and the patients see the clinical situation without the test and with the test, then follow those patients to see how they did [on HER2DX-informed treatment]," said Aleix Prat, study coauthor and CSO at Reveal Genomics.
HER2DX gauges the expression of 27 genes and measures immune infiltration, luminal differentiation, tumor cell proliferation, and HER2 amplicon expression in tumor tissue alongside various clinical data inputs. The test produces scores on the likelihood of cancer recurrence, treatment outcomes, and ERBB2 expression level. The key differentiating factor for HER2DX, according to Prat, is its assessment of immune-related biomarkers.
Reveal, in 2022, first made the test commercially available in Spain, where it is based. In the US, the test is available for research use only, but Reveal hopes to bring it to the market soon.
In the real-world study, HER2DX identified around 53 percent of patients as having a low risk of recurrence and the rest as having a high risk of recurrence. The test also identified at baseline that around 37 percent of patients had a low likelihood of experiencing a pathological complete response (pCR), 29 percent had a medium likelihood of a pCR, and 35 percent had a high likelihood of having a pCR. Most patients included in the study, around 70 percent, had high ERBB2 mRNA expression, and around 10 percent had low ERBB2 expression, and nearly 19 percent had medium ERBB2 expression. These results were consistent with prior validation studies.
Based on these results, researchers reported treatment plan changes for around 48 percent of cases. Most of the patients with treatment changes, around 74 percent, had their treatment de-escalated. Of those, 56 percent had a reduction in chemotherapy intensity, 27 percent experienced a reduction in anti-HER2 therapy, and 17 percent had reductions in both.
"What we saw is that, in the vast majority of cases, there was de-escalation of therapy, mostly of chemotherapy," Prat said. "We're very pleased about that because it really shows that physicians want to de-escalate, and a tool like HER2DX can really help them make that decision."
In the one-quarter of patients who had their treatment intensity increased based on HER2DX results, 57 percent had another anti-HER2 agent added to Genentech's Herceptin (trastuzumab), such as Genentech's Perjeta (pertuzumab) or Puma Biotechnology's Nerlynx (neratinib); 20 percent had more intensive chemotherapy; and 23 percent received both.
Of 182 patients who had pCR results as of the data cutoff, the researchers found that the HER2DX-predicted pCR likelihood score was significantly associated with the actual pathological complete response outcomes. The pCR rate was comparable between patients who had HER2DX-informed treatment changes and those who didn't, 56 percent versus 57 percent, respectively.
Patients who according to HER2DX had a high likelihood of achieving pCR fared similarly on single-agent chemo with dual HER2 treatments Herceptin and Perjeta or multi-agent chemo with dual HER2 blockade. Of pCR-high patients who received single-agent chemo with the HER2 therapies, 82 percent achieved a pCR, compared to 69 percent for pCR-high patients who received multi-agent chemo with the HER2 treatments.
"When the physician de-escalated to a single-agent taxane [chemo], trastuzumab, and pertuzumab instead of multi-agent chemo, trastuzumab, and pertuzumab, which is a big thing for patients in terms of toxicity and duration of therapy, the pCR rates were similar," Prat said. "This suggests when you de-escalate using the HER2DX test, you don't compromise the efficacy of these therapies."
Among patients that HER2DX predicted had a medium likelihood of achieving a pCR, around 70 percent achieved a pCR on multi-agent chemo with dual HER2 blockade, compared to 48 percent who received single-agent chemo with dual HER2 blockade. In the group of patients predicted to have a low chance of pCR, the actual pCR outcomes were similar between the single-agent and multi-agent chemo groups, 35 percent and 39 percent, respectively.
In the study, the researchers also measured whether treating physicians had confidence in the HER2DX test results. The researchers asked the physicians to rate on a five-point scale their confidence level in their treatment plans before and after the HER2DX test results. They found that the median self-reported confidence score increased from four to five, the maximum confidence, after seeing the HER2DX results.
Finally, the researchers examined the cost-effectiveness of the HER2DX test and subsequent treatments. The HER2DX assay cost €2,950 ($3,190) per test, and the median turnaround time was seven working days. Across nearly 300 cases, they found there were significant cost savings in the regimens guided by HER2DX, with total net savings of €98,031. The researchers concluded that while the upfront cost was higher for HER2DX-guided regimens, the test facilitated regimen optimization and reduced overall treatment costs.
"We've seen over the years in early-stage HER2-positive, and also HER2-negative, disease that there's overtreatment and that has been escalating with new therapies. So, the need was there," Prat said. "For patients, the value of having treatment de-escalated with an appropriate assay is in terms of quality of life. For the health system, it's about reducing the resources that they use. And for physicians, they have confidence in their decisions and are able to tell patients that they have a tool that helped to make their decisions."
Reveal is continuing to study the use of HER2DX in the real-world setting. The firm is also conducting a prospective trial in seven countries in Europe in which half of the patients enrolled will have their treatment informed by HER2Dx. The study will measure patients' quality of life based on HER2DX-guided treatments and the utility of the test. In the US, ECOG-ACRIN is also evaluating HER2DX's predictive scores against patient outcomes.