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Genomic Testing in Early Breast Cancer – Who, Which Test, When

Dr. Reshma Mahtani, from Miami Cancer Institute, and Dr. Terry Mamounas from Orlando Health Cancer Institute, present during the first-ever US-based ESMO Conference – 2022 ESMO Florida.

At this year’s first-ever US ESMO Review conference held in Fort Lauderdale Florida, Dr Reshma Mahtani from Miami Cancer Institute, and Dr Terry Mamounas from Orlando Health Cancer Institute held a joint session dealing with diagnostic testing in early breast cancer, specifically, which patients to test, which test to use, and when to test.

Dr Mahtani began the discussion with an overview of the available genomic tests for early breast cancer, noting that these have been a valuable addition to the more traditional clinical and pathologic factors such as nodal status, and hormone receptor status as a means to direct patients to more aggressive therapies such as chemotherapy, or the need to extend treatments such as adjuvant endocrine treatment. She added, however, that when estimating risk of recurrence, genomic testing is an accurate predictor, but the addition of clinicopathologic factors can further improve risk assessment.

Dr Mamounas noted that, for all of the genomic tests currently in use, the ability to predict distant recurrence was a key endpoint in their validation, and that all genomic classifiers were shown to be independent predictors, over and above the traditional clinico-pathologic prognostic markers. Despite this, he noted that factors such as tumor size, nodal status, grade, and age of the patient continue to be factors that help to refine prognosis, even when genomic classifiers are taken into account. He used the example of the RSClin tool, which incorporates genomic recurrence score (RS), as determined by the Oncotype Dx test, as well as age, grade, and tumor size, and noted that all of these clinical factors were shown to add to the prognostic model for node-negative patients when incorporated with the RS. Dr Mamounas emphasized, however, that whereas clinical factors are prognostic (for recurrence risk) they are not necessarily predictive (i.e., for chemotherapy or endocrine therapy benefit).

Dr Mahtani then addressed the question of whether all of the available genomic tests are essentially the same, despite differences in technologies, the use of markedly different gene panels, and the methods by which they were developed. She noted the “somewhat unsettling” results from the OPTIMA trial, which showed disagreement in risk classification among the different tests approximately 60% of the time. In another 2018 analysis comparing the different tests on the basis of their gene profiles, Dr Mahtani noted that the RS score was found to be more weighted toward estrogen receptor driven genes, as opposed to known proliferative genes. Dr Mamounas noted too that, despite the fact that they are all prognostic for recurrence, some of the tests have no overlap whatsoever among the genes examined, although most tests appear to focus on similar biologic pathways.

In a comparison of the tests (originally presented at San Antonio Breast Cancer Symposium 2018), the results suggested that, for node negative (pN0) patients, compared to Oncotype Dx, the Prosigna, Breast Cancer Index (BCI), and EndoPredict tests were significantly more prognostic for overall and late distant recurrence, whereas none of the tests provided independent prognostic information for patients having between 1 and 3 positive nodes. An important caveat of this study which Dr Mamounas noted was that some of the tests included clinical factors as a component of the prognostic model, as opposed to genomic information only; a more ideal comparison would have incorporated only the genomic information or the genomic information plus the clinical factors (i.e., size, grade, nodal status) for all of the tests that were compared. Despite these limitations of the study, however, he emphasized that the available evidence to date shows that the tests are clearly different and should not be considered interchangeable.

Dr Mahtani also noted the significant problem of when patients are seen in a second opinion consultation, after having received more than one test, noting again the significant differences among the tests. She noted for example, one trial, PROMIS, in which tumors with an RS in the intermediate risk range (as determined by Oncotype Dx) were also tested using the 70-gene assay (MammaPrint). The 70-gene assay re-classified intermediate patients as low risk in almost 45%, and high risk in 56% of the patients. These high-risk and low-risk patients were found at every RS within the intermediate range.  Both panelists agreed there is no reason to order 2 tests (with the additional caution that insurance may not cover 2 tests) and that, when faced with the prospect of 2 conflicting test results, the test which provides the greatest amount of information in terms of making a treatment decision should be given preference.

The panelists briefly outlined the results from 3 major clinical trials integrating genomic testing, TailoRx, MINDACT, and RxPonder, all of which showed an apparent impact of age/menopausal status on chemotherapy benefit. They noted that that for premenopausal patients, or in those under 50 years of age, there was benefit from chemotherapy in patients with intermediate genomic risk, whereas there was no benefit in postmenopausal patients. They noted this could be due (at least in part) to an indirect effect of chemotherapy inducing ovarian function suppression (OFS), as opposed to a direct cytotoxic effect of the chemotherapy. In alignment with this hypothesis therefore, maximizing endocrine therapy by using OFS in combination with an aromatase inhibitor (AI) could provide a safe alternative to the use of chemotherapy in this subgroup of patients.

In this regard, the presenters also reviewed the design of the NRG Oncology BR009 trial, currently in development, which aims to assess the impact of chemotherapy in premenopausal, HR+/HER2- early-stage breast cancer patients treated with OFS plus an AI. Eligible patients for the trial include pN0 patients with RS 16-20 (high clinical risk) or RS 21-25, as well as pN1 patients with an RS of 0-25. Patients are stratified by nodal status (pN0 vs. pN1), RS (0-15 vs 16-25) and age (>40 vs. <40), and randomized to treatment with chemotherapy + OFS + AI (5 years), versus OFS + AI (5 years) without chemotherapy (or if AI is not tolerated, tamoxifen can be used).

Dr Mahtani noted that major guidelines such as those of the American Society for Clinical Oncology (ASCO) recommend the use of genomic tests in the population of patients who are hormone receptor (HR) positive, and HER2 negative, whereas no tests are currently indicated for those with HR negative or HER2 positive disease. There is also insufficient evidence at present to recommend any genomic test for node positive premenopausal patients 50 years of age or under, or in postmenopausal patients with 4 or more positive lymph nodes, although some studies are underway to address these questions.

With regard to the overall utility of using genomic testing to stratify patients, the presenters highlighted the worrisome finding that, despite 5 years of endocrine therapy and relevant clinical factors, some risk for recurrence nonetheless remains for all patients over time. For example, historical data show that even for patients with N0 disease, the risks for a distant recurrence and death from breast cancer are 22% and 15%, respectively, at 20 years. Dr Mamounas noted that, in terms of prognostic information, essentially all of the commercially available genomic tests predict both early and late recurrence risk (although for Oncotype Dx this is applicable to patients with high-ER expression by RT-PCR). The Breast Cancer Index (BCI), however, has been shown to not only predict risk of late recurrence risk but also to predict benefit from extended adjuvant endocrine therapy.

Summarizing the take home messages as presented at ESMO, it was noted that genomic tests can aid in clinical decisions regarding the need for chemotherapy in patients with HR+/HER2- early-stage breast cancer. Specifically, for post-menopausal patients with pN0 – pN1 tumors, those with genomic low or intermediate status can safely avoid chemotherapy, whereas chemotherapy should be used if their genomic risk is high. In premenopausal patients with pN0, those with low genomic risk can safely forgo chemotherapy, whereas for those with genomic intermediate risk, chemotherapy should be considered, and for those with genomic high-risk chemotherapy should be used. Notably, for those premenopausal patients with intermediate risk, a remaining question is whether similar improvement in outcomes seen with chemotherapy could be obtained by maximizing endocrine therapy with OFS + AI, and trials such as NRG Oncology BR009 are attempting to address this question more definitively.

Lastly, both panelists noted the important caveat that most of these genomic tests were validated using data from predominantly Caucasian populations, and as such, an important call to action that remains would be to validate these tests for use in more racially and/or ethnically diverse populations.

See more from the 2022 ESMO Florida Conference here.

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