Genomic Assays Advance Personalized Care in Early-Stage Breast Cancer

Mariana Chavez Mac Gregor, MD, MSc

The collective results of the MINDACT and TAILORx trials provided a better directive in terms of whether or not to give endocrine therapy alone or in combination with chemotherapy for patients with node-negative, early-stage hormone receptor (HR)—positive, HER2-negative breast cancer, said Mariana Chavez Mac Gregor, MD, MSc.

“In patients who have early-stage HR-positive, HER2-negative disease, genomic platforms have really changed clinical practice,” said Chavez Mac Gregor. “These tools are helping us identify patients who are not going to need chemotherapy, and in doing so, preserve outcomes without the toxicities of treatment.”

In both trials, the majority of women with a lower risk of recurrence according to 2 widely available genomic assays—MammaPrint and Oncotype DX—were as likely to benefit from endocrine therapy alone as they were from the addition of chemotherapy.^1,2

Although patients had predominantly node-negative disease in both studies, MINDACT accrued a small subset of patients with node-positive disease. These patients with clinically high-risk and genomically low-risk disease did well without chemotherapy, according to the subset analysis. However, the question of whether to continue giving chemotherapy to patients with lymph node involvement, thereby adhering to historical standards, remains unclear.

In the phase III RxPONDER trial (NCT01272037), investigators may be able to prove what has only been shown to be true retrospectively—that patients with node-positive disease may not need chemotherapy. In the trial, approximately 10,000 patients with 1 to 3 positive lymph nodes and a recurrence score of ≤25 will be randomized to receive either tamoxifen and aromatase inhibitor monotherapy or the combination for 5 to 10 years with or without chemotherapy.

In the interim, Chavez Mac Gregor explained that although these assays have helped shed light on what optimal adjuvant therapy looks like for patients, personalization and patient preference play equally important roles in these discussions.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Chavez Mac Gregor, associate professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the optimal applications of these genomic assays in patients with early-stage, HR-positive/HER2-negative breast cancer and shed light on the overall outlook of personalized medicine in this setting.

OncLive^®: What are the key takeaways from the TAILORx and MINDACT trials?

Chavez Mac Gregor: The data that were presented from the TAILORx trial at the 2018 ASCO Annual Meeting by Joseph Sparano, MD, of Albert Einstein College of Medicine, demonstrated that patients with a recurrence score between 11 and 25 and node-negative tumors do not benefit from chemotherapy. The only caveat is young patients, particularly those younger than the age of 50, may experience a benefit with chemotherapy.

Is a patient’s risk of recurrence the biggest directive in terms of treatment for these patients?

Correct. We want to cure these patients, and prevent a recurrence with our systemic treatments. We have tools available for patients with HR-positive tumors; one is endocrine therapy. We know that patients with HR-positive tumors should receive endocrine therapy. The question is, “Which patients need chemotherapy?” If we give chemotherapy, all patients are going to have side effects, and we're not going to benefit all of [the patients].

That's the key question, and we're evaluating that now in patients with node-positive disease. Clinical trials are evaluating this, such as RxPONDER, which we’re awaiting the results of. These trials will help us determine if patients with 1 to 3 positive lymph nodes with recurrence scores <25 benefit from chemotherapy or not.

We do have retrospective data in this group of patients suggesting that the biology is very important. Even in this group of higher-risk patients, those with lower recurrence scores may not benefit from chemotherapy. We have data from another genomic platform called MammaPrint. This assay was used in the MINDACT study and included patients with lymph node involvement. The trial showed that patients who are high-risk clinically, but low-risk genomically have excellent outcomes. This means that adding chemotherapy is probably not necessary. That's an area where we are also starting to think differently.

Many patients with lymph node involvement continue to receive chemotherapy. However, we're learning how to tailor and personalize treatment based not only on the extent of disease—which is what we have done traditionally—but also on the biology.

Pending these results, does chemotherapy remain the standard for patients with 1 to 3 involved lymph nodes?

In general terms, I still believe that chemotherapy is the standard of care. However, it's very important to individualize [treatment]. I have no doubt that chemotherapy would be of benefit to a young patient with 3 lymph nodes involved, those with lymphovascular invasion and high-grade tumors. It’s very different if a patient has a luminal grade 1 tumor. It’s very likely that if that patient benefits from chemotherapy, the benefit is going to be very small, at around a 1% to 2% absolute benefit. Of course, chemotherapy has toxicity. If you have an older patient, or a patient who has comorbidities, it's appropriate to question whether chemotherapy is appropriate and to discuss that benefit with them.

In my practice, I believe that patients need to be part of this discussion. I believe in shared decision making. The perception of risk and benefit is based on the individual. I have patients who are willing to take chemotherapy for a 2% to 3% benefit, whereas others will not consider it for more than a few seconds. It's a very challenging discussion, but it's very interesting, and it's going to change in the next 5 years with the results of all these trials.

Are consensus guidelines in agreement in terms of how to broach these options?

We have different guidelines. We have the ASCO guidelines, which do not endorse the use of Oncotype DX in node-positive patients. There may be a revision, but they're not endorsing its use in this setting yet. The National Comprehensive Cancer Network pathway-based guidelines include MammaPrint and Oncotype DX, but Oncotype DX comes as a lower category recommendation in node-positive patients. Both guidelines advise the use of one of these assays in node-negative patients; that has become standard of care. In summary, the guidelines are very consistent regarding which ones to use in node-negative patients. There is a little bit more variation in their recommendations in terms of lymph node—positive patients.

It's very important to mention that even when the guidelines are consistent, as is the case in the node-negative patients, that doesn't necessarily mean every single patient needs to get the test. I would not order a test, but rather recommend chemotherapy in a young patient who has clinical characteristics that suggest aggressive biology. The same is true in the opposite case. There’s no need to order the test in a sick patient with many comorbidities who wouldn’t be a candidate for chemotherapy, regardless of the score. There has to be some personalization and individualization [in our approach].

Moving forward, what research would you like to see further explored?

It's going to be very interesting to see the results from the RxPONDER trial. The trial just completed accrual and is randomizing patients with 1 to 3 positive lymph nodes with a recurrence score <25 to receive chemotherapy or not. The overall results are going to be very important in addition to the biomarker analysis. There might be more than just the absolute score [that we have to pay attention to]. Similarly, biomarker studies from MINDACT are going to be very interesting [in that we will be able to] see patients who have different types of mutations or different sensitivity to chemotherapy. [If we can identify whether there] are characteristics in their tumors, hopefully we'll be able to identify which patients need this treatment. This information will allow us to personalize and tailor our therapies even further.

References

1. Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi: 10.1056/NEJMoa1602253.
2. Sparano JA, Gray RJ, Wood WC, et al. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-neg- ative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol. 2018;36(18 suppl; abstr LBA1). doi: 10.1200/ JCO.2018.36.18_suppl.LBA1.