Does Precision Medicine Aid or Complicate Treatment Decisions in Cancer?

Based on the results of the MINDACT trial, investigators have concluded that chemotherapy is unnecessary in women with early-stage breast cancer who have a high clinical and low genomic risk of disease recurrence.

Five-year outcomes from the MINDACT trial—a multinational study that enrolled patients at 112 institutions across 9 European countries—have been published in the New England Journal of Medicine (NEJM). The study authors have concluded that chemotherapy is unnecessary in women with early-stage breast cancer who have a high clinical and low genomic risk of disease recurrence.

Adjuvant systemic therapy—either chemotherapy, endocrine therapy, or agents targeting the epidermal growth factor receptor 2—is common in early-stage breast cancer patients. However, there are mixed views on the impact of these treatments on improving clinical outcomes and to address this discrepancy several gene expression profiling studies were conducted to better predict a woman’s risk of disease progression and more importantly, response to treatment. One such test is the 21-gene Oncotype DX, which can predict disease recurrence and response to chemotherapy in estrogen receptor—positive, lymph node–negative early stage breast cancer. The other is MammaPrint, a 70-gene test that was evaluated by authors of the current NEJM study in a prospective trial “to support clinical—pathological criteria in selecting patients for adjuvant chemotherapy.”

MINDACT determined the genomic (using MammaPrint) and clinical (using a modified version of Adjuvant! Online) risk of 6693 women with early-stage breast cancer. Treatment criteria were:

  • Low clinical and genomic risk: no chemotherapy
  • High clinical and genomic risk: chemotherapy
  • Discordance between genomic risk and clinical risk: either result can be used to determine chemotherapy treatment.

The primary objective of the trial was to assess whether MammaPrint could help decide the need for use of chemotherapy in patients with high clinical risk and low genomic risk of disease recurrence. The primary trial endpoint was event-free 5-year survival; secondary endpoints were overall survival, disease-free survival, and proportion of patients who received chemotherapy based on clinical risk compared with genomic risk.

The trial found that about 23% of patients (1550) were at high clinical and low genomic risk; holding back chemotherapy resulted in a 94.7% 5-year survival rate in this group of patients (95% confidence interval [CI], 92.5 to 96.2). The absolute difference in survival rates was 1.5 percentage points—lower for the no-chemotherapy cohort.

The results could be confounding, especially for a patient who’s analyzing the information presented to her to make important life decisions. The authors acknowledge that their study identified important tradeoffs for patients deemed high-risk based on their clinical-pathological features. They observed obvious discordance between the risk-assignment methods: 63% of patients at high clinical risk with 1 positive node were deemed to have a low genomic risk by MammaPrint, while 55.8% of patients at high clinical risk and with 2 to 3 positive nodes were determined to have a low genomic risk based on their gene signature.

The study concludes that unnecessary toxic chemotherapy could be avoided in patients with a low genomic but high clinical risk of disease recurrence, with a slightly increased risk of distant metastases in the absence of chemotherapy. Is the slightly increased risk worth all the toxic effects that the women would have to endure with chemotherapy?

“The new tools will definitely be helpful, but they often will pose challenges about what the right decision is,” David Hunter, MBBS, MPH, ScD, professor of cancer prevention at Harvard's T.H. Chan School of Public Health, told NPR, adding that physicians as well as patients need better decision-support tools.

The authors are collecting more long-term (10-year outcomes) data for continued evaluation of risk of relapse in these patients.

MammaPrint and Onctotype DX both cost about $4000 and in many cases are covered by insurance.

Reference

Cardoso F, Van't Veer LJ, Bogaerts J, et al; MINDACT Investigators. 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.