Pathological Complete Response May Help Predict Breast Cancer Outcomes

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: The results of the I-SPY2 study point to a “strong and consistent association” between pathological complete response (pCR) to treatment and the likelihood of a high-risk breast cancer patient achieving 3-year event-free survival (EFS) and distant recurrence-free survival (DRFS).

The platform trial recruited 950 women with operable stage 2–3 breast cancer at least 2.5 cm in size who had not previously undergone surgery or systemic therapy, explain Laura Esserman, from the University of California, San Francisco in the USA, and fellow I-SPY2 Trial Consortium investigators.

This included 361 patients with hormone receptor (HR)-positive, HER2-negative disease, 173 with HR-positive, HER2-positive disease, 326 with HR-negative, HER2-negative tumours and 90 with HR-negative, HER2-positive disease.

However, the trial focused on patients with a high genomic risk of early recurrence, and excluded those with HR-positive, HER2-negative disease who had a low 70-gene assay score, “as there is no benefit of cytotoxic chemotherapy in this subpopulation”, the authors say.

Based on molecular subtypes, the patients were randomly assigned to receive standard of care neoadjuvant taxane chemotherapy alone or alongside one of nine different investigational agents or combinations, followed by doxorubicin plus cyclophosphamide, and followed up for a median 3.8 years.

More than a third (34.7%) of the patients achieved a pCR to their treatment regimen, with the lowest rate in patients with HR-positive, HER2-negative disease (17.4%) and the highest rate in those with HR-negative, HER2-positive disease (68.0%). Rates of pCR were higher in the investigational than control arms, the researchers observe.

Moreover, the majority (95%) of patients with a pCR achieved 3-year EFS and DRFS, the researchers report.

Patients who achieved a pCR were significantly more likely to achieve 3-year EFS and DRFS than those without a pCR, with hazard ratios of 0.19 and 0.21, respectively. And these hazard ratios were similar when analysing patients by molecular subtype, ranging from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS.

“Regardless of subtype or treatment regimen, a strong and consistent association between individual pCR and EFS/DRFS […] was observed”, summarise Laura Esserman et al in JAMA Oncology.

“After 3 years of follow-up, a clear separation of the curves suggests that these results will persist over time, but this awaits further analysis and follow-up.”

The authors of a linked editorial caution, however, that the I-SPY2 findings only demonstrate the “I-association” for individual-level data between the “surrogate end point” of pCR and the “true end point” of EFS or DRFS.

They explain that the small I-SPY2 subgroups for each treatment assessed do not provide the trial-level data required to validate the “T-association” between effect of treatment on pCR and the effect of treatment on EFS or DRFS.

Both the I-association and T-association are ncecessary to prove a candidate surrogate endpoint as the true endpoint, the editorialists emphasise.

“When it comes to expediting the drug approval process, surrogate end points remain a strong option when the validity of the surrogate can be proved with I-association and T-association”, write Yu Shyr, from Vanderbilt University School of medicine in Nashville, Tennessee, USA, and Derek Shyr, from Harvard TH Chan School of Public Health in Boston, Massachusetts, USA.

“If researchers are not careful, surrogate end points could lead to misleading conclusions that may result in ineffective treatments for patients”, they conclude.

References

• I-SPY2 Trial Consortium. Association of event-free and distant recurrence-free survival with individual-level pathologic complete response in neoadjuvant treatment of stages 2 and 3 breast cancer. Three-year follow-up analysis for the I-SPY2 adaptively randomized clinical trial. JAMA Oncol; Advance online publication 23 July 2020. doi:10.1001/jamaoncol.2020.2535
• Shyr Y, Shyr D. What constitutes a valid surrogate end point in cancer clinical trials? JAMA Oncol; Advance online publication 23 July 2020. doi:10.1001/jamaoncol.2020.1847