Stress and pain linked to worse outcomes in HER2-positive breast cancer patients

Secondary analyses of a phase 3 clinical trial have revealed that breast cancer patients who reported high levels of pain and stress were more likely than their study peers to experience worse invasive disease-free survival (iDFS) and worse overall survival (OS). Shipra Gandhi, MD, MS, Associate Professor of Oncology in the Department of Medicine, Roswell Park Comprehensive Cancer Center, will discuss the study as first and presenting author of "Association of higher baseline stress and pain with clinical outcomes: Secondary analysis from Alliance A011502" at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, May 31-June 4.

Alliance A011502, a randomized, double-blind clinical trial, enrolled 3,021 patients with high-risk, human epidermal growth factor receptor 2 (HER2)-positive breast cancer between January 2017 and December 2020. Its primary objective: to compare invasive disease-free survival between patients who received 300 mg of aspirin daily vs. those who received placebo. While the resulting data showed no difference in iDFS between the two groups, the study's secondary objective -; to look for links between inflammation-related factors such as stress, depression, poor sleep quality and pain -; led to the observation that patients who self-reported higher stress and pain at the time of randomization had worse outcomes than other participants.

We observed an association of high stress with worse clinical outcomes, and this underscores evidence gleaned from previous research that stress could weaken the immune system and increase a patient's vulnerability to cancer."

Dr. Shipra Gandhi, MD, MS, Associate Professor of Oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center

At baseline, 2,735 study participants completed the Perceived Stress Scale (PSS); 2,720 completed the Brief Pain Inventory (BPI); 2,422 completed the Pittsburgh Sleep Quality Index (PSQI); and 2,610 completed the Center for Epidemiologic Studies Depression Scale Revised (CESD-R). Stress was categorized by PSS scores: low (0-13), moderate (14-26) or high (27-40). Pain was categorized by BPI scores: none/mild (0-3) or moderate/severe (≥16). Median follow-up was 35 months.

While poor sleep quality and depression were associated with worse iDFS and OS, they were not statistically significant. However, high PSS correlated with significantly worse iDFS and (non-significant) worse OS. Moderate/severe average pain was significantly associated with worse iDFS and OS.

Given the possible association between cancer physiology and the sympathetic nervous system, the study raises the question of whether beta blockers could improve survival in those patients -; a strategy under investigation in clinical trials led by Dr. Gandhi and her Roswell Park colleagues. Previously the team discovered in preclinical studies that chronic stress activates nerves that produce norepinephrine, which weakens the immune system's ability to fight cancer -; but the beta blocker propranolol, widely used to treat high blood pressure, can block the action of norepinephrine. Roswell Park investigators were first to demonstrate in a prospective clinical trial that combining propranolol with pembrolizumab (Keytruda), a type of immunotherapy called an immune checkpoint inhibitor, produced a very promising 78% response rate in patients with metastatic melanoma, superior to the standard of care treatment.

"There's a clear need for additional research to generate more information about how pain and stress affect the immune system and how we might be able to mitigate those effects," says Dr. Gandhi. "We hope future clinical trials will support that effort by including questionnaires for cancer patients to self-report pain and stress at baseline, with the goal of finding ways to intervene and improve outcomes over the long term."

Abstract senior author Wendy Chen, MD, MPH, Senior Physician in Breast Oncology at Dana-Farber Cancer Institute, was study chair of the clinical trial, which was sponsored by the Alliance for Clinical Trials in Oncology and funded by grants from the National Cancer Institute.

Presentation details

Association of higher baseline stress and pain with clinical outcomes: Secondary analysis from Alliance A011502

  • Abstract 11016, Presentation 8
  • Monday, June 3, 2:21-2:27 pm CDT

In a related poster session, Dr. Gandhi will discuss a clinical trial in progress at Roswell Park that is evaluating the use of a beta blocker in combination with pembrolizumab for patients with metastatic triple-negative breast cancer: "A phase II trial to assess the impact of β2 adrenergic blockade in immune checkpoint inhibitor (ICI)-refractory metastatic triple negative breast cancer (mTNBC)."

  • Abstract TPS1141, Poster Board 108b
  • Sunday, June 2, 9-noon CDT

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