Researchers identified factors that could help predict chemotherapy response

BCRF researchers have discovered key differences in the breast cancer cells and their tumor microenvironments between young and older patients that may contribute to different chemotherapy responses.

The study, led by BCRF investigator and Scientific Advisory Board member Dr. Lajos Pusztai, builds on the results of the groundbreaking, BCRF-supported TAILORx and RxPONDER trials. Both TAILORx and RxPONDER demonstrated greater chemotherapy benefit in early-stage breast cancer in younger women compared to older women when all patients received endocrine/anti-estrogen therapies. The reason for the difference in chemotherapy benefit has been unclear, so in this new study, Dr. Pusztai’s team focused on deciphering the factors that could explain this phenomenon.

Predicting treatment outcomes

Tumors exist within a tissue architecture and microenvironment composed of signaling molecules, blood vessels, and support structures, as well as different types of immune cells. For this reason, researchers examine many elements in and around tumor cells to pinpoint those factors that affect how people respond to treatments. The data generated from this work could reveal valuable information that, ultimately, informs decisions made between patients and their doctors.

Over the past 20 years, three molecular tumor features have emerged as reliable indicators for how people with early-stage hormone receptor (HR)-positive/HER2-negative breast cancers will respond to hormone therapy or chemotherapy:

  • The expression of estrogen receptor (ER)–regulated genes predicts sensitivity to endocrine treatment.
  • Genes associated with tumor cell growth (also called cancer cell proliferation) indicate greater chemotherapy sensitivity.
  • Specific markers that signify immune cells’ presence in the tumor microenvironment also predict neoadjuvant (pre-surgery) chemotherapy benefit.

Since the tumor’s immune microenvironment has emerged as a critical factor influencing how tumors behave—including how they respond to anti-cancer treatments—researchers are investigating how its specific components interact to influence treatment response. For example, recent work by Dr. Pusztai and his team showed that the composition of the immune microenvironment could predict response to immunotherapies in patients with either ER-positive or triple-negative breast cancers (TNBC). Prior to this study, TNBC was considered the breast cancer most likely to respond to immunotherapy, so this finding could extend the use of immunotherapy to more patients.

Other studies showed that age is not only a risk factor for cancer, but it also influences whether HR-positive/HER2-negative breast cancers respond to adjuvant (after surgery) chemotherapy: In women younger than 50, chemotherapy improved metastasis-free survival compared to endocrine therapy alone. This was not observed in older women.

To understand why chemotherapy may be more beneficial in younger women, Dr. Pusztai and his colleagues compared genetic profiles of more than 4,500 ER-positive/HER2-negative breast cancer samples from women under 50—the group where most of the chemotherapy benefit is seen—to those 55 years and older for whom chemotherapy provided no added benefit in the TAILORx and RxPONDER trials.

Tumor microenvironment analysis reveals potential explanations for age-related response to chemotherapy

In his most recent study published in npj Breast Cancer, Dr. Pusztai and his collaborators made the novel discovery that breast tumors from younger women had a higher expression of immune-related genes than those in older women, suggesting an active anti-tumor immune response. This has not been previously reported and led the team to further explore drivers of immune activation in younger patients and how they might affect chemotherapy response.

CXCL13 is a key signaling molecule that activates an immune response and attracts immune cells into cancer tissues. Its levels were consistently higher in younger women’s tumor microenvironments. Other studies have shown that high CXCL13 levels are associated with better outcomes in both neoadjuvant (pre-surgical) and adjuvant (post-surgical) chemotherapy. The authors speculate that this higher immune presence may explain the chemotherapy benefit seen in younger women but not in older women in both TAILORx and RxPONDER trials, but further studies to confirm this are needed.

Findings from Dr. Pusztai’s study also indicated that younger patients' tumors had lower expressions of ESR1—the gene that codes for ER—and other ER-related genes compared with those in the over 55 age group. When the research team looked at the ER and immune-related profiles together, they found three distinct groups among younger women: those with high immune expression but low ER expression; those with intermediate immune and ER expression; and those with low immune expression and intermediate ER expression.

They hypothesize that chemotherapy benefit in these different groups occurs through discrete mechanisms. In tumors with a high immune presence but low ER expression, the chemotherapy effect is due to its direct toxicity to cancer cells augmented by the active immune system in the tumor environment. In tumors with low immune presence and intermediate or low ER expression, the chemotherapy effect may be due to its indirect ovarian suppression function that lowers estrogen levels and increases the efficacy of hormonal therapies. Indeed, the long-running, BCRF-supported trials SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) have shown that ovarian suppression combined with other forms of endocrine therapy improves outcomes in younger, premenopausal breast cancer patients.

What this means for patients

In the future, doctors may be able to guide treatment plans for younger women with breast cancer by measuring immune presence, estrogen receptor, or ER-related genes in cancer tissues. For those with intermediate levels of ER-related genes and low or no levels of immune cells, intensified endocrine therapy (i.e., ovarian suppression and other forms of hormonal therapy) may be the best course of action. Others might require chemotherapy to maximize chances for a complete cure when the ER-related genes are low but immune presence is high.  

Researchers are working to translate these findings into the clinic by developing reliable “clinical-grade” tests to measure immune presence. Dr. Pusztai expressed his optimism that this will come to fruition.

“I am excited about a future where immune gene signatures will further refine the prognostic and predictive accuracy of molecular diagnostic tests,” Dr. Pusztai said.

As more data is reported from the landmark TAILORx and RxPONDER trials, these study results will be validated more broadly to further fine-tune and personalize how breast cancer is treated and managed.

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