ECOG-ACRIN research highlights at ASCO 2021

New research results for patients with breast and HPV-associated throat cancers are the highlights among 23 presentations by ECOG-ACRIN Cancer Research Group researchers at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, occurring virtually June 4-8. The National Cancer Institute (NCI), part of the National Institutes of Health, funded these studies.

Abstract 605: About 80% of triple-negative breast cancers (TNBC) are a subtype called 'basal-like.' Typically, patients with TNBC receive chemotherapy before surgery to shrink the tumor(s). The presence of residual cancer in the breast after chemotherapy signals a higher likelihood that the cancer will progress after surgery. A previous clinical trial demonstrated that additional capecitabine chemotherapy after surgery helps decrease the chance of recurrence. Yet, although capecitabine helps, researchers do not know whether treatment with different chemotherapy drugs could have the same or better results than capecitabine. Other research showed that basal-like TNBCs are more sensitive to platinum chemotherapies that damage DNA.

This abstract presents data from study EA1131, a randomized phase III clinical trial conducted to assess whether platinum chemotherapy would be as effective or more effective than capecitabine (NCT02445391). The study was for patients in a very high-risk group: those who had basal-like triple-negative breast cancer that was still present after initial chemotherapy. Patients were randomly assigned to one of two treatment groups after receiving standard chemotherapy and surgery. The first group received capecitabine chemotherapy after surgery. The second group received a platinum chemotherapy--either cisplatin or carboplatin, after surgery.

After a recent interim analysis, the EA1131 trial was stopped early by the ECOG-ACRIN Data and Safety Monitoring Committee. The interim analysis showed it was unlikely that platinum chemotherapy would be any better than standard capecitabine chemotherapy at preventing recurrence in patients with residual basal-like triple-negative breast cancers following neoadjuvant chemotherapy.

On June 6, the study will be presented at the ASCO Annual Meeting and published in the Journal of Clinical Oncology.

First author Ingrid A. Mayer, MD (Vanderbilt-Ingram Cancer Center): "While platinum chemotherapy has been routinely adopted by many to treat basal-like triple-negative breast cancer still present after initial chemotherapy, the results of the randomized phase III trial EA1131 show that it should no longer be used in this setting. The group of women in the trial who received platinum chemotherapy had more serious side effects than those who received the standard chemotherapy drug capecitabine."

Abstract 12003: E1Z11 is the first clinical trial in a racially diverse group of postmenopausal women with early breast cancer to study severe pain in the bones, muscles, ligaments, tendons, and nerves caused by aromatase inhibitor (AI) treatment (NCT01824836). Previous similar studies mainly included white women, whereas E1Z11 set individual accrual goals for self-reported Black, Asian, and white participants. Total enrollment was 1,046, including Black (201), Asian (205), and white (640) participants. Women were eligible for the study if they had early (stage I to III) hormone receptor-positive breast cancer, were postmenopausal, had completed planned local therapy, and had not received prior AI therapy as first-line treatment.

AIs stop estrogen production and are widely prescribed in postmenopausal women, typically for five or more years after surgery/chemotherapy, to prevent a breast cancer recurrence. Yet their effectiveness is compromised because 40-50% of women stop treatment early due to the severe pain caused by AI-associated musculoskeletal symptoms (AIMSS). The syndrome was not recognized during the FDA registration trials for this class of drugs, which includes anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara).

The E1Z11 study collected data from women during their first year of AI therapy. More Black and Asian women developed severe musculoskeletal pain during this time than white women (48%, 50%, and 38%, respectively). Rates of AI discontinuation within one year were similar across the three cohorts (10%, 12%, and 13%, respectively).

Participants also completed extensive questionnaires about their symptoms, quality of life, and anxiety about recurrence. The surveys occurred every three months during the first year of AI treatment. Survey completion rates were high across all cohorts at every time point: 98% at baseline, 93% at three months, 89% at six months, 88% at nine months, and 90% at 12 months. The choice for patients to complete questionnaires on paper or online contributed to the extraordinarily high survey completion rates.

E1Z11 participants also contributed blood samples to build a biobank to examine germline genetic variants in DNA for this and future research. Genotyping success rates were high across all cohorts (>95%). This analysis was not able to demonstrate associations between AIMSS symptom development and ten germline DNA variants thought to be predictors. However, one gene (rs2296972/HTR2A) warrants further study.

First author Vered Stearns, MD (Johns Hopkins University): "More Black and Asian postmenopausal women than white women with early breast cancer developed severe musculoskeletal pain within the first year of aromatase inhibitor (AI) therapy. However, the rates of early discontinuation of AI therapy were similar across the three groups. The E1Z11 biospecimens bank and patient-reported outcomes data are a treasure trove for future discovery across the three racial cohorts. For example, there will be data from this trial on the tolerability of AIs from the patient's perspective, yielding important insights on how to support women from minoritized groups to gain maximum benefit from treatment."

Abstract 6010: The phase II E3311 trial offers new information about using less treatment in patients with HPV-associated oropharynx cancer and a medium risk of recurrence (NCT01898494). While surgeons and patients widely favor the organ-preservation approach of transoral robotic surgery, there remain serious concerns about both short- and long-term toxicities associated with chemotherapy. First, this trial found a better way to assess each patient's individual risk (presented at ASCO 2020). The new method uses tumor testing along with patient characteristics to measure the level of risk: low, intermediate (medium), or high. Physicians may safely consider offering patients less therapy if their risk of recurrence is low. High-risk patients may receive standard chemotherapy and radiation after surgery. But what about patients with intermediate, or medium risk? The E3311 phase II study proved that medium-risk patients could safely forego chemotherapy altogether and receive transoral surgery (TOS) followed by a lower dose of radiation than is standard and still have good outcomes.

This analysis reports three-year progression-free survival (PFS) data. The three-year PFS estimate for the two medium-risk groups is 94.9% for a 50 Gy dose of radiation and 93.5% for a 60 Gy dose. It also reports on an exploratory comparison of quality of life between the two medium-risk groups. Patient reports (FACT HN) completed at baseline (before TOS) and six months post-radiation therapy revealed that 63% vs. 49% of patients in the 50 or 60 Gy arms, respectively, had stable/improved quality of life.

First author Robert L. Ferris, MD, PhD (UPMC Hillman Cancer Center): "Primary transoral surgery followed by reduced-dose radiation therapy is safe in patients with intermediate-risk HPV-positive oropharyngeal cancer, with favorable quality of life and functional outcomes. With three years of follow-up, this group continued to have better outcomes than the group on usual high-dose radiation plus chemotherapy. Our patient stratification identified low and intermediate-risk patients well, preserving patients' throat function and sparing them unnecessary short- and long-term toxicities. These data support ECOG-ACRIN's plans for a phase III confirmatory trial."

First author Joseph A. Sparano, MD, is the recipient of the 2021 ASCO Gianni Bonadonna Breast Cancer Award and Lecture. Learn more about Dr. Sparano, a pioneer in cancer research, in this ASCO Daily News tribute article.

Abstract 520: Systemic inflammation may contribute to the progression or recurrence of early breast cancer. This analysis mined a bank of biospecimens collected before treatment from women with stage II-III HER2-negative breast cancer in a previous randomized phase III trial, E5103 (Miller KM. J Clin Oncol. 2018 Sep 1). Here, researchers utilized serum samples (PMC6118403) to test the hypothesis that higher levels of inflammatory cytokines and chemokines (proteins in immune cells that participate in the body's immune response) might be associated with cancer coming back in a part of the body away from the breast (distant recurrence). The only biomarker associated with a significantly increased distant recurrence risk when adjusted for multiple testing was the pro-inflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Komen Foundation and the Breast Cancer Research Foundation also funded this study, along with the National Cancer Institute.

First author Joseph A. Sparano, MD (Montefiore Medical Center/Albert Einstein College of Medicine): "We found an association between higher levels of the cytokine IL-6 at diagnosis and a significantly higher risk of distant recurrence in patients with high-risk stage II-III, HER2-negative breast cancer, despite optimal adjuvant systemic therapy. This discovery provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway."

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The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) is a membership-based scientific organization that designs and conducts cancer research involving adults who have or are at risk of developing cancer. ECOG-ACRIN comprises nearly 1300 member institutions in the United States and around the world. Approximately 15,000 physicians, translational scientists, and associated research professionals from the member institutions are involved in Group research. ECOG-ACRIN is supported primarily through National Cancer Institute research grant funding and receives funding from private sector organizations through philanthropy and collaborations. Its headquarters are in Philadelphia, Pa. Visit http://www.ecog-acrin.org, follow us on Twitter @eaonc, Facebook, and LinkedIn, or call 215.789.3631.