Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

BACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

BACKGROUND The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger

The patient experience

The impact of improved treatments for the management of hormone-sensitive breast cancer extends beyond clinical responses. Thanks to appropriate literature and access to the internet, patient awareness of treatment options has grown and patients are now, in many cases, able to engage their oncologists in informed conversations regarding treatment and what to expect in terms of efficacy and safety. Indeed, patients realize that although there is no cure for metastatic disease, treatment can greatly reduce the risk of progression and in the adjuvant setting, where treatment is administered with a curative intent, current treatment options reduce the risk of relapse. The approval of letrozole throughout the breast cancer continuum has provided patients with many reassuring options. The improvement in outcome with letrozole is achieved without a detrimental effect on overall quality of life. Adverse events such as hot flushes, arthralgia, vaginal dryness, and potential osteoporosis are most significant from the patient’s perspective, and it is important that caregivers pay attention to patients experiencing these events, as they can impact compliance unless effectively explained and managed. The major benefits of letrozole are to improve prospects for long-term survivorship in the adjuvant setting and to delay progression and the need for chemotherapy in the metastatic setting

Prospective Validation of a 21-Gene Expression Assay in Breast Cancer

Prior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker

Effect on clinical trial participation by integration of a clinical pathway program into an electronic health record (EHR)

BACKGROUND: Patient enrollment to clinical trials is lower than desired. Even large organizations with extensive research support services have many barriers to recruitment and poor rates of enrollment. Barriers to clinical trial participation can be physician related, system related, or patient related. Physician related issues are the largest barrier to patient accrual. Physicians are often not aware that a trial may be available for a patient. While all initial patients are manually screened in our system, screening for subsequent lines of therapy are not. Provider awareness and appropriate patient identification are areas of potential improvement in a large, multisite, hospital affiliated, community oncology setting. METHODS: Our oncology group recently implemented Via Oncology (Via), an EHR-integrated clinical pathway decision support tool. Information about the patient, their disease, and goals of care generate a recommended treatment algorithm. The pathways are expected to speed the integration of new treatments into practice and improve accrual to clinical trials. Use of Via is required for all new therapy changes. Within the decision algorithm, an appropriate available clinical trial is suggested as the first option when available. Clinical trial enrollment statistics are being tracked to determine if this method of potential patient identification results in increased enrollments. RESULTS: After 11 months of Via implementation and 103,515 visits, the visit capture rate was 82.7% suggesting that providers adapted to the pathways quickly. With 3,844 decisions made, 83.9% of all treatment decisions were on pathway. Clinical trial enrollment was 122 patients in the 459 days prior to Via implementation, and 102 patients in the 271 days afterwards. This increase in accrual rate was significant (p = 0.00174.) CONCLUSIONS: Early results suggest that Via implementation has resulted in a significant increase in clinical trial accrual. The system will eventually be able to track how often a trial is offered and how often it is accepted. We are hopeful that with complete visit capture of all patients, there will be continued improvement in our rate of clinical trial enrollment

Clinical trial participation assessed by age, sex, race, ethnicity, and socioeconomic status

INTRODUCTION: Individual demographic data and socioeconomic status (SES) factors from Census block group data may help define groups with disadvantaged access to clinical trials. METHODS: Individual demographic data from the Aurora Cancer Registry and SES factors corresponding to the Census block group of the patient\u27s address were studied for a six-year period ending July 31, 2019. RESULTS: The final study cohort included 39,968 patients (enrolled = 772, and not enrolled = 39,196). In univariate analysis, significantly fewer patients older than age 65 (p \u3c 0.001) and fewer men (p \u3c 0.001) were enrolled in clinical trials. Socioeconomic factors found to be significant during univariate analysis included: low household income (p \u3c 0.001), percentage below the poverty line (p \u3c 0.001), low percentage home ownership (p = 0.006), unemployment (p = 0.003), absence of a college degree (p = 0.037) and absence of a high school degree (p = 0.007). In multivariate analysis, patients older than age 65 were less likely to participate in a trial (odds ratio 0.574, p \u3c 0.001) and men were less likely to participate (odds ratio = 0.703, p \u3c 0.001). Only 1.4% of the variance in clinical trial participation was accounted for demographic and SES factors. CONCLUSIONS: The only groups with disadvantaged access to clinical trials in our institution were the elderly and men. Whether demographic or SES factors are related to accrual rates of clinical trials in other geographic regions or in other types of research studies warrants further investigation

Insights from building a new National Cancer Institute Community Oncology Research Network Program site

BACKGROUND: The new National Cancer Institute (NCI) Community Oncology Research Program (NCORP) went live August 1, 2014; 34 sites were selected for the program, including 7 new sites that previously did not have a research grant from the NCI. This report describes the first year of a new program site. METHODS: Accrual, investigator and site participation, and number of open studies by the program over the first 12 months of the grant were compared to performance at our institution over the prior 12 months. RESULTS: During the pre-NCORP period, 84 patients were accrued to NCI-sponsored trials and 106 patients to non–NCI-sponsored trials. In year 1 of the new program, 140 were accrued to NCI-sponsored trials—a 66% improvement, and 109 patients to non–NCI-sponsored trials (P =0.013 when comparing corresponding increases for NCI vs non-NCI trials). Success of the NCI-sponsored trials was associated with increased accrual to both treatment trials (P =0.03) and Alliance for Clinical Trials in Oncology-sponsored trials (P =0.0001). CONCLUSIONS: NCORP implementation was associated with a significant (P =0.013) improvement in accrual to NCI-sponsored trials that was immediate (1 year) and large (a 66% increase in accrual). In year 2, the intention is to increase cancer control studies; foster inclusion of radiation, surgical, gynecologic, and neurologic oncologists; and focus on minority outreach. Studies that accrue poorly will be assessed, and those accruing poorly on a national basis will be considered for closure. Studies accruing well nationally will be evaluated for barriers to local accrual