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PurposeTo determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI).MethodsThe American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease.ResultsOnly two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764).ConclusionChemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

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Background: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared to MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n=278; pMMR, n=283) from a phase 3 adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: While CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR vs pMMR tumors overall, inter-tumoral heterogeneity in densities between tumors was significantly higher by 30–88% among dMMR vs pMMR cancers (P<.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs high) CD3+IM was independently associated with poorer OS among dMMR (HR 4.76 [95% CI 1.43–15.87]; P=.0019) and pMMR tumors (P=.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater inter-tumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

A 42‐question survey on usage and beliefs regarding sales force automation (SFA) was collected, along with actual sales performance data, on 1,641 sales representatives of a large international pharmaceutical company in Germany, England, and the United States. The relationships between beliefs and usage and individual sales performance were examined both within and across countries and a cost‐benefit analysis completed. Factor analysis identified five usage groupings including: Planning and territory management; Administration and external information exchange; Within company communication; Active sales tool; and Passive sales tool. Significant usage, belief, and performance differences between countries were found, with the use of SFA explaining 16.4 per cent of the variance in sales performance across countries. General findings indicated that management and representatives believed SFA to be useful. US$22.2 million in sales increases were found to be attributable to SFA usage. At the same time, non‐discounted cash flow payback periods were found to range from 6.2 to 7.4 years. Potential contributing factors and implications are discussed.

We sought to investigate the roles of real and ideal others in romantic relationships and, in particular, to generalize and to test predictions of the notion of comparison levels in such relationships. Members of 24 couples involved in romantic relationships completed three scales of interpersonal involvement regarding (a) their feelings toward the other, (b) their feelings toward an ideal other, (c) their perceptions of the other's feelings toward them, and (d) their perceptions of an ideal other toward them. Subjects also provided ratings of satisfaction with their relationship. We found that both absolute levels and comparison levels for feelings make independent contributions to satisfaction in relationships. We also found that (a) feelings regarding the other member of the couple are more predictive of satisfaction than are feelings regarding the ideal other member; (b) feelings toward the other and perceived feelings of the other toward the self matter about equally for satisfaction; (c) there exist at least six comparison levels that can be used to assess satisfaction in romantic relationships, five of which are predictive of such satisfaction; (d) higher levels of feelings for men but not for women predict discrepancies in experienced levels of satisfaction for the two members of a couple; and (e) perceived rather than actual differences between members' feelings better predict satisfaction. We concluded that it is neither the ideal nor the actual other but rather the perceived other that may be key to satisfaction in a relationship.According to the Thibaut-Kelley (1959) theory, one's happiness in a relationship will depend on the degree to which the relationship falls above or below one's CL: If the outcomes 1586 This document is copyrighted by the American Psychological Association or one of its allied publishers.This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.