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Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations.All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM.The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM.Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered.

Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens.We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data.We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c.We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies.

Purpose: To evaluate the expression of cathepsin K (CTSK) and CXCL14 in stromal and epithelial cells in human breast tumor progression.Experimental Design: We did immunohistochemical analyses of CTSK and CXCL14 expression in normal breast tissue, biopsy sites, benign lesions, ductal carcinoma in situ, and invasive breast tumors of different stages. Expression patterns were related to histopathologic characteristics of the tumors and clinical outcome. The effect of CTSK+ breast stromal fibroblasts on CTSK- breast cancer cells was assessed in coculture.Results: Epithelial expression of CTSK was rarely detected in any of the tissue samples analyzed, whereas CXCL14-positive epithelial cells were found in all tissue types. The expression of CXCL14 was not associated with any tumor or patient characteristics analyzed. Stromal CTSK expression was significantly higher in invasive compared with in situ carcinomas, and in one of the two data sets analyzed, it correlated with higher tumor stage. Among all samples examined, the highest stromal CTSK levels were detected in biopsy sites. Neither epithelial nor stromal expression of CTSK was significantly associated with recurrence-free or overall survival. Coculture of CTSK+ fibroblasts enhanced the invasion of CTSK- breast tumor epithelial cells and this was blocked by CTSK inhibitors.Conclusions: CTSK may function as a paracrine factor in breast tumorigenesis. CTSK+ fibroblasts may play a role in tumor progression by promoting the invasiveness of tumor epithelial cells. The possibility that CTSK inhibitors may have a clinical role in decreasing the risk of tumor progression merits further investigation.

Supplementary Data from Epithelial and Stromal Cathepsin K and CXCL14 Expression in Breast Tumor Progression

Supplementary Figure 1 from Identification of GATA3 as a Breast Cancer Prognostic Marker by Global Gene Expression Meta-analysis

GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast. Here we did a meta-analysis of the available breast cancer cDNA data sets on a cohort of 305 patients and found that GATA3 was one of the top genes with low expression in invasive carcinomas with poor clinical outcome. To validate its prognostic utility, we did a tissue microarray analysis on a cohort of 139 consecutive invasive carcinomas (n = 417 tissue samples) immunostained with a monoclonal antibody against GATA3. Low GATA3 expression was associated with higher histologic grade (P < 0.001), positive nodes (P = 0.002), larger tumor size (P = 0.03), negative estrogen receptor and progesterone receptor (P < 0.001 for both), and HER2-neu overexpression (P = 0.03). Patients whose tumors expressed low GATA3 had significantly shorter overall and disease-free survival when compared with those whose tumors had high GATA3 levels. The hazard ratio of metastasis or recurrence according to the GATA3 status was 0.31 (95% confidence interval, 0.13-0.74; P = 0.009). Cox multivariate analysis showed that GATA3 had independent prognostic significance above and beyond conventional variables. Our data suggest that immunohistochemical analysis of GATA3 may be the basis for a new clinically applicable test to predict tumor recurrence early in the progression of breast cancer. (Cancer Res 2005; 65(24): 11259-64)

Supplementary Tables 1-2 from Identification of GATA3 as a Breast Cancer Prognostic Marker by Global Gene Expression Meta-analysis

Personalized risk prediction calculators abound in medicine, and they carry important information about the effect of prognostic factors on outcomes of interest. How to use that information in order to analyze local datasets is a pressing question, and several recent proposals have attempted to pool information from external calculators to local datasets using parameter sharing approaches. Here, we adopt a weighting approach using convex optimization in order to transfer information. Rather than directly modeling parameters, we instead pool information on a per-sample basis. In particular, we develop prediction-guided analyses, along with an attendant inferential strategy, for incorporating information from the external risk calculator. We also supplement this analytical approach with an exploratory technique using trees to describe what we term as ‘calculator-guided observations.’ In addition, the optimization problem itself can yield insights on the potential transferability of the external calculator to the local dataset. The methodology is illustrated by simulation studies as well as an application of risk calculators to the prediction of sentinel lymph node positivity in melanoma.

BACKGROUND AND OBJECTIVES Surgical oncology patients are vulnerable to persistent opioid use. As such, we aim to compare opioid prescribing to opioid consumption for common surgical oncology procedures. METHODS We prospectively identified patients undergoing common surgical oncology procedures at a single academic institution (August 2017-March 2018). Patients were contacted by telephone within 6 months of surgery and asked to report their opioid consumption and describe their discharge instructions and opioid handling practices. RESULTS Of the 439 patients who were approached via telephone, 270 completed at least one survey portion. The median quantity of opioid prescribed was significantly larger than consumed following breast biopsy (5 vs. 2 tablets of 5 mg oxycodone, p

Retroperitoneal and abdominopelvic sarcomas are rare heterogeneous malignancies. The only therapy proven to improve disease-free survival (DFS) is R0/R1 surgical resection. We sought to analyze whether additional factors such as radiation and systemic therapy were associated with DFS and abdominal recurrence-free survival (RFS).Retrospective review of adults (≥18) with resectable abdominopelvic and retroperitoneal sarcomas who underwent intent-to-cure surgery at a high-volume tertiary referral center between 1998 and 2015. The main outcome measures were DFS and abdominal RFS.Overall, 159 patients met the criteria for inclusion. Median follow-up was 4.8 years (range 0.1-18.9 years). The most common histology was liposarcoma (49%). Systemic therapy was administered to 48% of patients and was not associated with improved outcomes. The neoadjuvant radiotherapy group (11%) had improved adjusted DFS (5.46 years, 95% CI [3.68, 7.24] vs. 3.1 years, 95% CI [2.48, 3.73]) and abdominal RFS (6.14 years, 95% CI [4.38, 7.89] vs. 3.22 years, 95% CI [2.61, 3.84]). The adjuvant radiotherapy group (19%) had no improvement.In a cohort of patients undergoing resection for retroperitoneal or abdominopelvic sarcoma, neoadjuvant radiation improved DFS and abdominal RFS. A follow-up of over three years was needed to appreciate a difference in outcomes.

Background: Despite increasing representation of women in medicine, gender bias remains pervasive. The authors sought to evaluate speaker introductions by gender in the grand rounds of multiple specialties at a large academic institution to understand the cultural context of this behavior and identify predictors of formality. Materials and Methods: The authors reviewed grand rounds recordings of speakers with doctorates presenting to the departments of family medicine, general surgery, internal medicine, obstetrics and gynecology, and pediatrics at one institution from 2014 to 2019. The primary outcome was whether a speaker's professional title was used as the first form of address. The authors assessed factors correlated with professional introduction using multivariable logistic regression. Results: Speakers were introduced professionally in 346/615 recordings (56.3%). Female introducers were more likely to introduce speakers professionally (odds ratio [OR]: 2.52). A significant interaction existed between speaker gender and home institution: female speakers visiting from an external institution were less likely than male external speakers to be introduced professionally (OR: 0.49), whereas female speakers internal to the institution were more likely to be introduced professionally than male internal speakers (OR: 1.75). Use of professional titles varied by specialty and was higher than average for family medicine (83.2%), surgery (75.8%), and pediatrics (64.0%) and lower for internal medicine (37.5%) and obstetrics and gynecology (50.7%). Conclusions: These findings suggest a complex relationship between gender and formality of introduction that merits further investigation. Understanding differences in culture across specialties is important to inform efforts to promote equity.

Sentinel lymph node biopsy (SLNB) is increasingly utilized after neoadjuvant chemotherapy (NAC) in responsive adenopathy, particularly with placement of a marking clip in the involved node(s). This may allow a subset of patients to avoid axillary lymph node dissection. SLNB is still discouraged in inflammatory breast cancer (IBC). The purpose of this study is to examine the axillary pathologic complete response (AXpCR) in IBC patients with clinical adenopathy. There may be an implication to approach a subset of IBC patients for SLNB after NAC. A single-institution institutional review board-approved database was reviewed. Inclusion criteria were clinicopathologic diagnosis of IBC and age ≥ 18 years. Stage IV disease was excluded. We collected data on demographics, tumor characteristics including histology and subtype, axillary status, and treatment effect details. Sixty-six patients fulfilled criteria. Mean follow-up was 4.1 years. The AXpCR was 6% for luminal A and luminal B [human epidermal growth factor receptor (HER)2 −] subtypes, and 24% for basal subtype. The AXpCR rate was 64% for HER2-enriched and luminal B (HER2 +) patients. Achievement of AXpCR among these HER2-positive patients was statistically significant (p = 0.0001). There was minimal difference in achieving AXpCR in HER2-overexpressing patients regardless of hormone receptor status (p = 1.000). Understanding the best patients to select for use of SLNB or targeted lymph node dissection after treatment is evolving. This unique series identified and described the axillary pathologic characteristics of IBC patients following NAC. Further research is needed to confirm that the approach, axillary node clip placement prior to treatment, is feasible and accurate in IBC.

The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55–94 years). The mean tumor length was 8.1 mm (range, 8–14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8–14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Simple Summary Glioblastoma (GBM) is the most aggressive form of glioma (WHO grade IV), and mounting evidence suggests that glioblastoma stem-like cells (GSCs) play an important role in tumor growth and response to therapy. In the current study, we sought to understand the metabolic dependencies of GSCs using high-resolution proton magnetic resonance spectroscopy (1H-NMR). In a defined experimental setting, we stratified in vitro GSC models into two subtypes (Gln/GluHigh, Gln/GluLow) and used diverse molecular approaches to perform comprehensive analyses in GSC neurosphere cultures and primary GBM samples. Abstract Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.

Merkel cell carcinoma (MCC) is an aggressive form of skin cancer which, while chemosensitive, has high rates of relapse and chemoresistance, limiting the impact of chemotherapy. An immunogenic tumor, the management of advanced MCC has changed dramatically with the introduction of checkpoint inhibitors. This review will focus on the impact of immunotherapy in unresectable and metastatic MCC, ongoing research in the adjuvant and neoadjuvant settings, and future directions of immune-based strategies for this challenging cancer.

BACKGROUND: The management of clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC) has progressed with the potential to avoid the morbidity of axillary lymph node dissection in patients with complete response to therapy. This study addresses the impact of pretreatment nodal burden and tumor subtype on axillary pathologic complete response (AXpCR) in patients treated with NAC to better inform axillary surgical management. METHODS: A prospective database was reviewed to identify clinically node-positive patients who underwent NAC followed by axillary lymph node dissection. Patients were stratified in accordance with abnormal nodal burden on pretreatment axillary imaging defined as low (1–2 nodes) or high (3 nodes), and biologic subtype defined by hormone receptor (HR+, HR−) and HER2 (human epidermal growth factor receptor 2) status. The primary outcome was AXpCR. RESULTS: AXpCR was 43% in the study population. There was no difference in AXpCR between low and high nodal burden groups (44% versus 42%, P = 0.87). Subtype correlated to AXpCR (P < 0.001) with the highest rate (78%) in the HR−/HER2+ group. Overall, HER2+ patients had a significantly higher AXpCR than HER2− subtypes (66% versus 28% P < 0.001). HR and HER2 status were also predictive of AXpCR when comparing patient, tumor, and treatment variables. CONCLUSIONS: Biologic subtype better correlated with rates of AXpCR than nodal burden alone with the highest rates of AXpCR in HER2+ patients. Consideration of tumor biology is more informative than nodal burden when evaluating options for axillary management after NAC.

INTRODUCTION: Guidelines allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥70 years old with hormone receptor positive (HR+) breast cancer. Despite this, national data suggest these procedures have not been widely de-implemented. Our objectives were to evaluate trends in SLNB and post-lumpectomy radiotherapy utilization in patients who are eligible for omission and evaluate patient preferences as a target for de-implementation of low-value care. METHODS: We performed a sequential explanatory mixed-methods study by first analyzing an institutional database of patients ≥70 years old with HR+ breast cancer who received surgical treatment from 2014-2018. Based on the quantitative data, we conducted semi-structured interviews with women identified as high or low utilizers of breast cancer treatments to elicit patient perspectives on de-implementation. RESULTS: SLNB and post-lumpectomy radiotherapy were performed in 68% and 43% of patients who met criteria for omission, respectively. There was a significant decrease in SLNB rates from 2014-2018. Forty-nine percent of patients were classified as high utilizers and 26% were classified as low utilizers. Qualitative analysis found that the most important factors influencing decision-making regarding SLNB and post-lumpectomy radiotherapy omission for both high and low utilizers were trust in their provider and desire for peace of mind. CONCLUSIONS: Despite efforts to de-implement low-value care, older women with HR+ breast cancer remain at risk of overtreatment. Patient perspectives suggest that multi-level de-implementation strategies will need to target provider practice patterns and patient-provider communication to promote high quality decision-making and reduction in breast cancer overtreatment.

Each year Clinical Cancer Advances: ASCO’s Annual Report on Progress Against Cancer highlights the most important clinical research advances of the past year, including the Advance of the Year, and identifies priority areas where ASCO believes research efforts should be focused moving forward. In 2020, ASCO names the Refinement of Surgical Treatment of Cancer as the Advance of the Year. Years of progress in developing new systemic cancer therapies has not only improved patient survival and quality of life but is now transforming surgical approaches to cancer treatment. The emergence of novel systemic therapies combined in new and better ways is significantly changing the role of cancer surgery. ASCO’s selection of Refinement of Surgical Treatment of Cancer as the 2020 Advance of the Year recognizes recent strides seen in the effectiveness of these treatments in reducing the amount of surgery, and even the need for it, while increasing the number of patients who can undergo surgery when needed. Other advances highlighted in the report include progress in cancer prevention, molecular diagnostics, and cancer treatment—surgery, radiotherapy, combination therapy, immunotherapy, and other types of therapies. The report also features ASCO's 2020 list of Research Priorities to Accelerate Progress Against Cancer. These priorities represent promising areas of research that have the potential to significantly improve the knowledge base for clinical decision-making and address vital unmet needs in cancer care. A MESSAGE FROM ASCO’S PRESIDENT Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn’t been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies. Clinical research is about saving and improving the lives of individuals with cancer. It’s a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO’s Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology. ASCO’s 2020 Advance of the Year—Refinement of Surgical Treatment of Cancer—highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery. Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer. While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can’t rest on our laurels. With ASCO’s Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we’ve identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress. Of course, the effectiveness or number of new treatments is meaningless if patients don’t have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge. Sincerely, Howard A. “Skip” Burris III, MD, FACP, FASCO ASCO President, 2019-2020

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1–3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1–3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p, Genomics: NF1 mutations more frequent in recurrent breast cancer Women with breast cancer who relapse following surgery frequently harbor genomic alterations in a pathway linked to cell proliferation and anti-tumor immune responses. A USA-based team led by Funda Meric-Bernstam from the University of Texas MD Anderson Cancer Center in Houston, and Kimberly Keene from the University of Alabama at Birmingham conducted a thorough molecular analysis of tumor samples obtained from 115 women with 5 years of follow-up after a mastectomy and, oftentimes, adjuvant chemotherapy or hormonal therapy. RNA profiles did not significantly differ between women who experienced local recurrence, developed distant metastases or were still in remission. However, DNA analyses identified significantly more mutations in patients whom recurred in the mitogen-activated protein kinase cell signaling pathway, specifically NF1, implicated in cell growth and immunity. If validated, the findings support targeting this pathway to prevent disease recurrence.

Purpose Locoregional control for inflammatory breast cancers and chest wall recurrences is suboptimal, which has motivated interest in radiosensitization to intensify therapy. Preclinical studies have suggested a favorable therapeutic index when poly (ADP-ribose) polymerase inhibitors are used as radiosensitizers; clinical investigation is necessary to establish appropriate dosing and confirm safety. Patients and Methods We conducted a multi-institutional phase I study of veliparib and concurrent radiotherapy (RT) to the chest wall and regional lymph nodes in 30 patients with inflammatory or locally recurrent breast cancer after complete surgical resection. RT consisted of 50 Gy to the chest wall and regional lymph nodes plus a 10-Gy boost. A Bayesian time-to-event continual reassessment method escalated dose through four levels, with a 30% targeted rate of dose-limiting toxicity (DLT) measured during the 6 weeks of treatment plus 4 weeks of follow-up. DLTs were defined as confluent moist desquamation > 100 cm2, nonhematologic toxicity grade ≥ 3, toxicity that requires an RT dose delay > 1 week, absolute neutrophil count < 1,000/mm3, platelet count < 50,000/mm3, or hemoglobin < 8.0 g/dL if possibly, probably, or definitely related to study treatment. Results Five DLTs occurred: Four were moist desquamation (two each at 100 and 150 mg twice a day), and one was neutropenia (at 200 mg twice a day). The crude rate of any grade 3 toxicity (regardless of attribution) was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, six of 15 surviving patients had severe fibrosis in the treatment field. Conclusion Although severe acute toxicity did not exceed 30% even at the highest tested dose, nearly half of surviving patients demonstrated grade 3 adverse events at 3 years, which underscores the importance of long-term monitoring of toxicity in trials of radiosensitizing agents.

Purpose This study was conducted to determine the effect of iCanDecide, an interactive and tailored breast cancer treatment decision tool, on the rate of high-quality patient decisions—both informed and values concordant—regarding locoregional breast cancer treatment and on patient appraisal of decision making. Methods We conducted a randomized clinical trial of newly diagnosed patients with early-stage breast cancer making locoregional treatment decisions. From 22 surgical practices, 537 patients were recruited and randomly assigned online to the iCanDecide interactive and tailored Web site (intervention) or the iCanDecide static Web site (control). Participants completed a baseline survey and were mailed a follow-up survey 4 to 5 weeks after enrollment to assess the primary outcome of a high-quality decision, which consisted of two components, high knowledge and values-concordant treatment, and secondary outcomes (decision preparation, deliberation, and subjective decision quality). Results Patients in the intervention arm had higher odds of making a high-quality decision than did those in the control arm (odds ratio, 2.00; 95% CI, 1.37 to 2.92; P = .0004), which was driven primarily by differences in the rates of high knowledge between groups. The majority of patients in both arms made values-concordant treatment decisions (78.6% in the intervention arm and 81.4% in the control arm). More patients in the intervention arm had high decision preparation (estimate, 0.18; 95% CI, 0.02 to 0.34; P = .027), but there were no significant differences in the other decision appraisal outcomes. The effect of the intervention was similar for women who were leaning strongly toward a treatment option at enrollment compared with those who were not. Conclusion The tailored and interactive iCanDecide Web site, which focused on knowledge building and values clarification, positively affected high-quality decisions largely by improving knowledge compared with static online information. To be effective, future patient-facing decision tools should be integrated into the clinical workflow to improve decision making.

BACKGROUND The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy. METHODS All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis of their tumor and methylation subgroup annotation (Heidelberg brain tumor methylation classifier v11b4; calibrated score > 0.5 required). Overall survival (OS) was compared between a pooled cohort of tumors of the RTK I/MES subgroups and RTK II tumors. RESULTS In the CCNU/TMZ arm of CeTeG/NOA-09, OS was prolonged in RTK I/MES (n = 16; median not reached, 4-year OS 69%) as compared to RTK II patients (n = 14; median 20.6 months, 4-year OS 23%; p = 0.004 logrank test). In the standard temozolomide arm of CeTeG/NOA-09, OS tended to be shorter in RTK I/MES (n = 7; median 23.7 months, 4-year OS 17%) as compared to RTK II patients (n = 17; median 35.2 months; 4-year OS 38%, p = 0.15). CONCLUSION The CCNU/TMZ-dependent survival prolongation in patients with RTK I/MES tumors as opposed to RTK II seen in CeTeG/NOA-09 suggests that methylation-based subgrouping could be predictive for CCNU/TMZ efficacy in newly diagnosed MGMT-methylated glioblastoma.

PURPOSE Identifying molecular subtypes in gliomas has prognostic and therapeutic value, traditionally after invasive neurosurgical tumor resection or biopsy. Recent advances using artificial intelligence (AI) show promise in using pre-therapy imaging for predicting molecular subtype. We performed a systematic review of recent literature on AI methods used to predict molecular subtypes of gliomas. METHODS Literature review conforming to PRSIMA guidelines was performed for publications prior to February 2021 using 4 databases: Ovid Embase, Ovid MEDLINE, Cochrane trials (CENTRAL), and Web of Science core-collection. Keywords included: artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and glioblastoma. Non-machine learning and non-human studies were excluded. Screening was performed using Covidence software. Bias analysis was done using TRIPOD guidelines. RESULTS 11,727 abstracts were retrieved. After applying initial screening exclusion criteria, 1,135 full text reviews were performed, with 82 papers remaining for data extraction. 57% used retrospective single center hospital data, 31.6% used TCIA and BRATS, and 11.4% analyzed multicenter hospital data. An average of 146 patients (range 34-462 patients) were included. Algorithms predicting IDH status comprised 51.8% of studies, MGMT 18.1%, and 1p19q 6.0%. Machine learning methods were used in 71.4%, deep learning in 27.4%, and 1.2% directly compared both methods. The most common algorithm for machine learning were support vector machine (43.3%), and for deep learning convolutional neural network (68.4%). Mean prediction accuracy was 76.6%. CONCLUSION Machine learning is the predominant method for image-based prediction of glioma molecular subtypes. Major limitations include limited datasets (60.2% with under 150 patients) and thus limited generalizability of findings. We recommend using larger annotated datasets for AI network training and testing in order to create more robust AI algorithms, which will provide better prediction accuracy to real world clinical datasets and provide tools that can be translated to clinical practice.

Although clinical trials have shown no survival advantage and only a modest improvement in local control from adjuvant radiotherapy after lumpectomy in older women with stage I, estrogen receptor-positive (ER+) breast cancer, radiotherapy is commonly administered, raising concerns about overtreatment. Therefore, we sought to evaluate physician views on omission of radiotherapy in older women with favorable prognosis breast cancer. We surveyed a national sample of 713 radiation oncologists and 879 surgeons. Of these, 1504 were eligible and 825 responded (55%). We assessed responses to clinical scenarios, knowledge of pertinent risk information, and correlates of views on radiotherapy omission. Omission of radiotherapy in patients age ≥70 years with stage I, ER+ breast cancer, treated with lumpectomy and endocrine therapy, was felt to be unreasonable by 40% of surgeons and 20% of radiation oncologists. Many surgeons (29%) and radiation oncologists (10%) erroneously associated radiotherapy in older women with improvement in survival. Similarly, 32% of surgeons and 19% of radiation oncologists tended to substantially overestimate the risk of locoregional recurrence in older women with omission of RT. In a scenario with an 81-year-old with multiple comorbidities, 31% of surgeons and 35% of radiation oncologists would still recommend radiotherapy. Many radiation oncologists and surgeons continue to consider omission of radiotherapy as substandard therapy and overestimate the benefits of radiotherapy. Surgeons, in addition to radiation oncologists, may have an opportunity to play a pivotal role in reducing overuse of aggressive care in this setting.

Background and Objectives Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. Methods Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. Results Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2, and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. Conclusions SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2, and/or with ulceration. Thin melanoma

A MESSAGE FROM ASCO’S PRESIDENT I am pleased to present Clinical Cancer Advances 2017, which highlights the most promising advances in patient-oriented cancer research over the past year. The report gives us an opportunity to reflect on what an exciting time it is for cancer research and how swiftly our understanding of cancer has improved. One year ago, the White House announced the national Cancer Moonshot program to accelerate progress against cancer. This shared vision of progress has reinvigorated the research community, identified new areas of scientific collaboration, and raised our ambitions regarding what may be possible beyond the progress we have already made. When I entered the field 35 years ago, I could not have imagined where we would be today. We can now detect cancer earlier, target treatments more effectively, and manage adverse effects more effectively to enable patients to live better, more fulfilling lives. Today, two of three people with cancer live at least 5 years after diagnosis, up from roughly one of two in the 1970s. This progress has resulted from decades of incremental advances that have collectively expanded our understanding of the molecular underpinnings of cancer. There is no better current example of this than ASCO’s 2017 Advance of the Year: Immunotherapy 2.0. Over the last year, there has been a wave of new successes with immunotherapy. Research has proven this approach can be effective against a wide range of hard-to-treat advanced cancers previously considered intractable. Researchers are now working to identify biologic markers that can help increase the effectiveness of treatment and determine who is most likely to benefit from immunotherapy. This knowledge will enable oncologists to make evidence-based decisions so as many patients as possible might benefit from this new type of treatment. Each successive advance builds on the previous hard work of generations of basic, translational, and clinical cancer researchers. Importantly, the advances described in this report would not have been possible without the individuals who volunteered to participate in clinical trials as part of their treatment. To turn the promising vision of a cancer moonshot into meaningful advances, we need sustained, robust federal funding for continued research and innovation. Approximately 30% of the research highlighted in this report was funded, at least in part, through federal dollars appropriated to the National Institutes of Health or the National Cancer Institute. Without this federal investment—unique internationally in scale, duration, and impact for decades—I fear we may lose the forward momentum needed to further the progress we see highlighted in this report. Federal lawmakers can further fuel progress by advancing initiatives that facilitate the use of big data to achieve the common good of high-quality care for all patients. Such programs, like ASCO’s CancerLinQ, will rapidly increase the pace of progress and dramatically expand the reach of treatment advances to the millions of patients who are living with cancer today or who will do so in the future. This investment will yield medical, scientific, economic, and societal benefits for years to come. Much work still lies ahead. Many questions remain about how cancer develops and spreads and how best to treat it. As you read through Clinical Cancer Advances 2017, I hope you are as inspired as I am by the gains the clinical cancer research community has made over the past year and by the promise of a new era of advances just over the horizon. Daniel F Hayes, MD, FASCO, FACP ASCO President, 2016 to 2017

Background: S100A8 and S100A9 are members of a family of calcium binding proteins that regulate inflammatory response, and are biomarkers of inflammatory diseases, S100A8/A9 preferentially form heterodimers that interact with their receptor, RAGE, to activate signaling pathways (ERK1/2 MAPK, JNK, and NF-κB) and stimulate tumor cells. Elevated expression of S100A8/A9 has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8/A9 are expressed intratumorally by cancer cells and in the stroma by infiltrating immune and myeloid cells as well. We investigated the associations of elevated expression of intratumoral and stromal S100A8 with survival outcomes in breast cancer. Methods: Tissue microarrays (TMA) were constructed from breast cancer specimens from patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004-2006, ensuring a minimum of 10-year follow-up. Each patient was represented on the TMA by representative regions of non-necrotic tumor and distant normal tissue. Automative Quantitative Immunofluorescence (AQUA) was performed for S100A8 protein, and samples were scored for intratumoral and stromal S100A8 expression. S100A8 staining was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations with disease-free survival (DFS) or overall survival (OS) and S100A8 expression, either as continuous value or based on the exploratory cutoffs, were determined using the Kaplan-Meier method and Cox proportional hazards models. Results: In the entire patient cohort, high intratumoral S100A8 expression, as a continuous measure, was a significant prognostic factor for OS (univariable hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.02-1.56, p=0.036), and for DFS (multivariable HR [95%CI] = 1.24 [1.01-1.53], p = 0.043). Exploratory analyses demonstrated optimal cutoffs of intratumoral and intrastromal staining that greatly separated survival curves. We evaluated whether the prognostic significance of S100A8 expression is different in breast cancer patients based on hormone receptor status and determined that neither intratumoral nor stromal S100A8 expression were significantly associated with outcomes. Conclusions: Elevated intratumoral and stromal expression of S100A8 are significant indicators of poor outcome in breast cancer patients. These data further support a biological role for S100A8 signaling in mammary carcinogenesis and aggressive tumor behavior. Evaluation of S100A8 protein expression might provide additional prognostic information beyond traditional breast cancer prognostic biomarkers. Further validation is necessary to investigate these findings. Citation Format: Miller P, Kidwell K, Thomas D, Sabel M, Rae J, Hayes DF, Lippman ME, El-Ashry D. High intratumoral and stromal S100A8 expression is prognostic of poor outcome in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-13.

Although blockade of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint has revolutionized cancer treatment, how it works on tumor-infiltrating CD8(+) T cells recognizing the same antigen at various differentiation stages remains elusive. Here, we found that the chemokine receptor CX3CR1 identified 3 distinct differentiation states of intratumor CD8(+) T cell subsets. Adoptively transferred antigen-specific CX3CR1(–)CD8(+) T cells generated phenotypically and functionally distinct CX3CR1(int) and CX3CR1(hi) subsets in the periphery. Notably, expression of coinhibitory receptors and T cell factor 1 (Tcf1) inversely correlated with the degree of T cell differentiation defined by CX3CR1. Despite lower expression of coinhibitory receptors and potent cytolytic activity, in vivo depletion of the CX3CR1(hi) subset did not alter the antitumor efficacy of adoptively transferred CD8(+) T cells. Furthermore, differentiated CX3CR1(int) and CX3CR1(hi) subsets were impaired in their ability to undergo proliferation upon restimulation and had no impact on established tumors upon second adoptive transfer compared with the CX3CR1(–) subset that remained effective. Accordingly, anti–PD-L1 therapy preferentially rescued proliferation and cytokine production of the CX3CR1(–) subset and enhanced antitumor efficacy of adoptively transferred CD8(+) T cells. These findings provide a better understanding of the phenotypic and functional heterogeneity of tumor-infiltrating CD8(+) T cells and can be exploited to develop more effective immunotherapy.

Purpose In patients with newly diagnosed glioblastoma that harbors a nonmethylated O6-methylguanine–DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. Patients and Methods In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m2 every 2 weeks) or to daily TMZ (75 mg/m2) during RT followed by six courses of TMZ (150-200 mg/m2/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). Results In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P Conclusion BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Although the increasing use of bilateral mastectomies is multifaceted, one source of influence may be the media, including coverage of celebrity breast cancer treatment. We examined trends in media reporting that might impact decision making among women with breast cancer. We performed searches of two comprehensive online databases for articles from major U.S. print publications mentioning celebrities and terms related to the word “breast” and terms related to cancer treatment. Automated analysis using custom-created dictionaries was used to determine word frequencies over time. An analysis of net media tone was conducted using Lexicoder Sentiment Dictionaries. Celebrity breast cancer media reports significantly increased since 2004 (p

BACKGROUND Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Recent studies suggest that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations. METHODS MGMT promoter methylation and TERT promoter mutation status were assessed in an exploratory prospective cohort of IDH-wildtype glioblastoma patients of the German Glioma Network (GGN) (n=298) and validated in a retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n=302). RESULTS In the prospective GGN discovery cohort of patients with MGMT promoter-unmethylated tumors, TERT promoter mutation showed inferior outcome (p=0.044). In contrast, TERT promoter mutations were not associated with improved outcome in patients with MGMT promoter-methylated tumors. Different TERT promoter hotspot mutations were not associated with distinct outcomes. The association of TERT promoter mutation in MGMT promoter-unmethylated tumors was not confirmed in the retrospective validation cohort. CONCLUSIONS Analysis of two independent cohorts of glioblastoma patients, including the prospective GGN cohort, did not confirm previous data suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in IDH-wildtype glioblastoma patients.

176 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect that manifests in the hands or feet primarily as numbness or tingling but can also have motor or painful components. CIPN monitoring is typically conducted by patients self-reporting symptoms during appointments or via questionnaires. Objective CIPN testing may improve early detection but is not typical during treatment, perhaps due to the need for specialized equipment and personnel. The objective of this pilot study was to conduct initial testing of a smartphone app that collects patient-reported and objective CIPN data. Methods: NeuroDetect V1.0 (available in iOS app store) includes a patient-reported CIPN questionnaire (EORTC CIPN20) and two functional assessments available within ResearchKit, the Gat and Balance and 9-Hole Peg tests. Patients who had completed neurotoxic chemotherapy were enrolled to complete NeuroDetect assessments one time. Study participants were classified as CIPN cases if they answered ≥ 3 for at least one of the first four CIPN20 questions, which ask about numbness or tingling in the hands or feet on a 1-4 scale. User acceleration data features were extracted with two open source tools, mhealthtools and pdkit. The results of the functional assessments were compared between CIPN cases and controls in principal component analysis and partial least squares discriminant analysis. Results: Twenty-four patients who had completed neurotoxic chemotherapy enrolled and completed the NeuroDetect assessments. Integration across all 87 features measured in the gait and balance test explained 42% of the difference between CIPN cases (n = 14) and controls (n = 10) and 9 individual features were significantly different between cases and controls (all p < 0.05). In the 9-hole Peg Test, hand speed explained 77% of the difference between CIPN cases and controls. CIPN cases took longer to complete the 9-hole peg test though the difference was not statistically significant (dominant hand mean 407.3 vs. 406.2 ms, p = 0.075). Conclusions: App-based functional assessment may detect evidence of CIPN. We are developing additional CIPN functional assessments for NeuroDetect V2.0 to test CIPN detection in a longitudinal study of patients undergoing neurotoxic chemotherapy.