Patient values in breast cancer surgical decision-making - The WhySurg study.

BACKGROUND: The objective of this study was to describe patient values and personality traits associated with breast surgery choice for patients with breast cancer. METHODS: A survey based on qualitative patient interviews and the Big-Five personality trait profile was distributed to Love Research Army volunteers aged 18-70 years old who underwent breast cancer surgery from 2009 to 2020. Multivariable logistic regression analysis was used to determine independent patient values and personality traits for the choice of breast-conserving surgery (BCS), unilateral mastectomy (UM) and bilateral mastectomy (BM). RESULTS: 1497 participants completed the survey. Open-mindedness was associated with UM and sociability was associated with BM. A majority of patients prioritized cancer outcomes. Compared to BM patients, BCS and UM patients were significantly more likely to choose values associated with maintaining their self-image, optimizing surgical recovery, and following their doctor's recommendation. CONCLUSIONS: Other values besides cancer outcomes differentiate patient surgical choice for BCS or mastectomy.

Rates of newly diagnosed breast cancer at commission on cancer facilities during the early phase of the COVID-19 pandemic.

INTRODUCTION: The objective of this study was to examine the impact of the early part of the COVID-19 pandemic on the number of newly diagnosed breast cancer cases at Commission on Cancer (CoC)-accredited facilities relative to the United States (U.S.) population. METHODS: We examined the incidence of breast cancer cases at CoC sites using the U.S. Census population as the denominator. Breast cancer incidence was stratified by patient age, race and ethnicity, and geographic location. RESULTS: A total of 1,499,806 patients with breast cancer were included. For females, breast cancer cases per 100,000 individuals went from 188 in 2015 to 203 in 2019 and then dropped to 176 in 2020 with a 15.7% decrease from 2019 to 2020. Breast cancer cases per 100,000 males went from 1.7 in 2015 to 1.8 in 2019 and then declined to 1.5 in 2020 with a 21.8% decrease from 2019 to 2020. For both females and males, cases per 100,000 individuals decreased from 2019 to 2020 for almost all age groups. For females, rates dropped from 2019 to 2020 for all races and ethnicities and geographic locations. The largest percent change was seen among Hispanic patients (-18.4%) and patients in the Middle Atlantic division (-18.6%). The stage distribution (0-IV) for female and male patients remained stable from 2018 to 2020. CONCLUSION: The first year of the COVID-19 pandemic was associated with a decreased number of newly diagnosed breast cancer cases at Commission on Cancer sites.

Exploring Breast Surgeons' Attitudes on Universal Genetic Testing: A Qualitative Study.

BACKGROUND: The American Society of Breast Surgeons released a consensus statement that genetic testing should be made available to all patients with a personal history of breast cancer. However, it is not clear whether physicians feel comfortable with universal genetic testing (UGT) or if they have sufficient knowledge to interpret results and manage them appropriately. OBJECTIVE: The purpose of this study was to explore breast surgeons' attitudes toward UGT. METHODS: Breast surgeons were consented and scheduled for a semi-structured virtual interview. Transcripts were uploaded into qualitative analysis software where they were exhaustively and iteratively coded. Codes were then organized into higher-order categories and themes and data saturation were assessed. RESULTS: Thirty-one surgeons completed the qualitative interview. Most surgeons practiced in the academic or community setting and most practiced in the Midwest (71.0%). The majority (90.3%) reported having a structured genetics program. The majority (96.8%) referred their patients to genetics for counseling and most preferred ordering testing through a genetic services provider. Some surgeons had concerns about access to genetic services. A minority of surgeons order UGT for all newly diagnosed breast cancer patients. The majority of respondents thought that more training in genetics was needed for surgeons. Many surgeons expressed concern about the psychosocial effects of UGT on patients. CONCLUSIONS: Many surgeons expressed concerns about UGT, mainly related to discomfort with their training, access to genetic services, and the psychosocial impact on their patients. Future work is needed to determine how to improve surgeon's comfort level in implementing UGT.

Trends in bilateral mastectomy rates among different racial backgrounds: A National Cancer Database study.

INTRODUCTION: Studies have shown a decrease in bilateral mastectomy (BM) rates over the past five to ten years, but it is not clear if these decreases are the same across different patient races. METHODS: Using the National Cancer Database (NCDB) we examined BM rates for patients with AJCC Stage 0-II unilateral breast cancer from 2004 to 2020 for White versus nonwhite races (Blacks, Hispanics, and Asians). Multivariable logistic regression was used to identify patient and facility factors associated with BM by patient race from 2004 to 2006 and 2018-2020. RESULTS: Of 1,187,864 patients, 791,594 (66.6%) had breast conserving surgery (BCS), 258,588 (21.8%) had unilateral mastectomy (UM) and 137,682 (11.6%) had BM. Our patient population was 927,530 (78.1%) White patients, 124,636 (10.5%) Black patients, 68,048 (5.7%) Hispanic patients, and 48,341 (4.1%) Asian patients. The BM rate steadily increased from 5.6% to 15.6% from 2004 to 2013, at which point the BM rate decreased to 11.3% in 2020. The decrease in BM was seen across all races, and in 2020, 6,487 (11.7%) Whites underwent BM compared to 506 (10.7%) Hispanics, 331 (9.2%) Asians, and 723 (9.1%) Blacks. Race was a significant independent factor for BM in 2004-2006 and 2018-2020 but all races were more likely to undergo BM in 2004 compared to 2020 after adjusting for patient and facility factors. Compared to Whites, the odds of undergoing BM were OR 0.41 (0.37-0.45) in 2004 compared to OR 0.66 (0.63-0.69) in 2020 for Blacks, OR 0.44 (0.38-0.52) and OR 0.61 (0.57-0.65) for Asians and OR 0.59 (0.52-0.66) and OR 0.71 (0.67-0.75) for Hispanics, respectively. CONCLUSION: BM rates for all races have declined since 2013, and differences in rates of BM amongst races have narrowed.

Potential evidence of peritoneal recurrence in Stage-II colon cancer from the control arm of CALGB9581.

BACKGROUND: Relapse of early-stage colon cancer (CC) after curative-intent resection occurs. We hypothesized that known risk factors for peritoneal metastases (PM) can define a high-risk state (HRS) that predicts recurrence and mortality. METHODS: CALGB9581 trial patients receiving no adjuvant treatment after stage-II CC resection were included. Positive radial margins, T4 invasion, obstruction/perforation or lymphovascular invasion defined the HRS. Cox proportional hazard models determined association with overall (OS) and disease-free survival (DFS). RESULTS: Median follow-up in 873 included patients was 8.1 years. Five-year OS was 85.8%. HRS+ patients had lower 5-year DFS (68.7 vs. 82.4%, P = 0.003) and OS (75.5 vs. 87.8%, P = 0.001). HRS+ was independently predictive of worse DFS and OS (HR 1.52 and 1.64, P < 0.01). Among recurrences, HRS+ patients showed shorter median OS (3.3 vs. 5.3 years, P = 0.01). CONCLUSIONS: HRS criteria identify a cohort of CC patients at high-risk of recurrence and death. Studies of novel surveillance techniques in such patients are warranted.

A Multi-institutional Study of Peritoneal Recurrence Following Resection of Low-grade Appendiceal Mucinous Neoplasms.

BACKGROUND: Peritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is known about the natural history of localized (non-disseminated) LAMNs. OBJECTIVE: The goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs. METHODS: We performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence. RESULTS: We identified 217 patients with localized LAMNs. Median age was 59 years (11-95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1 months (0-271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4 months (2.5-47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (p < 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (p = 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (p = 0.355) had recurrence. CONCLUSIONS: This multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.

RIG-I-Like Receptor LGP2 Is Required for Tumor Control by Radiotherapy.

Dendritic cells (DC) play an essential role in innate immunity and radiation-elicited immune responses. LGP2 is a RIG-I-like receptor involved in cytoplasmic RNA recognition and antiviral responses. Although LGP2 has also been linked to cell survival of both tumor cells and T cells, the role of LGP2 in mediating DC function and antitumor immunity elicited by radiotherapy remains unclear. Here, we report that tumor DCs are linked to the clinical outcome of patients with breast cancer who received radiotherapy, and the presence of DC correlates with gene expression of LGP2 in the tumor microenvironment. In preclinical models, host LGP2 was essential for optimal antitumor control by ionizing radiation (IR). The absence of LGP2 in DC dampened type I IFN production and the priming capacity of DC. In the absence of LGP2, MDA5-mediated activation of type I IFN signaling was abrogated. The MDA5/LGP2 agonist high molecular weight poly I:C improved the antitumor effect of IR. This study reveals a previously undefined role of LGP2 in host immunity and provides a new strategy to improve the efficacy of radiotherapy. SIGNIFICANCE: These findings reveal an essential role of LGP2 in promoting antitumor immunity after radiotherapy and provide a new strategy to enhance radiotherapy.

4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.

Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.

Evaluation of the Order SMARTT: An Initiative to Reduce Phlebotomy and Improve Sleep-Friendly Labs on General Medicine Services.

We assessed the effectiveness of a quality improvement project to reduce routine labs in clinically stable patients, while also promoting sleep-friendly lab timing. The electronic health record was modified with an "Order Sleep" shortcut to facilitate sleep-friendly lab draws. A "4 AM Labs" column was added to electronic patient lists to signal which patients had early morning labs ordered. Among 7,045 patients over 50,951 total patient-days, on average we observed 26.3% fewer routine lab draws per patient-day per week postintervention (4.68 before vs 3.45 after; difference, 1.23; 95% CI, 0.82-1.63; P < .05). In interrupted time series analysis, the "Order Sleep" tool was associated with a significant increase in sleep-friendly lab orders per encounter per week on resident medicine services (intercept, 1.03; standard error (SE), 0.29; P < .001). The "4 AM Labs" column was associated with a significant increase in sleep-friendly lab orders per patient encounter per week on the hospitalist medical service (intercept, 1.17; SE, 0.50; P = .02). We demonstrate the success of an initiative to simultaneously reduce daily labs and improve sleep-friendly ordering.

The modern approach to the nipple-sparing mastectomy.

A modern perspective on the nipple-sparing mastectomy (NSM) looking at current indications as well as the most up-to-date evidence both in the literature and from our institution. There is an in-depth description of our NSM technique and an overview of alternative approaches, including the robotic technique. The complicated concept of the learning curve is addressed and ideas on how to train other NSM adopters.

The "Nipple Whipple"?! A Pilot Study to Assess the Ergonomic Effects of Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomies (NSMs) with reconstruction are believed to be more difficult to perform than skin-sparing mastectomies (SSMs), but there is little quantitative data to support this claim. METHODS: This prospective study analyzed four surgeons performing mastectomies. Electromyography (EMG) electrodes placed on selected muscle groups on each surgeon were used to capture muscle exertion intraoperatively and a percentage of maximum voluntary exertion was calculated (%MVE). Data regarding surgeon demographics, exercise habits, musculoskeletal problems, and surgery-specific workload was collected using a questionnaire. RESULTS: A total of 61 mastectomies were analyzed; 40 were NSM and 21 were SSM/total mastectomies. NSM were considered to be more mentally demanding and physically demanding than SSM (p < 0.001). When the surgeons' EMG data was analyzed as a group, there was a statistically significant difference in %MVE for NSM versus SSM at high muscle activity in bilateral anterior deltoid muscle groups and at average muscle activity for the left anterior deltoid muscle only. At low muscle activity, there was a statistically significant increase in activation for SSM versus NSM in bilateral cervical erector spinae. Repeated measures ANOVA was performed, which showed statistically significant differences at high muscle activity between NSM and SSM in the left cervical erector spinae and bilateral anterior deltoid muscles. CONCLUSIONS: Our pilot study shows that intraoperative EMGs can assess muscle activity for mastectomy operations and show a difference between NSM and SSM. This is the first study to provide quantitative data on muscle strain with NSM.

DNA Methylation Controls Metastasis-Suppressive 14q32-Encoded miRNAs.

Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer. In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2'-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression. 5-Aza-dC activated demethylation of the MEG3-DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC-induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver metastasis and correlated with improved clinical outcomes in patients with metastatic cancer. These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs. SIGNIFICANCE: This study investigates epigenetic regulation of metastasis-suppressive miRNAs and the effect on metastasis.

Obstruction predicts worse long-term outcomes in stage III colon cancer: A secondary analysis of the N0147 trial.

BACKGROUND: Patients with colon cancer often present with obstruction. Large series have reported obstruction among the high-risk features, yet prospective data on its specific prognostic influence are lacking. We hypothesized that obstruction is an independent risk factor for poor prognosis in patients with stage III colon cancer. METHODS: N0147 was a trial conducted between 2004 and 2009 that randomly assigned patients with stage III colon cancer to adjuvant regimens of folinic acid (leucovorin calcium), fluorouracil, and oxaliplatin or fluorouracil, leucovorin, and irinotecan, with or without cetuximab. Patient-level data from the control chemotherapy-only arms were obtained. Patient, tumor, and treatment characteristics were abstracted. Disease-free survival and overall survival were estimated by the Kaplan-Meier method. Proportions were compared by χ2 and Fisher exact tests. Univariable and multivariable survival analyses were performed using Cox proportional hazards models. RESULTS: Of 1,543 patients with stage III colon cancer, 250 (16.2%) presented with obstruction. Patients with obstruction were equally likely to complete 12 cycles of adjuvant chemotherapy (75.9% vs 77.1%, P = .6). With median follow-up time of 30.9 months among survivors, five-year overall survival and disease-free survival were worse among patients with obstruction (overall survival 67.7% vs 78.0%, P < .001; disease-free survival 53.9% vs 67.0%, P < .0001). On multivariable analysis, obstruction remained significantly associated with worse survival after adjusting for T stage, N stage, performance status, age, sex, histologic grade, and body mass index (overall survival hazard ratio 1.57, 95% confidence interval 1.12-2.20, P = .001; disease-free survival 1.52, 95% confidence interval 1.18-1.95, P < .001). CONCLUSION: In this prospectively followed cohort of patients with stage III colon cancer treated with adjuvant chemotherapy, obstruction was associated with recurrence and worse survival. Moreover, this effect was independent of T and N stage and histologic grade. These results suggest that obstruction should be incorporated into novel risk-stratification models.

Advanced Animal Model of Colorectal Metastasis in Liver: Imaging Techniques and Properties of Metastatic Clones.

Patients with a limited number of hepatic metastases and slow rates of progression can be successfully treated with local treatment approaches1,2. However, little is known about the heterogeneity of liver metastases, and animal models capable of evaluating the development of individual metastatic colonies are needed. Here, we present an advanced model of hepatic metastases that provides the ability to quantitatively visualize the development of individual tumor clones in the liver and estimate their growth kinetics and colonization efficiency. We generated a panel of monoclonal derivatives of HCT116 human colorectal cancer cells stably labeled with luciferase and tdTomato and possessing different growth properties. With a splenic injection followed by a splenectomy, the majority of these clones are able to generate hepatic metastases, but with different frequencies of colonization and varying growth rates. Using the In Vivo Imaging System (IVIS), it is possible to visualize and quantify metastasis development with in vivo luminescent and ex vivo fluorescent imaging. In addition, Diffuse Luminescent Imaging Tomography (DLIT) provides a 3D distribution of liver metastases in vivo. Ex vivo fluorescent imaging of harvested livers provides quantitative measurements of individual hepatic metastatic colonies, allowing for the evaluation of the frequency of liver colonization and the growth kinetics of metastases. Since the model is similar to clinically observed liver metastases, it can serve as a modality for detecting genes associated with liver metastasis and for testing potential ablative or adjuvant treatments for liver metastatic disease.

Molecular Subtype-Specific Expression of MicroRNA-29c in Breast Cancer Is Associated with CpG Dinucleotide Methylation of the Promoter.

Basal-like breast cancer is a molecularly distinct subtype of breast cancer that is highly aggressive and has a poor prognosis. MicroRNA-29c (miR-29c) has been shown to be significantly down-regulated in basal-like breast tumors and to be involved in cell invasion and sensitivity to chemotherapy. However, little is known about the genetic and regulatory factors contributing to the altered expression of miR-29c in basal-like breast cancer. We here report that epigenetic modifications at the miR-29c promoter, rather than copy number variation of the gene, may drive the lower expression of miR-29c in basal-like breast cancer. Bisulfite sequencing of CpG sites in the miR-29c promoter region showed higher methylation in basal-like breast cancer cell lines compared to luminal subtype cells with a significant inverse correlation between expression and methylation of miR-29c. Analysis of primary breast tumors using The Cancer Genome Atlas (TCGA) dataset confirmed significantly higher levels of methylation of the promoter in basal-like breast tumors compared to all other subtypes. Furthermore, inhibition of CpG methylation with 5-aza-CdR increases miR-29c expression in basal-like breast cancer cells. Flourescent In Situ Hybridization (FISH) revealed chromosomal abnormalities at miR-29c loci in breast cancer cell lines, but with no correlation between copy number variation and expression of miR-29c. Our data demonstrated that dysregulation of miR-29c in basal-like breast cancer cells may be in part driven by methylation at CpG sites. Epigenetic control of the miR-29c promoter by epigenetic modifiers may provide a potential therapeutic target to overcome the aggressive behavior of these cancers.