Update on Management of Ductal Carcinoma in Situ.

Ductal carcinoma in situ (DCIS) represents 18% to 25% of all diagnosed breast cancers, and is a noninvasive, nonobligate precursor lesion to invasive cancer. The diagnosis of DCIS represents a wide range of disease, including lesions with both low and high risk of progression to invasive cancer and recurrence. Over the past decade, research on the topic of DCIS has focused on the possibility of tailoring treatment for patients according to their risk for progression and recurrence, which is based on clinicopathologic, biomolecular and genetic factors. These efforts are ongoing, with recently completed and continuing clinical trials spanning the continuum of cancer care. We conducted a review to identify recent advances on the topic of diagnosis, risk stratification and management of DCIS. While novel imaging techniques have increased the rate of DCIS diagnosis, questions persist regarding the optimal management of lesions that would not be identified with conventional methods. Additionally, among trials investigating the potential for omission of surgery and use of active surveillance, 2 trials have completed accrual and 2 clinical trials are continuing to enroll patients. Identification of novel genetic patterns is expanding our potential for risk stratification and aiding our ability to de-escalate radiation and systemic therapies for DCIS. These advances provide hope for tailoring of DCIS treatment in the near future.

Ergonomics Workshop Improves Musculoskeletal Symptoms in General Surgery Residents.

INTRODUCTION: Poor operative ergonomics can lead to muscle fatigue and injury. However, formal ergonomics education is uncommon in surgical residencies. Our study examines the prevalence of musculoskeletal (MSK) symptoms, baseline ergonomics knowledge, and the impact of an ergonomics workshop in general surgery residents. METHODS: An anonymous voluntary presurvey and postsurvey was distributed to all general surgery residents at a single academic residency, assessing resident characteristics, MSK symptoms, and ergonomic knowledge before and after an ergonomics workshop. The workshop consisted of a lecture and a personalized posture coaching session with a physiatrist. RESULTS: The presurvey received 33/35 (94%) responses. Of respondents, 100% reported some degree of MSK pain. Prevalence of muscle stiffness and fatigue decreased with increasing height. Females reported higher frequencies of MSK pain (P = 0.01) and more muscle fatigue than males (100% versus 73%, P = 0.03). All residents reported little to no ergonomics knowledge with 68% reporting that ergonomics was rarely discussed in the operating room. The postsurvey received 26/35 (74%) responses. Of respondents, 100% reported the workshop was an effective method of ergonomics education. MSK symptom severity improved in 82% of residents. Reports that ergonomics was rarely discussed in the operating room significantly decreased to 22.8% of residents (P < 0.01). CONCLUSIONS: Surgical resident ergonomics knowledge is poor and MSK symptoms are common. Resident characteristics are associated with different MSK symptoms. Didactic teaching and personalized posture coaching improve ergonomics knowledge and reduce MSK symptom severity. Surgical residencies should consider implementing similar interventions to improve resident wellbeing.

Using ecological momentary assessment to understand associations between daily physical activity and symptoms in breast cancer patients undergoing chemotherapy.

PURPOSE: Understanding real-time relationships between physical activity (PA) and symptoms during chemotherapy (CT) could have important implications for intervention. This study used ecological momentary assessment to examine the relationship between objective PA and symptoms during CT. METHODS: Breast cancers patients (n = 67; Mage = 48.6 (SD = 10.3)) participated in data collection at three time points during CT: beginning, middle, and end. At each time point, participants answered four prompts assessing symptoms and wore an accelerometer for 10 days (3 days pre-CT, day of CT, and 6 days post-CT). Multilevel linear regression models examined the between- and within-person associations between moderate to vigorous (MVPA) and light-intensity physical activity (LPA) and same and next-day symptom ratings controlling for covariates. RESULTS: On days when individuals engaged in more LPA or MVPA, separately, they reported improved affect, anxiety, fatigue, physical functioning (walking and activities of daily living), pain, and cognition that day (p < 0.001 for all). Findings were consistent for next-day symptom ratings with the exception that only previous day LPA was related to next-day fatigue and neither LPA nor MVPA were related to next-day cognition (p < 0.001 for all). No between-person effects were found. CONCLUSIONS: Within person higher than usual PA on a given day, regardless of intensity, is associated with improved symptoms ratings on the current and next day. IMPLICATIONS FOR CANCER SURVIVORS: Encouraging breast cancer patients undergoing CT to engage in daily PA could help manage CT-associated symptoms.

A Single-Center Study of Adherence to Breast Cancer Screening Mammography Guidelines by Transgender and Non-Binary Patients.

BACKGROUND: Adherence to screening guidelines among transgender and non-binary (TGNB) populations is not well studied. This study examines breast cancer screening patterns among TGNB patients at an urban academic medical center. METHODS: Demographic information, risk factors, and screening mammography were collected. Mammography rates were calculated in populations of interest according to national guidelines, and mammogram person-years were also calculated. Univariate and multivariate logistic regression was performed. RESULTS: Overall, 253 patients were analyzed: 193 transgender women and non-binary people designated male at birth (TGNB DMAB) and 60 transgender men and non-binary people designated female at birth (TGNB DFAB). The median (interquartile range) age was 53.2 years (42.3-62.6). Most patients had no family history of breast cancer (n = 163, 64.4%) and were on hormone therapy (n = 191, 75.5%). Most patients where White (n = 164, 64.8%), employed (n = 113, 44.7%), and had public insurance (n = 128, 50.6%). TGNB DFAB breast screening rates were low, ranging from 2.0 to 50.0%, as were TGNB DMAB screening rates, ranging from 7.1 to 47.6%. The screening rates among the TGNB DFAB and TGNB DMAB groups did not significantly differ from one another. Among TGNB DFAB patients, univariate analyses showed no significant predictors for mammography. Among TGNB DMAB patients, not being on hormone therapy resulted in fewer odds of undergoing mammography. There were no significant findings on multivariate analyses. CONCLUSION: Mammography rates in the TGNB population are lower than institutional and national rates for cisgender patients, which are 77.3% and 66.7-78.4%, respectively. Stage of transition, organs present, hormone therapy, and risk factors should be considered to guide screening.

A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours.

Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumours. Although this function is traditionally attributed to dendritic cells, tumour-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumour-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbour hyperactive cysteine protease activity in their lysosomes, which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) that targets the lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases that is present specifically inside the lysosomes of TAMs, improves their ability to cross-present antigens and attenuates tumour growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumour regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.

Evaluation of the Novel 4R Oncology Care Planning Model in Breast Cancer: Impact on Patient Self-Management and Care Delivery in Safety-Net and Non-Safety-Net Centers.

PURPOSE: Optimal cancer care requires patient self-management and coordinated timing and sequence of interdependent care. These are challenging, especially in safety-net settings treating underserved populations. We evaluated the 4R Oncology model (4R) of patient-facing care planning for impact on self-management and delivery of interdependent care at safety-net and non-safety-net institutions. METHODS: Ten institutions (five safety-net and five non-safety-net) evaluated the 4R intervention from 2017 to 2020 with patients with stage 0-III breast cancer. Data on self-management and care delivery were collected via surveys and compared between the intervention cohort and the historical cohort (diagnosed before 4R launch). 4R usefulness was assessed within the intervention cohort. RESULTS: Survey response rate was 63% (422/670) in intervention and 47% (466/992) in historical cohort. 4R usefulness was reported by 79.9% of patients receiving 4R and was higher for patients in safety-net than in non-safety-net centers (87.6%, 74.2%, P = .001). The intervention cohort measured significantly higher than historical cohort in five of seven self-management metrics, including clarity of care timing and sequence (71.3%, 55%, P < .001) and ability to manage care (78.9%, 72.1%, P = .02). Referrals to interdependent care were significantly higher in the intervention than in the historical cohort along all six metrics, including primary care consult (33.9%, 27.7%, P = .045) and flu vaccination (38.6%, 27.9%, P = .001). Referral completions were significantly higher in four of six metrics. For safety-net patients, improvements in most self-management and care delivery metrics were similar or higher than for non-safety-net patients, even after controlling for all other variables. CONCLUSION: 4R Oncology was useful to patients and significantly improved self-management and delivery of interdependent care, but gaps remain. Model enhancements and further evaluations are needed for broad adoption. Patients in safety-net settings benefited from 4R at similar or higher rates than non-safety-net patients, indicating that 4R may reduce care disparities.

High-Resolution Full-3D Specimen Imaging for Lumpectomy Margin Assessment in Breast Cancer.

BACKGROUND: Two-dimensional (2D) specimen radiography (SR) and tomosynthesis (DBT) for breast cancer yield data that lack high-depth resolution. A volumetric specimen imager (VSI) was developed to provide full-3D and thin-slice cross-sectional visualization at a 360° view angle. The purpose of this prospective trial was to compare VSI, 2D SR, and DBT interpretation of lumpectomy margin status with the final pathologic margin status of breast lumpectomy specimens. METHODS: The study enrolled 200 cases from two institutions. After standard imaging and interpretation was performed, the main lumpectomy specimen was imaged with the VSI device. Image interpretation was performed by three radiologists after surgery based on VSI, 2D SR, and DBT. A receiver operating characteristic (ROC) curve was created for each method. The area under the curve (AUC) was computed to characterize the performance of the imaging method interpreted by each user. RESULTS: From 200 lesions, 1200 margins were interpreted. The AUC values of VSI for the three radiologists were respectively 0.91, 0.90, and 0.94, showing relative improvement over the AUCs of 2D SR by 54%, 13%, and 40% and DBT by 32% and 11%, respectively. The VSI has sensitivity ranging from 91 to 94%, specificity ranging from 81 to 85%, a positive predictive value ranging from 25 to 30%, and a negative predicative value of 99%. CONCLUSIONS: The ROC curves of the VSI were higher than those of the other specimen imaging methods. Full-3D specimen imaging can improve the correlation between the main lumpectomy specimen margin status and surgical pathology. The findings from this study suggest that using the VSI device for intraoperative margin assessment could further reduce the re-excision rates for women with malignant disease.

Is Breast Magnetic Resonance Imaging an Accurate Predictor of Nodal Status After Neoadjuvant Chemotherapy?

BACKGROUND: With increasing use of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC), preoperative imaging assessment of axillary lymph nodes (ALNs) has become more important in operative planning and patient counseling. We aimed to assess if MRI is an accurate predictor of the ALN status after NAC. METHODS: We used our institutional proprietary prospective database to review all patients with newly diagnosed breast cancer between August 2015 and March 2017 who received NAC, underwent post-NAC MRI, and axillary surgery. Imaging findings, axillary surgery, and histopathology results were analyzed. RESULTS: Of 114 patients receiving NAC, 50 underwent post-NAC MRI before surgery. The mean age was 46 y; 36% were triple-negative, 26% were triple-positive, 26% were ER-positive and HER2/neu-negative, and 12% were ER-negative and Her2/neu-positive. Post-NAC MRI ALN status was normal in 35 patients, of which 30 underwent SLNB and five went directly to axillary lymph node dissection (ALND). 26 of these 35 were negative for metastasis on final pathology resulting in a negative-predictive value of 74.3%. In 15 patients with an abnormal post-NAC MRI ALN status, eight went directly to ALND and seven underwent SLNB. Eight of these 15 were positive for metastasis on final pathology resulting in a positive predictive value of 53.3%. CONCLUSIONS: Assessment of axillary imaging findings on post-NAC MRI predicts the absence of nodal disease with higher accuracy than its presence but not with adequate accuracy as surrogate for surgical pathologic evaluation of ALNs. This information is valuable in both patient counseling and axillary surgical management after NAC.

Daily Physical Activity and Symptom Reporting in Breast Cancer Patients Undergoing Chemotherapy: An Intensive Longitudinal Examination.

BACKGROUND: Increased activity is beneficial during chemotherapy, but treatment-related symptoms may be a barrier. This study examines the relationship between daily fluctuations in symptoms and activity during chemotherapy. METHODS: Women undergoing chemotherapy for breast cancer [n = 67; M age = 48.6 (SD = 10.3)] wore an accelerometer 24 hours/day and received four text prompts/day to rate symptoms for 10 consecutive days at the beginning, middle, and end of chemotherapy. Mixed-effects models were used to examine the between and within-person relationships between symptom ratings on a given day and moderate to vigorous physical activity (MVPA) and light physical activity (LPA) on that day and the following day controlling for relevant covariates and using the Bonferroni correction for multiple comparisons. RESULTS: For MVPA and LPA, within-person associations were statistically significant for same day affect, fatigue, pain, walking, activities of daily living (ADL) physical function, and cognitive function. Previous day anxiety was associated with next day LPA. Every one point worse symptom rating than an individual's overall average was associated with: (i) between 1.49 (pain) and 4.94 (fatigue) minutes less MVPA and between 4.48 (pain) and 24.72 (ADL physical function) minutes less LPA that day, and (ii) 11.28 minutes less LPA the next day. No between-person effects were significant for MVPA or LPA. CONCLUSIONS: Daily within-person variations in symptoms were associated with MVPA and LPA during chemotherapy for breast cancer. IMPACT: Future work should explore relationships between symptoms and activity further and identify whether tailoring to symptoms enhances efficacy of physical activity promotion interventions during chemotherapy.

Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy.

Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy.

Radiology as the Point of Cancer Patient and Care Team Engagement: Applying the 4R Model at a Patient's Breast Cancer Care Initiation.

Radiologists aspire to improve patient experience and engagement, as part of the Triple Aim of health reform. Patient engagement requires active partnerships among health providers and patients, and rigorous teamwork provides a mechanism for this. Patient and care team engagement are crucial at the time of cancer diagnosis and care initiation but are complicated by the necessity to orchestrate many interdependent consultations and care events in a short time. Radiology often serves as the patient entry point into the cancer care system, especially for breast cancer. It is uniquely positioned to play the value-adding role of facilitating patient and team engagement during cancer care initiation. The 4R approach (Right Information and Right Care to the Right Patient at the Right Time), previously proposed for optimizing teamwork and care delivery during cancer treatment, could be applied at the time of diagnosis. The 4R approach considers care for every patient with cancer as a project, using project management to plan and manage care interdependencies, assign clear responsibilities, and designate a quarterback function. The authors propose that radiology assume the quarterback function during breast cancer care initiation, developing the care initiation sequence, as a project care plan for newly diagnosed patients, and engaging patients and their care teams in timely, coordinated activities. After initial consultations and treatment plan development, the quarterback function is transitioned to surgery or medical oncology. This model provides radiologists with opportunities to offer value-added services and solidifies radiology's relevance in the evolving health care environment. To implement 4R at cancer care initiation, it will be necessary to change the radiology practice model to incorporate patient interaction and teamwork, develop 4R content and local adaption approaches, and enrich radiology training with relevant clinical knowledge, patient interaction competence, and teamwork skill set.

Examining the Relationship between Pre-Malignant Breast Lesions, Carcinogenesis and Tumor Evolution in the Mammary Epithelium Using an Agent-Based Model.

INTRODUCTION: Breast cancer, the product of numerous rare mutational events that occur over an extended time period, presents numerous challenges to investigators interested in studying the transformation from normal breast epithelium to malignancy using traditional laboratory methods, particularly with respect to characterizing transitional and pre-malignant states. Dynamic computational modeling can provide insight into these pathophysiological dynamics, and as such we use a previously validated agent-based computational model of the mammary epithelium (the DEABM) to investigate the probabilistic mechanisms by which normal populations of ductal cells could transform into states replicating features of both pre-malignant breast lesions and a diverse set of breast cancer subtypes. METHODS: The DEABM consists of simulated cellular populations governed by algorithms based on accepted and previously published cellular mechanisms. Cells respond to hormones, undergo mitosis, apoptosis and cellular differentiation. Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism. 3000 simulations of the 40-year period of menstrual cycling were run in wild-type (WT) and BRCA1-mutated groups. Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis. RESULTS: Cancer incidence in WT (2.6%) and BRCA1-mutated (45.9%) populations closely matched published epidemiologic rates. Hormone receptor expression profiles in both WT and BRCA groups also closely matched epidemiologic data. Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p < .01). ER- tumors carried significantly more mutations and carried more early mutations in BRCA1, c-MYC and genes associated with epithelial-mesenchymal transition. CONCLUSIONS: The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma in situ (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.

The Breast-Thyroid Cancer Link: A Systematic Review and Meta-analysis.

Rates of thyroid cancer in women with a history of breast cancer are higher than expected. Similarly, rates of breast cancer in those with a history of thyroid cancer are increased. Explanations for these associations include detection bias, shared hormonal risk factors, treatment effect, and genetic susceptibility. With increasing numbers of breast and thyroid cancer survivors, clinicians should be particularly cognizant of this association. Here, we perform a systematic review and meta-analysis of the literature utilizing PubMed and Scopus search engines to identify all publications studying the incidence of breast cancer as a secondary malignancy following a diagnosis of thyroid cancer or thyroid cancer following a diagnosis of breast cancer. This demonstrated an increased risk of thyroid cancer as a secondary malignancy following breast cancer [OR = 1.55; 95% confidence interval (CI), 1.44-1.67] and an increased risk of breast cancer as a secondary malignancy following thyroid cancer (OR = 1.18; 95% CI, 1.09-1.26). There is a clear increase in the odds of developing either thyroid or breast cancer as a secondary malignancy after diagnosis with the other. Here, we review this association and current hypothesis as to the cause of this correlation.

Commentary on the Canadian National Breast Screening study.

In the setting of the 25-year follow-up of the Canadian National Breast Screening Study, the Society of Surgical Oncology continues to endorse mammographic screening for women beginning at 40 years of age, while acknowledging that mammography has both risks and benefits. Further investigation is warranted to develop better screening methods and to determine optimal screening schedules for women based on their risk of future breast cancer and their imaging characteristics.

Utilization of radiotherapy for malignant phyllodes tumors: analysis of the National Cancer Data Base, 1998-2009.

BACKGROUND: Malignant phyllodes tumors of the breast have traditionally been treated with surgical excision. Recently, the use of adjuvant radiotherapy has been advocated to reduce the risk of local recurrence; however, this recommendation is controversial in the absence of consistent outcome data. We hypothesize that there has been a trend toward increased utilization of adjuvant radiotherapy for malignant phyllodes tumors despite its uncertain effect on outcomes. METHODS: Using the National Cancer Data Base, predictors of radiotherapy utilization were examined for women with malignant phyllodes from 1998 to 2009. Kaplan-Meier and Cox regression models were generated to determine the effect of radiotherapy on local recurrence (LR), disease-free survival (DFS), and overall survival (OS). RESULTS: Of the 3,120 patients with malignant phyllodes, 57 % underwent breast conservation surgery and 42 % underwent mastectomy. Overall, 14.3 % of women received adjuvant radiotherapy. Utilization of radiotherapy doubled over the study period (9.5 % in 1998-1999 vs. 19.5 % in 2008-2009, p < 0.001). Women were significantly more likely to receive radiotherapy if they were diagnosed later in the study, were age 50-59 years old, had tumors >10 cm, or had lymph nodes removed. For the 1,774 patients with available recurrence data, overall recurrence was 14.1 %, and LR was 5.9 %. In adjusted models, adjuvant radiotherapy reduced LR (aHR 0.43, 95 % CI 0.19-0.95) but did not impact DFS or OS after 53 months' median follow-up. CONCLUSIONS: Utilization of adjuvant radiotherapy for malignant phyllodes doubled from 1998 to 2009. Radiotherapy significantly reduced LR but had no effect on DFS or OS.

Dietary intakes of total and specific lignans are associated with clinical breast tumor characteristics.

Dietary lignans may affect breast cancer by modifying tumor characteristics likely to affect prognosis. We investigated usual dietary intakes of total and specific lignans with tumor characteristics in 683 women with breast cancer and 611 healthy women without breast cancer enrolled in the Data Bank and BioRepository at Roswell Park Cancer Institute (RPCI). Clinicopathologic data were abstracted from the RPCI breast cancer database. Dietary lignan intakes were calculated from FFQ. OR and 95% CI were estimated with logistic regression adjusting for potential confounders and stratified by menopausal status. Women in the highest compared to the lowest tertile of total lignan intakes had a 40-50% lower odds of breast cancer regardless of menopausal status and substantially reduced odds of an invasive tumor, especially among premenopausal women [OR 0.48 (95% CI 0.26-0.86)]. Lignan intakes were inversely associated with odds of grade 3 tumors among premenopausal women. Lignan intakes were inversely associated with risk of estrogen receptor (ER) negative (ER(-)) breast cancer among premenopausal women [OR 0.16 (95% CI 0.03-0.44)] and particularly triple negative tumors [ER(-), progesterone receptor negative, HER2 negative; OR 0.16 (95% CI 0.04-0.62)]. There were significant differences in the contribution to these effects by specific lignans, especially matairesinol and lariciresinol. In summary, in this case-control study of dietary lignan intakes and breast cancer, we found that higher lignan intakes were associated with lower risks of breast cancer with more favorable prognostic characteristics. Future investigations are warranted to explore the strong associations observed with ER(-) cancer in premenopausal women.

The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence.

BACKGROUND: Over-expression of HER2 in a subset of breast cancers (HER2+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients. METHODS: A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in HER2+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in HER2+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI). RESULTS: TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 HER2+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 HER2+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts. CONCLUSIONS: Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in HER2+ breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with HER2 targeted therapy.