Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Mediators of a Mindfulness-Based Intervention for Younger Breast Cancer Survivors: Effects on Depressive Symptoms.

OBJECTIVE: Depression is associated with poor outcomes in breast cancer patients, with higher prevalence among younger women. Although mindfulness-based interventions (MBIs) have demonstrated therapeutic effects, the mechanisms of intervention effects are poorly understood. We investigated whether rumination, self-kindness, intrusive thoughts about cancer, cancer-related worry, or a sense of meaning and peace mediated the intervention effects of an MBI, Mindful Awareness Practices (MAPs), on depressive symptoms. Additionally, we explored the same variables as mediators of a psychoeducation program, Survivorship Education (SE). METHODS: Women diagnosed with stage 0-III breast cancer at age <50 years were randomized to 6 weeks of MAPs ( n = 85), SE ( n = 81), or wait-list control (WLC; n = 81). During preintervention, postintervention, and 6-month follow-up (FU), we assessed depressive symptoms, rumination, self-kindness, intrusive thoughts, worry, and meaning and peace. RESULTS: MAPs and SE significantly reduced depressive symptoms at postintervention, and reductions remained through 6-month FU for MAPs. Models revealed that reductions in rumination ( ß = -0.68, 95% confidence interval [CI] = -1.64 to -0.07) and intrusive thoughts ( ß = 1.17, 95% CI = -2.17 to -0.37) and improvements in self-kindness ( ß = -1.09, 95% CI = -2.37 to -0.28) and meaning and peace ( ß = -1.09, 95% CI = -3.16 to -0.56) mediated MAPs' effects at all time points. Reductions in worry ( ß = -1.34, 95% CI = -2.47 to -0.45]) mediated effects at postintervention only. Worry and intrusive thoughts mediated SE effects at postintervention and 6-month FU, respectively. CONCLUSIONS: Findings identified depression-relevant mediators of MAPs' effects, expanding the understanding of MBI mechanisms. Results highlight pathways that could be leveraged to optimize intervention outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03025139 .

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

BACKGROUND: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment. METHODS: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes. RESULTS: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant. CONCLUSIONS: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.

Work Productivity Among Younger Breast Cancer Survivors: The Impact of Behavioral Interventions for Depression.

OBJECTIVES: The Pathways to Wellness randomized controlled trial found that 2 behavioral interventions, mindfulness awareness practices and survivorship education, reduced depressive symptoms in younger breast cancer survivors (BCSs) compared with wait-list control. This secondary analysis examines whether the interventions led to reduced loss of work productivity among younger BCSs and whether such reductions were mediated by reductions in depressive symptoms. METHODS: The Work Productivity and Activity Impairment scale was used to measure work productivity loss at 4 assessment time points. Correlates of productivity loss at enrollment were examined using multivariable linear regression. Differences in change over time in productivity loss between each intervention group and control were assessed using linear mixed models. Reduced depressive symptoms were tested as a mediator of reduced productivity loss. RESULTS: Of 247 trial participants, 199 were employed and included in the analyses. At enrollment, higher productivity loss was associated with chemotherapy receipt (P = .003), younger age (P = .021), more severe cognitive problems (P = .002), higher musculoskeletal pain severity (P = .002), more depressive symptoms (P = .016), and higher fatigue severity (P = .033). The mindfulness intervention led to significantly less productivity loss compared with control at all 3 postintervention assessment points (all P < .05), with about 54% of the effect mediated by reduction in depressive symptoms. Survivorship education was not associated with reduced loss of productivity. CONCLUSIONS: These findings suggest that addressing depressive symptoms through behavioral interventions, such as mindfulness, may mitigate impacts on work productivity in younger BCSs.

Overall side effect assessment of oxaliplatin toxicity in rectal cancer patients in NRG oncology/NSABP R04.

PURPOSE: Regulatory guidance suggests capturing patient-reported overall side effect impact in cancer trials. We examined whether the Functional Assessment of Cancer Therapy (FACT) GP5 item ("I am bothered by side effects of treatment") post-neoadjuvant chemotherapy/radiotherapy differed between oxaliplatin vs. non- oxaliplatin arms in the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial of stage II-III rectal cancer patients. METHODS: The R-04 neoadjuvant trial compared local-regional tumor control between patients randomized to receive 5-fluorouracil or capecitabine with radiation, with or without oxaliplatin (4 treatment arms). Participants completed surveys at baseline and immediately after chemoradiotherapy. GP5 has a 5-point response scale: "Not at all" (0), "A little bit" (1), "Somewhat" (2), "Quite a bit" (3), and "Very much" (4). Logistic regression compared the odds of reporting moderate-high side effect impact (GP5 2-4) between patients receiving oxaliplatin or not after chemoradiotherapy, controlling for relevant patient characteristics. We examined associations between GP5 and other patient-reported outcomes reflecting side effects. RESULTS: Analyses were performed among 1132 study participants. Participants receiving oxaliplatin were 1.58 times (95% CI: 1.22-2.05) more likely to report moderate-high side effect bother at post-chemotherapy/radiation. In both arms, worse overall side effect impact was associated with patient-reported diarrhea, nausea, vomiting, and peripheral sensory neuropathy (p < 0.01 for all). CONCLUSION: This secondary analysis of R-04 found that GP5 distinguished between patients receiving oxaliplatin or not as part of their post-neoadjuvant chemoradiotherapy, adding patient-centric evidence on the reduced tolerability of oxaliplatin and demonstrating that GP5 is sensitive to known toxicity differences between treatments. CLINICALTRIALS: GOV: NCT00058474.

Validating the PROMIS cognitive function short form in cancer survivors.

PURPOSE: The Patient-Reported Outcome Measurement Information System Cognitive Function Short Form 8a  (PROMIS Cog) could provide a shorter, useful alternative to the often used Functional Assessment of Cancer Therapy - Cognition (FACT-Cog) in research and clinical care. This study aimed to determine the convergent validity and internal reliability of the PROMIS Cog in 3 separate samples of breast cancer survivors and to explore clinical cut points. METHODS: Data from three samples of breast cancer survivors were used for this secondary analysis. Convergent validity was determined by evaluating correlation strength among the derived PROMIS Cog and measures of depression, anxiety, stress, fatigue, sleep, loneliness, the FACT-Cog . Clinical cut-points for the PROMIS Cog were determined by plotting the receiver operating characteristic curves. RESULTS: 3 samples of breast cancer survivors (N = 471, N = 132, N = 90) were included. Absolute values of correlations demonstrating convergent validity ranged from 0.21 to 0.82, p's < 0.001, and were comparable to correlations with the full FACT-Cog 18 item perceived cognitive impairments (PCI) scale. ROC curve plots indicated a clinical cut off < 34 for the combined sample. CONCLUSION: The 8-item PROMIS Cog demonstrated good convergent validity and internal reliability in breast cancer survivors, comparable to the 18-item FACT-Cog PCI. The PROMIS Cog 8a is a brief self-report measure that can be easily incorporated into cancer-related cognitive impairment research designs or used in clinical settings.

American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline.

Answer questions and earn CME/CNE The purpose of the American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline is to provide recommendations to assist primary care and other clinicians in the care of female adult survivors of breast cancer. A systematic review of the literature was conducted using PubMed through April 2015. A multidisciplinary expert workgroup with expertise in primary care, gynecology, surgical oncology, medical oncology, radiation oncology, and nursing was formed and tasked with drafting the Breast Cancer Survivorship Care Guideline. A total of 1073 articles met inclusion criteria; and, after full text review, 237 were included as the evidence base. Patients should undergo regular surveillance for breast cancer recurrence, including evaluation with a cancer-related history and physical examination, and should be screened for new primary breast cancer. Data do not support performing routine laboratory tests or imaging tests in asymptomatic patients to evaluate for breast cancer recurrence. Primary care clinicians should counsel patients about the importance of maintaining a healthy lifestyle, monitor for post-treatment symptoms that can adversely affect quality of life, and monitor for adherence to endocrine therapy. Recommendations provided in this guideline are based on current evidence in the literature and expert consensus opinion. Most of the evidence is not sufficient to warrant a strong evidence-based recommendation. Recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, health promotion, and care coordination/practice implications are made.

Simulation study comparing analytical methods for single-item longitudinal patient-reported outcomes data.

PURPOSE: Efficient analytical methods are necessary to make reproducible inferences on single-item longitudinal ordinal patient-reported outcome (PRO) data. A thorough simulation study was performed to compare the performance of the semiparametric probabilistic index models (PIM) with a longitudinal analysis using parametric cumulative logit mixed models (CLMM). METHODS: In the setting of a control and intervention arm, we compared the power of the PIM and CLMM to detect differences in PRO adverse event (AE) between these groups using several existing and novel summary scores of PROs. For each scenario, PRO data were simulated using copula multinomial models. Comparisons were also exemplified using clinical trial data. RESULTS: On average, CLMM provided substantially greater power than the PIM to detect differences in PRO-AEs between the groups when the baseline-adjusted method was used, and a small advantage in power when using the baseline symptom as a covariate. CONCLUSION: Although the CLMM showed the best performance among analytical methods, it relies on assumptions difficult to verify and that might not be fulfilled in the real world, therefore our recommendation is the use of PIM models with baseline symptom as a covariate.

Health-related quality of life outcomes after neoadjuvant chemoradiotherapy for rectal cancer in NRG Oncology/NSABP R-04.

BACKGROUND: There has been limited evaluation of health-related quality of life (HRQOL) in rectal cancer patients receiving neoadjuvant chemoradiotherapy. HRQOL outcomes in the National Surgical Adjuvant Breast and Bowel Project R-04 trial are examined in this article. METHODS: Between 2004 and 2010, R-04 patients were invited to enroll in the HRQOL substudy, with questionnaires administered before randomization, after completion of chemoradiotherapy, and 1-year after surgery. HRQOL measures included: Functional Assessment of Cancer Therapy for colorectal cancer (FACT-C); Short Form-36v.2 Vitality scale; a treatment-specific symptom scale; and the FACT neurotoxicity scale. A 5-year postsurgery assessment was added to the protocol in 2012. Mixed-effects models examined neoadjuvant therapy treatment effects in the 1-year sample and models that explored associations of host factors and treatment impact on 5-year HRQOL. RESULTS: A total of 1373 patients completed baseline HRQOL and at least one additional assessment. The average age was 58 years (range, 23-85 years), male (68%), and 59% Stage II. There were no statistically significant differences in HRQOL outcomes by treatment arm, but HRQOL worsened from baseline to postneoadjuvant chemoradiotherapy, with statistically significant effect sizes changes ranging from 0.6 (Vitality) to 0.9 (FACT-C Trial Outcome Index). Neurotoxicity was greater in the oxaliplatin-treated groups. Obese/overweight patients had statistically significantly worse FACT-C Trial Outcome Index scores than did underweight/normal weight groups. At 5 years, younger patients and those with normal baseline weight had statistically significantly better physical function scores and older patients had better mental health outcomes. CONCLUSIONS: HRQOL did not differ across the four R-04 treatment arms; however, host factors explained significant variation in posttreatment HRQOL. CLINICALTRIALS: gov: NCT00058474 (https://ClinicalTrials.gov/ct2/show/NCT00058474). LAY SUMMARY: This article reports on the health-related quality of life (HRQOL) outcomes of patients treated with four different chemotherapy regimens combined with radiation in rectal cancer patients before definitive surgical treatment. There were no significant differences in HRQOL by treatment regimen, but all patients experienced decreased vitality (energy) and physical functioning. By 1 year after treatment, most patients had returned to pretreatment vitality and physical functioning, with the exception of increased neurotoxicity. In a subsample of patients assessed at 5 years after surgery, physical function was better in those who at pretreatment were younger, normal weight, and had better performance status. Mental function was better in those who at pretreatment were older and had better performance status.

A mixed method study of medical oncologists' perceived barriers and motivators to addressing long-term effects in breast cancer survivors.

PURPOSE: The purpose of this study was to identify oncologist-reported barriers and motivators in addressing long-term effects with breast cancer survivors. METHODS: This study is a secondary analysis of data from a survey of U.S. medical oncologists (n = 217) about breast cancer survivorship care in clinical practice. Using both closed- and open-ended questions, we asked oncologists to report barriers and motivators they perceived in addressing long-term effects with breast cancer patients. Descriptive statistics were used to summarize and rank items endorsed by oncologists in analyses of quantitative data; content analysis was used to identify salient categories of barriers and motivators in qualitative data. RESULTS: Key barriers to managing physical long-term effects included lack of time during appointments (n = 128 oncologists, 59%) and perceived lack of evidence-based interventions (n = 89, 41%). With respect to psychosocial effects, oncologists reported lack of knowledge (n = 88, 40.6%) and challenges making referrals to mental health providers (n = 115, 53%). From the qualitative data, three distinct barrier categories emerged: "Competing priorities during brief appointments;" "Discussing long-term effects-Who? What? When?;" and "Beyond my expertise and comfort level." Two motivator categories emerged: "I owe it to them;" and "Giving people a life worth living." CONCLUSION: Oncologists' key motivators for addressing long-term effects were focused on professional values, relationships with survivors, and their commitment to prioritizing patients' quality of life. Future efforts should leverage oncologists' professional and interpersonal motivators to enhance the delivery of survivorship care for breast cancer.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Psychosocial Resilience to Inflammation-Associated Depression: A Prospective Study of Breast-Cancer Survivors.

Stress can lead to depression, in part because of activation of inflammatory mechanisms. It is therefore critical to identify resilience factors that can buffer against these effects, but no research to date has evaluated whether psychosocial resilience mitigates the effects of stress on inflammation-associated depressive symptoms. We therefore examined psychosocial resources known to buffer against stress in a longitudinal study of women with breast cancer (N = 187). Depressive symptoms and inflammation were measured over a 2-year period extending from after diagnosis into survivorship. Cancer-related stress and psychosocial resources-social support, optimism, positive affect, mastery, self-esteem, and mindfulness-were measured after diagnosis. As hypothesized, women who reported having more psychosocial resources showed weaker associations between stress and depressive symptoms and weaker associations between stress and inflammation-related depressive symptoms. Results highlight the importance of psychosocial resilience by demonstrating a relationship between psychosocial resources and sensitivity to inflammation-associated depressive symptoms.

Socioeconomic Status and Inflammation in Women with Early-stage Breast Cancer: Mediation by Body Mass Index.

BACKGROUND: Breast cancer is the most common cancer among women in the US, and women of low socioeconomic status (SES) show markedly poorer outcomes than those of high SES. SES may influence health through inflammation, although links between SES and inflammatory biomarkers have not been investigated in women with breast cancer. This study tested the hypothesis that breast cancer patients of lower SES would show higher levels of inflammation than those of higher SES. BMI was examined as a mediator of this association. METHODS: Women recently diagnosed with early-stage breast cancer (N = 194) were recruited before neoadjuvant or adjuvant therapy. Participants completed questionnaires and provided blood samples for immune assessment. SES was indexed by participants' self-reported education and annual household income, BMI was determined by height and weight measurements, and blood was assayed for inflammatory biomarkers linked with cancer outcomes: IL-6, CRP, TNF-α, and sTNF-RII. General linear models tested associations between SES and inflammation, and mediation models examined indirect effects through BMI. RESULTS: Consistent with hypotheses, education status was associated with CRP, (F(2,185) = 4.72, p = 0.001), and sTNF-RII, (F(2,185) = 4.19, p = 0.02), such that lower education was associated with higher levels of both biomarkers. Further, BMI mediated the associations between education and CRP, (95% CIs [-0.62, -0.11; -0.76, -0.21]), sTNF-RII, (95% CIs [-0.09, -0.01; -0.10, -0.02]), and IL-6, (95% CIs [-0.32, -0.05; -0.38, -0.09]). Annual household income was not significantly associated with inflammation (ps > 0.25), and indirect effects on inflammation through BMI were not significant. CONCLUSIONS: Lower education was associated with higher levels of inflammation in this sample, which may presage poor breast cancer-related and clinical outcomes. SES should inform the development of interventions targeting BMI and inflammation in breast cancer.

A Survivorship Educational Tool for Latino Adolescent and Young Adult Cancer Survivors.

BACKGROUND: Low receipt of survivorship care by Latino adolescent and young adult (AYA) cancer survivors necessitates development of age-appropriate and culturally tailored interventions aimed at increasing their perceived need for survivorship care. METHOD: This study describes the development and acceptability testing of a culturally tailored intervention, a photonovela, as part of a community-partnered participatory research (CPPR) project. A four-step approach to the photonovela's development was implemented: (a) literature review, (b) RAND-modified Delphi method, (c) photonovela booklet development, and (d) photonovela acceptability testing through focus groups. Using the CPPR approach, community and academic experts and members worked together at all stages of this project to identify educational domains for the photonovela and ensure that community views and scientific knowledge were equally represented. RESULTS: Cancer survivors and their families described the photonovela as entertaining and relatable. Its story positively reflected their own experiences, and they connected strongly with its characters. Acceptability testing of the photonovela played a significant role in its final script and content, and provided additional new insights into understanding survivorship care perspectives for Latino AYA survivors and their families. CONCLUSION: Equal and shared community and academic involvement through CPPR is essential in identifying unique needs and developing culturally acceptable educational interventions for Latino AYA cancer survivors. The photonovela was seen as an important educational resource in enhancing knowledge and increasing perceived need for survivorship care in this population.

Do all patients with cancer experience fatigue? A longitudinal study of fatigue trajectories in women with breast cancer.

BACKGROUND: Fatigue is a common and expected side effect of cancer treatment. However, the majority of studies to date have focused on average levels of fatigue, which may obscure important individual differences in the severity and course of fatigue over time. The current study was designed to identify distinct trajectories of fatigue from diagnosis into survivorship in a longitudinal study of women with early-stage breast cancer. METHODS: Women with stage 0 to stage IIIA breast cancer (270 women) were recruited before (neo)adjuvant therapy with radiotherapy, chemotherapy, and/or endocrine therapy and completed assessments at baseline; posttreatment; and at 6 months, 12 months, and 18 months of follow-up. Growth mixture modeling was used to identify trajectories of fatigue, and differences among the trajectory groups with regard to demographic, medical, and psychosocial variables were examined. RESULTS: Five distinct trajectories of fatigue were identified: Stable Low (66%), with low levels of fatigue across assessments; Stable High (13%), with high fatigue across assessments; Decreasing (4%), with high fatigue at baseline that resolved over time; Increasing (9%), with low fatigue at baseline that increased over time; and Reactive (8%), with increased fatigue after treatment that resolved over time. Both psychological and treatment-related factors were found to be associated with fatigue trajectories, with psychological factors most strongly linked to high fatigue at the beginning of and over the course of treatment. CONCLUSIONS: There is considerable variability in the experience of fatigue among women with early-stage breast cancer. Although the majority of women report relatively low fatigue, those with a history of depression and elevated psychological distress may be at risk of more severe and persistent fatigue.

A qualitative study to evaluate physician attitudes regarding omission of surgery among exceptional responders to neoadjuvant systemic therapy for breast cancer (NRG-CC006).

PURPOSE: Accrual to clinical trials that challenge well-established treatment paradigms represents a unique challenge. Physician opinions on investigation of a novel approach to breast cancer treatment, in which patients with complete response to neoadjuvant chemotherapy are offered omission of lumpectomy, are unknown. NRG-CC006 sought to describe physician attitudes toward a novel approach to breast cancer treatment. METHODS: We recruited 18 participants in the fields of surgery, medical oncology, and radiation oncology to participate in the semi-structured telephone interviews. Main outcomes are qualitative themes associated with omission of surgery. RESULTS: Of 18 interview participants, specialty and gender were evenly represented across surgery, medical oncology, and radiation oncology. Qualitative themes included general attitudes toward treatment de-escalation, stakeholder considerations, and trial/protocol considerations. The vast majority of participants expressed interest in investigation of omission of surgery, with all participants endorsing need for further investigation into treatment de-escalation. Stakeholder considerations in opening such a trial emphasized need for multidisciplinary involvement and, particularly, the unique role of surgeons as gatekeepers in breast cancer treatment. Finally, participants endorsed a need for further foundational studies to develop ways to predict complete pathologic response to chemotherapy without surgical intervention. CONCLUSIONS: Physicians expressed interest in investigating a novel approach to breast cancer treatment that would omit surgery in complete responders to neoadjuvant chemotherapy. Multidisciplinary input, and specifically surgeon engagement, will be key to the success of future investigations. Ongoing work to develop approaches to predict pathologic complete response accurately is needed to achieve the promise of this idea. ClinTrials #: BR005: NCT03188393 June 13, 2017.

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

Executive Functioning and Depressive Symptoms After Cancer: The Mediating Role of Coping.

OBJECTIVE: Cognitive difficulties are a common complaint among patients with breast cancer and may adversely affect psychological well-being. In particular, problems with executive functioning (EF) may interfere with coping, which is known to influence depressive symptoms. The current study was designed to examine correlations between EF, coping, and depressive symptoms in breast cancer survivors and to longitudinally test the hypothesis that coping mediates the relationship between EF and depressive symptoms. METHODS: Participants included 171 women with early-stage breast cancer assessed at the end of primary treatment with surgery, radiation, and/or chemotherapy and at 6 months, 1 year, and 2 years after treatment follow-ups as part of the Mind-Body Study. Participants completed questionnaires to assess subjective EF, approach and avoidant coping, and depressive symptoms, and neuropsychological testing was conducted to assess objective EF. Bivariate correlations were used to examine associations between EF, coping, and depressive symptoms. Mediation analyses were conducted using a bootstrapping approach (PROCESS). RESULTS: At 1 year after treatment, objective and subjective EFs were correlated with avoidant coping (r = -0.172 [p = .024] and r = 0.297 [p < .001], respectively). In longitudinal analyses, use of the avoidant strategy behavioral disengagement at 1 year mediated the association between objective (95% bootstrap confidence interval = -0.282 to -0.042) and subjective (95% bootstrap confidence interval = 0.020 to 0.254) EFs at 6 months and depressive symptoms at 2 years. CONCLUSIONS: This study highlights how problems with EF during survivorship are associated with avoidant coping and depressive symptoms. Thus, these findings identify potential cognitive and affective targets for depression intervention in this population.

Vulnerability to inflammation-related depressive symptoms: Moderation by stress in women with breast cancer.

BACKGROUND: Stress precipitates depression and may do so in part by increasing susceptibility to inflammation-induced depressive symptoms. However, this has not been examined among individuals facing a major life stressor. Accordingly, the present study tested the moderating role of stress on the longitudinal association between inflammation and depressive symptoms among women with breast cancer. METHODS: Women recently diagnosed with early-stage breast cancer (N = 187) were enrolled before starting adjuvant/neoadjuvant treatment. Blood draws and self-reported depressive symptoms were collected pre-treatment, post-treatment, and at 6, 12, and 18-month post-treatment follow ups. C-reactive protein (CRP) was used to index inflammation. Measures of psychological stress, including cancer-related stress, general stress perceptions, and childhood stress, were administered pre-treatment. RESULTS: Stress moderated the association between CRP and depressive symptoms, such that higher levels of CRP were associated with elevated depressive symptoms only among women who reported high cancer-related stress (ß = 0.080, p = .002) and perceived stress (ß = 0.053, p = .044); childhood stress effects were non-significant. Moreover, elevated CRP was associated with increased odds of exhibiting clinically significant depressive symptoms (OR = 1.64, p < .001) among women who reported high cancer-related stress. Results were independent of age, BMI, race and cancer-related covariates. CONCLUSIONS: Stress was found to heighten sensitivity to inflammation-associated depressive symptoms over a 2-year period, with notably stronger effects for subjective stress responses to a concurrent life event. Individuals who are most distressed following a major life event may exhibit the greatest risk for inflammation-induced depression.

Survivorship, Version 1.2021.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor's complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.