Clinical implications of receptor conversions in breast cancer patients who have undergone neoadjuvant chemotherapy.

PURPOSE: In this study, we aimed to determine the incidence of receptor conversions after neoadjuvant chemotherapy (NAC) for breast cancer and assess the rate at which receptor conversion leads to changes in adjuvant therapy regimens. METHODS: We performed a retrospective review of female breast cancer patients treated with NAC at an academic breast center between January 2017 and October 2021. Patients with residual disease on surgical pathology and complete receptor status information for both pre-NAC and post-NAC specimens were included. Incidence of receptor conversions, defined as a change in at least one hormone receptor (HR) or HER2 status compared to preoperative specimens, was tabulated, and adjuvant therapy modalities were reviewed. Factors associated with receptor conversion were analyzed using chi-square tests and a binary logistic regression. RESULTS: Of the 240 patients with residual disease after NAC, 126 (52.5%) had receptor testing repeated. After NAC, 37 specimens (29%) had a receptor conversion. Receptor conversion resulted in the addition or removal of an adjuvant therapy in 8 patients (6%), indicating a number needed to screen of 16. Prior history of cancer, receipt of initial biopsy at an outside site, HR-positive tumors, and a pathologic stage of II or lower were factors associated with receptor conversions. CONCLUSION: HR and HER2 expression profiles frequently change after NAC and drive adjustments in adjuvant therapy regimens. Repeat testing of HR and HER2 expression should be considered in patients who receive NAC, especially in patients with early stage, HR-positive tumors whose initial biopsies were performed externally.

The effects of resistance exercise on appetite sensations, appetite related hormones and energy intake in hormone receptor-positive breast cancer survivors.

Appetite is a determinant of dietary intake and is impacted by sex hormones, exercise, and body composition among individuals without chronic conditions. Whether appetite is altered by exercise in the context of estrogen suppression and cancer survivorship is unknown. This randomized cross-over study compared appetite and ad libitum energy intake (EI) after acute resistance exercise (REx) versus sedentary (SED) conditions and in relation to body composition and resting metabolic rate (RMR) in breast cancer survivors (BCS). Physically inactive premenopausal females with previous stage I-III estrogen receptor-positive breast cancer completed a single bout of REx or SED 35 minutes after a standardized breakfast meal. Appetite visual analog scales and hormones (total ghrelin and peptide-YY [PYY]) were measured before and 30, 90, 120, 150, and 180 minutes post-meal and expressed as area under the curve (AUC). Participants were offered a buffet-type meal 180 minutes after breakfast to assess ad libitum EI. Body composition (dual X-ray absorptiometry) and RMR (indirect calorimetry) were measured during a separate visit. Sixteen BCS were included (age: 46 ± 2 y, BMI: 24.9 ± 1.0 kg/m2). There were no differences in appetite ratings or EI between conditions. There were no differences in appetite hormone AUC, but REx resulted in lower ghrelin 120 (-85 ± 39 pg/mL, p = 0.031) and 180 (-114 ± 43 pg/mL, p = 0.018) minutes post-breakfast and higher PYY 90 (21 ± 10 pg/mL, p = 0.028) and 120 (14 ± 7 pg/mL, p = 0.041) minutes post-breakfast. Fat-free mass and RMR negatively correlated with hunger and prospective food consumption AUC after SED, but not REx. In sum, a single REx bout temporarily reduces orexigenic and increases anorexic appetite hormones, but not acute subjective appetite sensations or EI.

No One-Size-Fits-All: Sexual Health Education Preferences in Patients with Breast Cancer.

BACKGROUND: Using explanatory mixed methods, we characterize the education that patients with breast cancer received about potential sexual health effects of treatment and explore preferences in format, content, and timing of education. PATIENTS AND METHODS: Adult patients with stage 0-IV breast cancer seen at an academic breast center during December 2020 were emailed questionnaires assessing sexual health symptoms experienced during treatment. Patients interested in further study involvement were invited to participate in semistructured interviews. These interviews explored sexual health education provided by the oncology team and patient preferences in content, format, and timing of education delivery. RESULTS: Eighty-seven (32%) patients completed the questionnaire. Most patients reported decreased sexual desire (69%), vaginal dryness (63%), and less energy for sexual activity (62%) during/after treatment. Sixteen patients participated in interviews. Few women reported receiving information about potential sexual effects of breast cancer treatment; patients who did reported a focus on menopausal symptoms or fertility rather than sexual function. Regarding preferences in format, patients were in favor of multiple options being offered rather than a one-size-fits-all approach, with particular emphasis on in-person options and support groups. Patients desired education early and often throughout breast cancer treatment, not only about sexual side effects but also on mitigation strategies, sexual function, dating and partner intimacy, and body image changes. CONCLUSION: Few patients received information about the sexual health effects of breast cancer treatment, though many experienced symptoms. Potential adverse effects should be discussed early and addressed often throughout treatment, with attention to strategies to prevent and alleviate symptoms and improve overall sexual health.

Longitudinal Risk Management for Patients with Increased Risk for Breast Cancer.

INTRODUCTION: This study aims to characterize longitudinal care management and evaluate the relationship between various patient factors and the likelihood of choosing risk-reducing behaviors in women with increased risk of developing breast cancer. METHODS: A retrospective study was conducted to evaluate all adult female patients who had at least one clinic visit with a surgical provider for discussion of breast cancer risk assessment between January, 2017 to July, 2020 at an academic center. Patients with prior history of breast cancer were excluded. Patient details and strategies pursued at clinic visits were recorded. A time-to-event analysis was performed, and hazard ratios were determined to characterize associations between patient characteristics and time to pursuing risk-reducing care management. RESULTS: There were 283 participants with at least one follow-up visit and 48 (17.0%) ultimately changed their initial strategy to either chemoprevention or prophylactic mastectomy. Patients with gene mutations were 6 times more likely to engage in risk-reducing management compared to those without (hazard ratio (HR) 5.99, P < 0.001). Those with histories of high-risk proliferative changes (HR 7.62, P < 0.001) and hysterectomy (HR 2.99, P = 0.019) were also more likely to engage in risk-reducing management. Age, race, and increased predicted risk of developing breast cancer (estimated by various calculators) were not associated with increased likelihood of engaging in risk-reducing strategies. CONCLUSION: Known gene mutations, history of high-risk proliferative changes, and prior hysterectomy were factors associated with women who were more likely to engage in risk-reducing strategies. These findings, when paired with patient reported outcome measures, may help guide shared decision-making.

Sexual health after a breast cancer diagnosis in young women: clinical implications for patients and providers.

PURPOSE: Sexual dissatisfaction after breast cancer treatment is a common phenomenon that, unfortunately, places a significant strain on young women and is becoming more common as treatment regimens rely more and more on anti-endocrine therapies. METHODS: A PubMed review of peer reviewed manuscripts between the years 1998-2020 evaluating sexual health and wellbeing in cancer patients, primarily young women with breast cancer, was conducted. RESULTS: There are several categories of sexual dissatisfaction women may experience as a result of her breast cancer diagnosis, including menopausal symptoms and dyspareunia, negative body image, reduced sexual desire, strained relationships and partner communication, and anxiety about cancer disclosure in dating relationships. Several methods of addressing each domain have been studied. While hormonal replacement therapy remains controversial, other medication regimens have been shown to be effective in treating menopausal symptoms and dyspareunia. Cognitive behavioral therapy, sex therapy, and couples' therapy are all effective in addressing a variety of symptoms across multiple domains. CONCLUSIONS: Oncologists are often not prepared to discuss sexual health concerns as frequently as women need. Further work is needed to bring easily digestible and meaningful educational opportunities into clinical practice so young breast cancer survivors can receive comprehensive post-cancer survivorship care.

The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition.

OPINION STATEMENT: The advent of multiple-gene germline panel testing has led to significant advances in hereditary breast and ovarian cancer risk assessment. These include guideline-specific cancer risk management recommendations for patients and their families, such as screening with breast magnetic resonance imaging and risk-reducing surgeries, which have the potential to reduce substantially the morbidity and mortality associated with a hereditary cancer predisposition. However, controversy remains about the clinical validity and actionability of genetic testing in a broader patient population. We discuss events leading to the wider availability of commercialized multiple-gene germline panel testing, the recent data that support using this powerful tool to improve cancer risk assessment and reduction strategies, and remaining challenges to clinical optimization of this new genetic technology.

Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer.

INTRODUCTION: Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment. METHODS: We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS. RESULTS: We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013). CONCLUSIONS: CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.

Effectiveness of PARP Inhibitor Maintenance Therapy in Ovarian Cancer by BRCA1/2 and a Scar-Based HRD Signature in Real-World Practice.

PURPOSE: The purpose of the study was to compare the effectiveness of PARP inhibitor maintenance therapy (mPARPi) in real-world practice by biomarker status [BRCA1/2 alterations (BRCAalt) and a homologous recombination deficiency signature (HRDsig)] in advanced ovarian cancer. EXPERIMENTAL DESIGN: Patients with ovarian cancer receiving first-line platinum-based chemotherapy and either mPARPi or no maintenance were included. Patient data were obtained by a US-based de-identified ovarian cancer Clinico-Genomic Database, from ∼280 US cancer clinics (01/2015-03/2023). Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by biomarker status using Cox models, weighted by propensity scores. RESULTS: Of 673 patients, 160 received mPARPi [31.2% BRCAalt and 51.9% HRDsig(+)] and 513 no maintenance [15.6% BRCAalt and 34.1% HRDsig(+)]. BRCAalt patients receiving mPARPi versus no maintenance had favorable rwPFS [HR, 0.48; 95% confidence interval (CI), 0.26-0.87; P = 0.0154], as did BRCA wild-type (WT; HR, 0.76; 95% CI, 0.57-1.01; P = 0.0595). Favorable rwOS was not observed with mPARPi for BRCAalt or BRCA-WT. HRDsig(+) patients receiving mPARPi versus no maintenance had favorable rwPFS (HR, 0.36; 95% CI, 0.24-0.55; P < 0.001) and numerically favorable rwOS (HR, 0.46; 95% CI, 0.21-1.02; P = 0.0561). No differences were observed for HRDsig(-). mPARPi treatment interaction was observed for HRDsig(+) versus HRDsig(-) (rwPFS P < 0.001/rwOS P = 0.016) but not for BRCAalt versus BRCA-WT. Patients with BRCA-WT/HRDsig(+) receiving mPARPi had favorable rwPFS (HR, 0.40; 95% CI, 0.22-0.72; P = 0.003), whereas no difference was observed for BRCA-WT/HRDsig(-). CONCLUSIONS: HRDsig predicted benefit of mPARPi better than BRCAalt. Patients with HRDsig(+) status experienced favorable outcomes, even if they had BRCA-WT status. In contrast, patients with HRDsig(-) status did not show significant benefit from mPARPi treatment. HRDsig might predict benefit from mPARPi regardless of BRCAalt status.

Characterizing informational needs and information seeking behavior of patients with breast cancer.

BACKGROUND: Appropriate information may facilitate adjustment to cancer diagnoses. Our study aims to characterize informational satisfaction in breast cancer patients and assess resources used by patients to gain information. METHODS: Newly diagnosed Stage 0-III breast cancer patients seen at an academic medical center between May and September 2020 received questionnaires assessing information satisfaction. Patients indicated resources used to obtain information along with satisfaction with information received in various topics. A subset of questionnaire respondents completed semi-structured interviews. RESULTS: Fifty-two (35 â€‹%) patients completed the questionnaire. Patients received information from physicians (96 â€‹%), the internet (81 â€‹%), nurses (79 â€‹%), and fellow breast cancer patients (54 â€‹%). Interview participants preferred receiving information from providers when making medical decisions but found patient forums and social media to be important adjuncts for receiving information. CONCLUSION: Patients are satisfied with information received about diagnosis and treatment, but finances, sexual health, and fertility are less frequently discussed.

Implementation and impact of an electronic patient reported outcomes system in a phase II multi-site adaptive platform clinical trial for early-stage breast cancer.

OBJECTIVES: We describe the development and implementation of a system for monitoring patient-reported adverse events and quality of life using electronic Patient Reported Outcome (ePRO) instruments in the I-SPY2 Trial, a phase II clinical trial for locally advanced breast cancer. We describe the administration of technological, workflow, and behavior change interventions and their associated impact on questionnaire completion. MATERIALS AND METHODS: Using the OpenClinica electronic data capture system, we developed rules-based logic to build automated ePRO surveys, customized to the I-SPY2 treatment schedule. We piloted ePROs at the University of California, San Francisco (UCSF) to optimize workflow in the context of trial treatment scenarios and staggered rollout of the ePRO system to 26 sites to ensure effective implementation of the technology. RESULTS: Increasing ePRO completion requires workflow solutions and research staff engagement. Over two years, we increased baseline survey completion from 25% to 80%. The majority of patients completed between 30% and 75% of the questionnaires they received, with no statistically significant variation in survey completion by age, race or ethnicity. Patients who completed the screening timepoint questionnaire were significantly more likely to complete more of the surveys they received at later timepoints (mean completion of 74.1% vs 35.5%, P < .0001). Baseline PROMIS social functioning and grade 2 or more PRO-CTCAE interference of Abdominal Pain, Decreased Appetite, Dizziness and Shortness of Breath was associated with lower survey completion rates. DISCUSSION AND CONCLUSION: By implementing ePROs, we have the potential to increase efficiency and accuracy of patient-reported clinical trial data collection, while improving quality of care, patient safety, and health outcomes. Our method is accessible across demographics and facilitates an ease of data collection and sharing across nationwide sites. We identify predictors of decreased completion that can optimize resource allocation by better targeting efforts such as in-person outreach, staff engagement, a robust technical workflow, and increased monitoring to improve overall completion rates. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT01042379.

Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement.

Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low-dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met the criteria for Mayo Clinic cardiac stage III disease. Patients received up to nine cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28-day cycle); melphalan 0.18 mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, and 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. The overall survival rate at 1 year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front-line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high-risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. This trial was registered at www.clinicaltrials.gov (NCT00890552).

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2- advanced breast cancer.

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46-87); PS 1 (0-1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2-52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2- BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes.

Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (gBRCA1/2)-mutant advanced breast cancer, but its activity beyond gBRCA1/2 is poorly understood. We conducted Talazoparib Beyond BRCA ( NCT02401347 ), an open-label phase II trial, to evaluate talazoparib in patients with pretreated advanced HER2-negative breast cancer (n = 13) or other solid tumors (n = 7) with mutations in homologous recombination (HR) pathway genes other than BRCA1 and BRCA2. In patients with breast cancer, four patients had a Response Evaluation Criteria in Solid Tumors (RECIST) partial response (overall response rate, 31%), and three additional patients had stable disease of ≥6 months (clinical benefit rate, 54%). All patients with germline mutations in PALB2 (gPALB2; encoding partner and localizer of BRCA2) had treatment-associated tumor regression. Tumor or plasma circulating tumor DNA (ctDNA) HR deficiency (HRD) scores were correlated with treatment outcomes and were increased in all gPALB2 tumors. In addition, a gPALB2-associated mutational signature was associated with tumor response. Thus, talazoparib has been demonstrated to have efficacy in patients with advanced breast cancer who have gPALB2 mutations, showing activity in the context of HR pathway gene mutations beyond gBRCA1/2.

Moving Towards Targeted Therapies for Triple-Negative Breast Cancer.

PURPOSE OF REVIEW: In this review, we discuss targets of interest in Triple-negative breast cancer (TNBC), approved targeted agents and the results of the clinical trials that led to their approval. Additionally, we review ongoing clinical trials evaluating the use of novel targeted agents in the treatment of TNBC. RECENT FINDINGS: TNBC accounts for 15-20% of all breast cancer cases and is associated with worse clinical outcomes. Patients have a higher risk of metastatic recurrence and inferior overall survival compared to other breast cancer subtypes. Cytotoxic chemotherapy has historically been the mainstay of treatment for TNBC. In recent years, we have seen a surge in clinical trials investigating the use of targeted agents in TNBC and now have approval for targeted therapies in select patients. Inhibitors of PARP (olaparib and talazoparib), PD-L1 (atezolizumab) and an antibody drug conjugate targeting Trop-2 (sacituzumab govitecan-hziy) are now approved for the use in select groups of patients with TNBC. SUMMARY: Various novel targeted agents as monotherapy, dual targeted combinations, and chemotherapy combinations are currently under investigation. The results are promising and may significantly improve patient outcomes in TNBC.

Interventions to Improve Sexual Health in Women Living with and Surviving Cancer: Review and Recommendations.

Sexual health concerns, both physical and psychological, are common and represent an unmet need among women with and surviving cancer. Sexual challenges and conditions negatively impact body image, satisfaction, relationships, well-being, and quality of life, yet are widely reported to be under-recognized and undertreated. To guide clinical care and future research on sexual function in women with cancer, we performed a scoping review of interventions for sexual health concerns, including sexual function, body image, genitourinary symptoms, and hot flashes. Relevant publications between 2005 and 2020 were identified by searching PubMed with a combination of medical subject headings and keywords. Articles were included if they focused on the aforementioned topics, were primary research publications, and included female cancer survivors. Studies focusing on women receiving hormone therapy for breast cancer were also included. A total of 91 investigations conducted in the US and abroad were reviewed. Most commonly, interventions included a component of psychoeducation, although pharmacologic, exercise, and other approaches have been evaluated. Many studies have focused on survivors of breast or gynecologic cancer, among other sampling and methodological limitations. These limitations underscore the need for more work on this vital survivorship issue. Recommendations for future research in this area are also offered.

Hematologic toxicity in BRCA1 and BRCA2 mutation carriers during chemotherapy: A retrospective matched cohort study.

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild-type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild-type patients and among BRCA2 carriers vs matched wild-type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild-type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild-type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild-type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild-type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short-term repetitive hematopoietic stressors.

Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer.

Purpose: Tumor-infiltrating lymphocytes (TIL) in pretreatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC.Experimental Design: Data on treatments and diagnostic tests from electronic medical records of two health care systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM, and OM. For a subgroup with TIL data available, we explored the relationship between TILs and peripheral lymphocyte counts.Results: A total of 1,463 stage I-III TNBC patients were diagnosed from 2000 to 2014; 1,113 (76%) received neoadjuvant/adjuvant chemotherapy within 1 year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/µL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM [HR = 0.23; 95% confidence interval (CI), 0.16-0.35] and BCM (HR = 0.19; CI, 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (n = 70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.Conclusions: Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment. Clin Cancer Res; 24(12); 2851-8. ©2018 AACR.

Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients.

Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8+ T cells. Macrophages (CD11b+F480+) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC.Significance: This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4241/F1.large.jpg Cancer Res; 78(15); 4241-52. ©2018 AACR.