Second breast cancer: recurrence score results, clinicopathologic characteristics, adjuvant treatments, and outcomes-exploratory analysis of the Clalit registry.

Data on using the 21-gene Recurrence Score (RS) testing on second breast cancer (BC; second primary or local recurrence) are lacking. This cohort study examined patients with first and second BC, who underwent 21-gene testing both times. It included a 'study-cohort' (60 N0/N1mi/N1 ER + HER2‒ BC patients with ≥2 RS results >1 year apart) and a 'general 21-gene-tested BC-cohort' (2044 previously described N0/N1mi/N1 patients). The median time between the first and second BC was 5.2 (IQR, 3.1-7.1) years; the second BC was ipsilateral in 68%. Patient/tumor characteristics of the first- and second-BC in the 'study-cohort' were similar, except for the RS which was higher in the second BC (median [IQR]: 23 [17-30] vs 17 [14-22], p < 0.001). Overall, 56 patients had follow-up data, of whom 5 experienced distant recurrence (2 RS 11-25 patients and 3 RS 26-100 patients). Studies exploring the prognostic utility of the RS in this setting are warranted.

Clinical outcomes in estrogen receptor-positive early-stage breast cancer patients with Recurrence Score 26-30: observational real-world cohort study.

Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan-Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4-99.2%) vs 97.9% (94.6-99.2%); DRFS, 91.5% (86.6-94.7%) vs 91.2% (86.0-94.6%); BCSM, 0.5% (0.1-3.7%) vs 1.6% (0.5-4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2-8.6%] vs 6.2% [2.0-17.7%] for CT-treated and untreated patients, respectively, p = 0.024).

Controversies and Open Questions in Management of Cancer-Free Carriers of Germline Pathogenic Variants in BRCA1/BRCA2.

Females harboring germline BRCA1/BRCA2 (BRCA) P/LPV are offered a tight surveillance scheme from the age of 25−30 years, aimed at early detection of specific cancer types, in addition to risk-reducing strategies. Multiple national and international surveillance guidelines have been published and updated over the last two decades from geographically diverse countries. We searched for guidelines published between 1 January 2015 and 1 May 2022. Differences between guidelines on issues such as primary prevention, mammography screening in young (<30 years) carriers, MRI screening in carriers above age 65 years, breast imaging (if any) after risk-reducing bilateral mastectomy, during pregnancy, and breastfeeding, and hormone-replacement therapy, are just a few notable examples. Beyond formal guidelines, BRCA carriers' concerns also focus on the timing of risk-reducing surgeries, fertility preservation, management of menopausal symptoms in cancer survivors, and pancreatic cancer surveillance, issues that, for some, there are no data to support evidence-based recommendations. This review discusses these unsettled issues, emphasizing the importance of future studies to enable global guideline harmonization for optimal surveillance strategies. Moreover, it raises the unmet need for personalized risk stratification and surveillance in BRCA P/LPV carriers.

Leveraging Comprehensive Health Records for Breast Cancer Risk Prediction: A Binational Assessment.

Breast cancer (BC) risk models based on electronic health records (EHR) can assist physicians in estimating the probability of an individual with certain risk factors to develop BC in the future. In this retrospective study, we used clinical data combined with machine learning tools to assess the utility of a personalized BC risk model on 13,786 Israeli and 1,695 American women who underwent screening mammography in the years 2012-2018 and 2008-2018, respectively. Clinical features were extracted from EHR, personal questionnaires, and past radiologists' reports. Using a set of 1,547 features, the predictive ability for BC within 12 months was measured in both datasets and in sub-cohorts of interest. Our results highlight the improved performance of our model over previous established BC risk models, their ultimate potential for risk-based screening policies on first time patients and novel clinically relevant risk factors that can compensate for the absence of imaging history information.

Genetic testing in patients with triple-negative or hereditary breast cancer.

PURPOSE OF REVIEW: In recent years there has been a dramatic evolution in the clinical utility of genetic testing with expanding therapeutic implications for individuals with breast cancer who harbor a germline mutation in BRCA1/2. As these therapeutic opportunities expand and evolve, this requires the clinical and research community to rethink the approach to genetic testing for individuals with breast cancer. RECENT FINDINGS: Genetic testing is evolving from traditional testing models based on pretest counseling with the aim of identifying hereditary and individual risk for purposes of screening and risk reduction to contemporary models that utilize technology to improve accessibility and oncology led mainstreaming of testing where the oncologist refers for genetic testing, discloses the results and formal counseling occurs later in the process than in traditional models. The cost and accessibility to multigene panel testing have resulted in broad uptake despite the fact that clinical utility and appropriate interpretation of results are not yet well established. Furthermore, somatic testing for genomic alterations may also yield results beyond the disease with detection of germline mutations impacting the individual and their family more broadly than anticipated. SUMMARY: With the establishment of poly (adenosine diphosphate-ribose) polymerase inhibitors as part of the treatment armamentarium for early and advanced breast cancer, paradigms, algorithms, and resources for genetic testing need to rapidly change in order to adapt to the evolution of germline mutations from hereditary and individual risk predictors to predictive therapeutic biomarkers.

Risk-Reducing Mastectomy and Reconstruction Following Prophylactic Breast Irradiation: Hope Sustained.

Risk-reducing mastectomy (RRM) is often advocated for BRCA1/2 mutation carriers who face a heightened lifetime risk of breast cancer. However, many carrier patients seek alternative risk-reducing measures. In a phase II nonrandomized trial, we previously reported that prophylactic irradiation to the contralateral breast among BRCA carriers undergoing breast-conserving treatment significantly reduced subsequent contralateral breast cancer. Herein, we report the outcome of salvage mastectomy and reconstruction in 11 patients that suffered reoccurrences of breast cancer in either the ipsilateral or contralateral breast or elected to have the procedure for risk reduction during the eight-year follow-up period. Patients' satisfaction with the procedure and physicians' assessment of the cosmetic outcome were not inferior for previously irradiated compared to non-irradiated breasts. Although the numbers are small, the results are encouraging and sustain hope in a challenging population. Our findings support continuing research as well as a discussion of risk-reduction alternatives besides mastectomy, including prophylactic breast irradiation, in BRCA1/2 mutation carriers.

Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells.

The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women.

Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer.

PURPOSE: The subcutaneous (SC) administration of trastuzumab is highly preferred by patients. At home, administration of trastuzumab SC might further improve patient benefit. The aims of the BELIS study are to evaluate the safety and tolerability of trastuzumab SC when administered at home by a healthcare professional (HCP) and to evaluate patient-reported outcomes for treatment experience of at home cancer therapy. METHODS: This open-label phase IIIb study enrolled HER2-positive early breast cancer patients in Belgium and Israel who completed the first six cycles of trastuzumab IV (neo)adjuvant therapy. The study consisted of three consecutive treatment periods: three cycles of trastuzumab IV and SC each at the hospital and six cycles of trastuzumab SC at home. RESULTS: Between November 2013 and December 2014, 23 centres enrolled 102 patients in the intent-to-treat population of which 101 patients entered the safety population. No new safety signals were detected with as expected, more mild administration site events with trastuzumab SC when compared to IV treatment. All patients agreed that they had benefit from at home administration to a large (18/81; 22%) or very large (63/81; 78%) extent. All HCPs (21/21) agreed that SC is the quickest method from start of preparation to finish of administration and that less resource use is needed. CONCLUSION: The results of the BELIS study support that trastuzumab SC can be safely administered at home by a HCP and all patients considered this setting as beneficial. HCPs consider the SC formulation as the quickest method to administer trastuzumab. TRIAL REGISTRATION: EudraCT Identifier: 2013-000123-13. ClinicalTrials.gov Identifier: NCT01926886.

Radiation-Associated Secondary Malignancies in BRCA Mutation Carriers Treated for Breast Cancer.

PURPOSE: Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM. METHODS AND MATERIALS: Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with ≥5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined. RESULTS: Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma. CONCLUSIONS: In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers.

Prophylactic breast irradiation reduces background parenchymal enhancement (BPE) on MRI: A secondary analysis.

PURPOSE: We recently showed that prophylactic breast irradiation (PBI) reduces the risk of contralateral breast cancer in BRCA mutation carriers undergoing treatment for early breast cancer. It has been suggested that Background Parenchymal Enhancement (BPE) may be a biomarker for increased risk of breast cancer. METHODS: For participants in the trial we reviewed the MRI prior to enrollment and following radiation treatment and scored the contralateral breast for BPE and density. RESULTS: Significant reduction of BPE was more commonly noted following PBI (p = 0.011) compared to the control group. CONCLUSION: Reduction of BPE by PBI may contribute to its prophylactic effect.

Targeting DNA repair in breast cancer.

Targeting of DNA repair is an important therapeutic approach in breast cancer, particularly for BRCA1/2 associated breast cancers and those characterized by a "BRCAness" phenotype including those with "triple negative" subtype. Various assays and scores have been developed to evaluate degree of homologous recombination deficiency in the hope that this would aid in predicting for susceptibility to DNA repair targeting agents, and yet, presence of a germline mutation in BRCA1/2 remains the strongest predictor for therapeutic efficacy of such agents. Pre-clinical studies suggested increased sensitivity to agents that damage DNA in a way that interferes with DNA replication forks and which subsequently require DNA repair by homologous recombination, such as platinum salts, and this data was further confirmed clinically. Recently published phase III data favor the use of PARP inhibitors amongst patients with BRCA1/2 associated advanced breast cancer. Novel chemotherapeutic agents targeting DNA damage repair are under evaluation as well as further combinations of PARP inhibitors with immuno-therapeutics and other biological agents.

Symptom cluster of emotional distress, fatigue and cognitive difficulties among young and older breast cancer survivors: The mediating role of subjective stress.

OBJECTIVES: To examine the nature of the symptom cluster of emotional distress, fatigue, and cognitive difficulties in young and older breast cancer survivors (BCS); To assess the mediating role of subjective stress and coping strategies (emotional control and meaning-focused coping) in the association between age and symptom cluster. MATERIALS AND METHODS: Participants were 170 BCS, stages I-III, 1-12 months post-chemotherapy, filled-out the Fatigue, Emotional Control, Meaning-focused Coping, Emotional Distress and the Cognitive Difficulties Questionnaires. Statistical analyses included tests for difference between-groups Pearson correlations and Structural Equation Modeling for the assessment of the study model. RESULTS: Older BCS (aged 60-82) reported lower levels of emotional distress (M = 0.87, SD = 0.87), fatigue (M = 3.85, SD = 2.38), and cognitive difficulties (M = 1.17, SD = 1.07) compared to the younger BCS (aged 24-59) (emotional distress M = 1.17, SD = 0.85, fatigue M = 5.02, SD = 2.32, and cognitive difficulties M = 1.66, SD = 1.23, p < .01-,05). The older survivors reported lower levels of subjective stress and used more emotional control strategies compared to the younger BCS. The empirical model had good fit indices (χ2 = 27.60, p = 0.20, χ2/df = 1.26; CFI = 0.98; TLI = 0.98; NFI = 0.95; RMSEA = 0.04 (90% CI = 0.00, 10) and showed that subjective stress, but not coping strategies, mediated the effect of age on symptom cluster severity. CONCLUSIONS: Lower levels of subjective stress, but not coping strategies, mediated the association of age with the symptom cluster of emotional distress, fatigue and cognitive difficulties. Further research is needed to explore differences in subjective stress by age.

Everolimus Plus Letrozole for Treatment of Patients With HR+, HER2- Advanced Breast Cancer Progressing on Endocrine Therapy: An Open-label, Phase II Trial.

PURPOSE: In the Breast cancer trials of OraL EveROlimus-2 (BOLERO-2) trial, everolimus plus exemestane improved progression-free survival (PFS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) recurring or progressing on/after prior endocrine therapy (ET), suggesting that dual blockade using targeted therapy and ET was an effective treatment option. Here, we investigated the clinical benefit of combining everolimus with different endocrine partner, letrozole, in a similar patient population. METHODS: In this phase II, open-label, single-arm, multicenter trial, postmenopausal women with HR+, HER2- ABC who had recurrence/progression on/after prior ET received everolimus 10 mg daily and letrozole 2.5 mg daily. The primary end point was objective response rate; key secondary end points included disease-control rate, PFS, overall survival, and safety. RESULTS: A total of 72 patients were enrolled and followed-up for a median duration of 11.4 months. Everolimus plus letrozole achieved an overall response rate of 23.3% (95% confidence interval [CI], 13.4%-36.0%). The median PFS was 8.8 months (95% CI, 6.6-11.0 months), and the overall survival was 22.9 months (95% CI, 18.5-28.9 months). Disease-control rate was achieved in 51 (85%) patients. The safety profile was consistent with previously published data: The most frequently reported any grade adverse events (AEs) were fatigue (61.1%), stomatitis (54.2%), and rash (33.4%). The most frequently reported grade 3 AEs were stomatitis and anemia (8.3% each), fatigue and diarrhea (5.6% each), and hyperglycemia (4.2%). Only 1 patient had grade 4 AE of anemia. CONCLUSIONS: Everolimus plus letrozole demonstrated clinical benefit and could be a valid treatment option for postmenopausal women recurring/progressing on prior endocrine therapy.

Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry.

The 21-gene Recurrence Score® (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS ≥ 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18-30, and 10.4% RS ≥ 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18-30 and RS ≥ 31, respectively; the corresponding 5-year Kaplan-Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 (n = 304) and 11-25 (n = 1037) (TAILORx categorization) had 5-year Kaplan-Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan-Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11-25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit.

Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients.

miR-9 was initially identified as an epigenetically regulated miRNA in tumours, but inconsistent findings have been reported so far. We analysed the expression of miR-9-5p, miR-9-3p, pri-miRs and MIR9 promoters methylation status in 131 breast cancer cases and 12 normal breast tissues (NBTs). The expression of both mature miRs was increased in tumours as compared to NBTs (P < 0.001) and negatively correlated with ER protein expression (P = 0.005 and P = 0.003, for miR-9-3p and miR-9-5p respectively). In addition, miR-9-5p showed a significant negative correlation with PgR (P = 0.002). Consistently, miR-9-5p and miR-9 3p were differentially expressed in the breast cancer subgroups identified by ER and PgR expression and HER2 amplification. No significant correlation between promoter methylation and pri-miRNAs expressions was found either in tumours or in NBTs. In the Luminal breast cancer subtype the expression of miR-9-5p was associated with a worse prognosis in both univariable and multivariable analyses. Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p/miR-9-3p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p but not miR-9-3p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways.

Paclitaxel-induced pneumonitis in patients with breast cancer: case series and review of the literature.

Doxorubicin plus cyclophosphamide followed by paclitaxel is a common adjuvant treatment for high-risk breast cancer. It has been associated with pulmonary toxicity in several case reports. We describe three patients in whom interstitial pneumonitis developed immediately after the first paclitaxel exposure and worsened clinically over time. All reported dyspnoea, fever and progressive respiratory distress. Imaging revealed diffuse bilateral pulmonary infiltrates. Other causes of respiratory failure were excluded with laboratory work-up, imaging, biopsy studies and results of antibiotic treatment. The respiratory decline was reversed only after administration of high-dose steroids, an empirical treatment previously reported to be beneficial in similar cases. Although chemotherapy using concomitant or sequential drugs may make identification of the toxic agent difficult, we noted a clear temporal relationship between exposure to paclitaxel and the development of pulmonary toxicity. Furthermore, according to the available literature, it is less likely that a respiratory decline would be caused by either cyclophosphamide or trastuzumab. In conclusion, clinicians should be aware of the potentially life-threatening risk of pulmonary toxicity following paclitaxel treatment. If paclitaxel is halted early and the patient has good lung reserve, pulmonary toxicity can be reversed with high-dose steroid administration.

Expression and methylation patterns partition luminal-A breast tumors into distinct prognostic subgroups.

BACKGROUND: Breast cancer is a heterogeneous disease comprising several biologically different types, exhibiting diverse responses to treatment. In the past years, gene expression profiling has led to definition of several "intrinsic subtypes" of breast cancer (basal-like, HER2-enriched, luminal-A, luminal-B and normal-like), and microarray based predictors such as PAM50 have been developed. Despite their advantage over traditional histopathological classification, precise identification of breast cancer subtypes, especially within the largest and highly variable luminal-A class, remains a challenge. In this study, we revisited the molecular classification of breast tumors using both expression and methylation data obtained from The Cancer Genome Atlas (TCGA). METHODS: Unsupervised clustering was applied on 1148 and 679 breast cancer samples using RNA-Seq and DNA methylation data, respectively. Clusters were evaluated using clinical information and by comparison to PAM50 subtypes. Differentially expressed genes and differentially methylated CpGs were tested for enrichment using various annotation sets. Survival analysis was conducted on the identified clusters using the log-rank test and Cox proportional hazards model. RESULTS: The clusters in both expression and methylation datasets had only moderate agreement with PAM50 calls, while our partitioning of the luminal samples had better five-year prognostic value than the luminal-A/luminal-B assignment as called by PAM50. Our analysis partitioned the expression profiles of the luminal-A samples into two biologically distinct subgroups exhibiting differential expression of immune-related genes, with one subgroup carrying significantly higher risk for five-year recurrence. Analysis of the luminal-A samples using methylation data identified a cluster of patients with poorer survival, characterized by distinct hyper-methylation of developmental genes. Cox multivariate survival analysis confirmed the prognostic significance of the two partitions after adjustment for commonly used factors such as age and pathological stage. CONCLUSIONS: Modern genomic datasets reveal large heterogeneity among luminal breast tumors. Our analysis of these data provides two prognostic gene sets that dissect and explain tumor variability within the luminal-A subgroup, thus, contributing to the advancement of subtype-specific diagnosis and treatment.