Cross-sectional and longitudinal associations of adherence to WCRF/AICR cancer prevention recommendations with health-related quality of life in breast cancer survivors. Health-EpiGEICAM study.

OBJECTIVES: Adherence to healthy lifestyle recommendations has been reported to improve health-related quality of life (HRQL) in breast cancer (BC) patients, but the influence of long-term behavioral changes remains unknown. We evaluated the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and HRQL both, at BC diagnosis and the change 7-12 years later. DESIGN: Prospective cohort study. SETTINGS AND PARTICIPANTS: A total of 406 breast cancer survivors, from the EpiGEICAM study, were recruited in 16 Spanish hospitals. MEASUREMENTS: Epidemiological, clinical, dietary, physical activity and HRQL information was collected both at recruitment and 7-12 years later. A 7-item score to measure compliance with recommendations was assessed according to the 2018 WCRF/AICR scoring criteria. HRQL was evaluated using SF-36 questionnaire. Linear mixed models for longitudinal data were used to assess the cross-sectional and longitudinal association between adherence score and the physical and mental component summary scores. RESULTS: At diagnosis, for each unit increase in WCRF/AICR score adherence, the HRQL physical domain increased 0.78 points (95%CI: -0.04 to 1.60; P trend:0.06). The mean change in physical HRQL from diagnosis to follow-up per unit increase in within-subject adherence score was 0.73 points (95%CI: -0.18 to 1.65; P trend: 0.12). For the mental domain, no association was observed with compliance with the recommendations at diagnosis, nor with changes in adherence over time. CONCLUSIONS: Our results suggest that Increased adherence to WCRF/AICR cancer prevention recommendations over time could contribute to slightly improved long-term physical HRQoL in BC survivors.

Paraproteinaemic keratopathy simulating a crystalline keratopathy.

BACKGROUND: Paraproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with diffuse or patchy pseudo lipid deposits. We present an atypical case of paraproteinemic keratopathy which lead to an initial misdiagnosis of infectious crystalline keratopathy. CASE PRESENTATION: a 69-year-old woman with an asymptomatic keratopathy detected during a cataract intervention. Slit-lamp examination revealed several hyper refringent subepithelial foci with fern-shaped branches, resembling crystalline keratopathy, in her left eye. Anterior segment optical coherence tomography revealed exclusively subepithelial hyperreflective lesions limited to the anterior stroma. The progressive bilateralization and progression of the condition prompted us to include other entities with crystalline corneal deposits in our differential diagnosis. Hematological analysis showed a high number of free Kappa light chains. Despite the typical clinical appearance of crystalline keratopathy, the atypical evolution and test results led us to consider that monoclonal gammopathy could be the cause of this entity. CONCLUSIONS: Paraproteinemic keratopathy may present in its early stages as a unilateral subepithelial crystalline keratopathy. Thus, it must always be taken into account in the differential diagnosis of any crystalline keratopathy, particularly when there are no predisposing factors for an infectious crystalline keratopathy. Early recognition of this rare entity is important to address the associated potentially serious systemic disease.

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.

BACKGROUND: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. FINDINGS: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. INTERPRETATION: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. FUNDING: Daiichi Sankyo and AstraZeneca.

Dual neoadjuvant blockade plus chemotherapy versus monotherapy for the treatment of women with non-metastatic HER2-positive breast cancer: a systematic review and meta-analysis.

BACKGROUND: We aimed to determine the effect of dual anti-HER2 blockade compared to monotherapy on clinically important outcomes. METHODS: We carried out a systematic review updated until July 2022. The outcomes included pathological complete response (pCR), clinical response, event-free survival, and overall survival. RESULTS: We identified eleven randomized clinical trials (2836 patients). When comparing paclitaxel plus dual treatment versus paclitaxel plus trastuzumab or lapatinib, dual treatment was associated with a higher probability of achieving a pathological complete response (OR 2.88, 95% CI 2.02-4.10). Addition of a taxane to an anthracycline plus cyclophosphamide and fluorouracil, plus lapatinib or trastuzumab, showed that the dual treatment was better than lapatinib alone (OR 2.47, 95% CI 1.41-4.34), or trastuzumab alone (OR 1.89, 95% CI 1.13-3.16). Dual treatment may result in an increase in survival outcomes and tumour clinical response, although such benefits are not consistent for all the combinations studied. CONCLUSIONS: The use of dual blockade with combinations of trastuzumab and pertuzumab can be recommended for the neoadjuvant treatment of women with HER2-positive breast cancer. PROSPERO Registration number: CRD42018110273.

Clinical and Sociodemographic Determinants of Adherence to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Recommendations in Breast Cancer Survivors-Health-EpiGEICAM Study.

Breast cancer (BC) survivors are advised to follow the WCRF/AICR cancer prevention recommendations, given their high risk of developing a second tumour. We aimed to explore compliance with these recommendations in BC survivors and to identify potentially associated clinical and sociodemographic factors. A total of 420 BC survivors, aged 31-80, was recruited from 16 Spanish hospitals. Epidemiological, dietary and physical activity information was collected through questionnaires. A 7-item score to measure compliance with the recommendations was built according to the 2018 WCRF/AICR scoring criteria. Standardized prevalences and standardized prevalence ratios of moderate and high compliance across participant characteristics were estimated using multinomial and binary logistic regression models. The mean score was 3.9 (SD: 1.0) out of 7 points. Recommendations with the worst adherence were those of limiting consumption of red/processed meats (12% of compliance, 95% CI: 8.2-15.0) and high fibre intake (22% of compliance, 95% CI: 17.6-27.0), while the best compliance was observed for the consumption of fruits and vegetables (73% of compliance, 95% CI: 69.2-77.7). Overall, adherence was worse in women with university education and in those with first-degree relatives with BC. This information may be of interest to design and implement personalized preventive measures adapted to the characteristics of these patients.

Type does matter. Use VIRGIN olive oil as your preferred fat to reduce your risk of breast cancer: case-control EpiGEICAM study.

The Epi-GEICAM study comprises 1017 invasive BC cases matched with controls of similar age (49 ± 9 years) and residence. Diet and OO consumption were collected through a validated food frequency questionnaire. 75% of women referred OO, common (refined) or virgin, as the main fat source. Using conditional logistic regression models, we compared different scenarios of type and frequency of OO consumption, using as reference those women not always using OO for the three culinary practices (seasoning, cooking, and frying) and adding <2 tablespoons (tbsps.) per day during the meal to bread, salad, or dishes. A substantial inverse association was observed in those women always using VOO for the three culinary practices and consuming ≥2 tbsps. of OO per day during meals (adjusted OR, 0.72; 95% CI: 0.51, 1.03; P = 0.07). Potential benefits from OO consumption, at least as regards the protection provided for BC, could be mostly conferred with VOO, and when its consumption is high.

Trajectories of alcohol consumption during life and the risk of developing breast cancer.

BACKGROUND: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. OBJECTIVE: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman's life on development of breast cancer (BC). METHODS: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women's lifetime. RESULTS: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. CONCLUSIONS: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk.

Is there a correlation between HER2 gene amplification level and response to neoadjuvant treatment with trastuzumab and chemotherapy in HER2-positive breast cancer?

There are contradictory data regarding the correlation between HER2 amplification level determined by in situ hybridization and evolution after treatment with anti-HER2 therapies. The aim of this study was to correlate quantitative results of FISH (ratio HER2/CEP17 and number of HER2 signals/nucleus) with pathological response achieved after neoadjuvant treatment with trastuzumab and chemotherapy. For this purpose, we analysed 100 consecutive HER2-positive cases of breast carcinoma treated with neoadjuvant therapy. HER2 amplification determined by FISH was found in 92 of the 100 cases studied. pCR was obtained in 58% of the patients whose tumours presented amplification. In contrast, no pCR was obtained in the 8 patients with non-amplified tumours. A significant direct correlation between HER2 high amplification (HER2/CEP17 ratio > 5 or HER2 signals/nucleus > 10) and pCR was found. In conclusion, HER2 amplification levels are clinically relevant because they provide oncologists with valuable information on the possibilities of achieving pCR after neoadjuvant treatment.

Results of the implementation of a pharmacogenomics platform based on NGS technologies. Combining clinical and research approaches.

OBJECTIVE: As more genes are incorporated into pharmacogenomic care  processes and more importance is given to rare variants, the use of targeted  capture sequencing panels has been proposed as a very efficient alternative  due to their affordability, high throughput, and deep coverage, all of them  characteristics of high-quality next-generation sequencing data. The purpose of  this study is to describe the prevalence of clinically actionable  pharmacogenetic variants previously described in the scientific literature, as  well as that of new variants identified by next-generation sequencing  technologies, and to evaluate the drugs potentially affected by such variants. METHOD: A panel of 18 clinically actionable pharmacogenomics-related genes  was evaluated in 41 subjects diagnosed with breast cancer undergoing  neoadjuvant treatment. The prevalence of previously descri- bed clinically  actionable variants as well as of phenotypes classified according to current  interpretation standards was studied. The pharmacological treatments  potentially affected by the identified variants were also evaluated. An  estimation was made of the prevalence of not previously described, possibly  deleterious, variants selected using bioinformatics criteria. RESULTS: All subjects carried clinically actionable variants, with a mean of 4.02  genes affected by each variant per individual. VKORC1, CYP4F2, CYP2C19,  CYP2D6 and CYP2B6 were the most polymorphic genes and were present with  actionable phenotypes in more than 50% of patients; 15-50% had actionable  phonotypes in UGT1A1, SLCO1B1, CYP2C9 and TPMT and 2-15% in HLA-B,  CYP3A5, HLA-A and DPYD. No actionable variants were identified in RYR1,  CACNA1S, G6PD, F5 and NUDT15. These variants had the potential to affect  response to 84% of the drugs described in the leading pharmacogenetic  guidelines. Possibly deleterious variants not previously described accounted for  11.4% of all clinically actionable variants and were present in 12.2% of  patients. CONCLUSIONS: The results obtained show a high prevalence of clinically actionable variants, both common, i.e., previously described in the  literature, and rare, i.e., not previously studied with conventional technological  approaches. The latter are candidates for a more exhaustive  molecular and/or clinical characterization.

OBJETIVO: A medida que se incorporan más genes a los procesos  farmacogenómicos asistenciales y se otorga más importancia a las variantes raras, el uso de paneles de secuenciación dirigida por captura se ha  propuesto como una alternativa muy eficiente atendiendo a sus costes, su  rendimiento y la cobertura profunda, característica de los datos de  secuenciación de nueva generación de alta calidad. El objeto de este trabajo es  describir la prevalencia de variantes farmacogenéticas clínicamente  procesables descritas previamente en la literatura científica, así como de  nuevas variantes identificadas mediante tecnologías de secuenciación de nueva  generación y evaluar los fármacos potencialmente afectados por estas  variantes.Método: Se evaluó un panel de 18 genes relacionados con la  farmacogenómica clínicamente procesables en 41 individuos con diagnóstico de  cáncer de mama que van a recibir tratamiento adyuvante y neoadyuvante.  Se estudió  la literatura científica, así como de los fenotipos farmacogenéticos  clasificados según los estándares de interpretación actuales. Asimismo, se  evaluaron los tratamientos farmacológicos potencialmente afectados por las  variantes identificadas. Se estimó la prevalencia de variantes posiblemente  deletéreas no descritas previamente seleccionadas con criterios  bioinformáticos. RESULTADOS: Todos los individuos fueron portadores de variantes clínicamente procesables, con una media de 4,02 genes afectados por alguna variante por individuo. Los genes VKORC1, CYP4F2, CYP2C19, CYP2D6 y CYP2B6 fueron los más polimórficos, con más de un 50% de  pacientes con fenotipos procesables; un 15-50% en UGT1A1, SLCO1B1,  CYP2C9 y TPMT y un 2-15% HLA-B, CYP3A5, HLA-A y DPYD. No se  identificaron variantes procesables en RYR1, CACNA1S, G6PD, F5 y NUDT15.  Estas variantes afectarían a la respuesta de un 84% de los fármacos descritos  en las principales guías de farmacogenética. Las variantes posiblemente  deletéreas no descritas previamente supusieron un 11,4% del total de  variantes clínicamente procesables y están presentes en un 12,2% de los  pacientes. CONCLUSIONES: Los resultados obtenidos constatan una alta prevalencia de  variantes clínicamente procesables tanto comunes, previamente descritas en la  literatura, como raras, no estudiadas con abordajes tecnológicos convencionales y candidatas a una caracterización molecular y/o  clínica más exhaustiva.

Resultados de implementación de una plataforma farmacogenómica basada en tecnologías NGS. Combinación de abordajes asistencial y de investigación / Results of the implementation of a pharmacogenomics platform based on NGS technologies. Combining clinical and research approaches

Objetivo: A medida que se incorporan más genes a los procesos farmacogenómicos asistenciales y se otorga más importancia a las variantesraras, el uso de paneles de secuenciación dirigida por captura se ha propuesto como una alternativa muy eficiente atendiendo a sus costes, su rendimiento y la cobertura profunda, característica de los datos de secuenciaciónde nueva generación de alta calidad. El objeto de este trabajo es describirla prevalencia de variantes farmacogenéticas clínicamente procesables descritas previamente en la literatura científica, así como de nuevas variantesidentificadas mediante tecnologías de secuenciación de nueva generacióny evaluar los fármacos potencialmente afectados por estas variantes.Método: Se evaluó un panel de 18 genes relacionados con la farmacogenómica clínicamente procesables en 41 individuos con diagnóstico de cáncerde mama que van a recibir tratamiento adyuvante y neoadyuvante. Se estudió la prevalencia de variantes clínicamente procesables previamente descritas enla literatura científica, así como de los fenotipos farmacogenéticos clasificadossegún los estándares de interpretación actuales. Asimismo, se evaluaron lostratamientos farmacológicos potencialmente afectados por las variantes identificadas. Se estimó la prevalencia de variantes posiblemente deletéreas nodescritas previamente seleccionadas con criterios bioinformáticos. (AU)

Objective: As more genes are incorporated into pharmacogenomiccare processes and more importance is given to rare variants, the use oftargeted capture sequencing panels has been proposed as a very efficient alternative due to their affordability, high throughput, and deep coverage, all of them characteristics of high-quality next-generation sequencingdata. The purpose of this study is to describe the prevalence of clinicallyactionable pharmacogenetic variants previously described in the scientificliterature, as well as that of new variants identified by next-generationsequencing technologies, and to evaluate the drugs potentially affectedby such variants.Method: A panel of 18 clinically actionable pharmacogenomics-related genes was evaluated in 41 subjects diagnosed with breast cancerundergoing neoadjuvant treatment. The prevalence of previously described clinically actionable variants as well as of phenotypes classifiedaccording to current interpretation standards was studied. The pharmacological treatments potentially affected by the identified variants were alsoevaluated. An estimation was made of the prevalence of not previouslydescribed, possibly deleterious, variants selected using bioinformaticscriteria. (AU)

Serum Phospholipids Fatty Acids and Breast Cancer Risk by Pathological Subtype.

This study evaluates whether serum phospholipids fatty acids (PL-FAs) and markers of their endogenous metabolism are associated with breast cancer (BC) subtypes. EpiGEICAM is a Spanish multicenter matched case-control study. A lifestyle and food frequency questionnaire was completed by 1017 BC cases and healthy women pairs. Serum PL-FA percentages were measured by gas chromatography-mass spectrometry. Conditional and multinomial logistic regression models were used to quantify the association of PL-FA tertiles with BC risk, overall and by pathological subtype (luminal, HER2+ and triple negative). Stratified analyses by body mass index and menopausal status were also performed. Serum PL-FAs were measured in 795 (78%) pairs. Women with high serum levels of stearic acid (odds ratio (OR)T3vsT1 = 0.44; 95% confidence interval (CI) = 0.30-0.66), linoleic acid (ORT3vsT1 = 0.66; 95% CI = 0.49-0.90) and arachidonic to dihomo-γ-linolenic acid ratio (OR T3vsT1 = 0.64; 95% CI = 0.48-0.84) presented lower BC risk. Participants with high concentrations of palmitoleic acid (ORT3vsT1 = 1.65; 95% CI = 1.20-2.26), trans-ruminant palmitelaidic acid (ORT3vsT1 = 1.51; 95% CI = 1.12-2.02), trans-industrial elaidic acid (ORT3vsT1 = 1.52; 95% CI = 1.14-2.03), and high oleic to stearic acid ratio (ORT3vsT1 = 2.04; 95% CI = 1.45-2.87) showed higher risk. These associations were similar in all BC pathological subtypes. Our results emphasize the importance of analyzing fatty acids individually, as well as the desaturase activity indices.

Primary breast cancer and health related quality of life in Spanish women: The EpiGEICAM case-control study.

This study evaluates the impact of breast cancer (BC) in health related quality of life (HRQL) and in psychological distress (PD) during the initial phases of the disease and looks for contributing factors. A multicentric case-control study, EpiGEICAM, was carried out. Incident BC cases and age- and residence- matched controls were included. Clinical, epidemiological, HRQL (SF-36) and PD information (GHQ-28) was collected. We used multivariable logistic regression models to estimate OR of low HRQL and of PD in cases compared to controls, and to identify factors associated with low HRQL and with PD. Among 896 BC cases and 890 control women, cases had poorer scores than both, the reference population and the control group, in all SF-36 scales. BC women with lower education, younger, active workers, never smokers, those with comorbidities, in stage IV and with surgical treatment had lower physical HRQL; factors associated with low mental HRQL were dissatisfaction with social support, being current smoker and having children. Cases had a fivefold increased odds of PD compared to controls. Managing comorbidities and trying to promote social support, especially in younger and less educated women, could improve well-being of BC patients.

Correction to: NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer.

After the publication of this work [1] the authors have reported that in Table 3 The letter "T" in columns 5 and 7 should not be there.

NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer.

PURPOSE: The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. EXPERIMENTAL DESIGN: pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. RESULTS: The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34-66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24-54]) or neratinib (33% [95%CI 20-50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR-) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. CONCLUSIONS: Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR- patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion.

BACKGROUND: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples. METHODS: A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion. FINDINGS: CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3-29) and 9 (range, 1-38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). CONCLUSIONS: Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution.

Phase III evaluating the addition of fulvestrant (F) to anastrozole (A) as adjuvant therapy in postmenopausal women with hormone receptor-positive HER2-negative (HR+/HER2-) early breast cancer (EBC): results from the GEICAM/2006-10 study.

PURPOSE: GEICAM/2006-10 compared anastrozole (A) versus fulvestrant plus anastrozole (A + F) to test the hypothesis of whether a complete oestrogen blockade is superior to aromatase inhibitors alone in breast cancer patients receiving hormone adjuvant therapy. METHODS: Multicenter, open label, phase III study. HR+/HER2- EBC postmenopausal patients were randomized 1:1 to adjuvant A (5 years [year]) or A + F (A plus F 250 mg/4 weeks for 3 year followed by 2 year of A). Stratification factors: prior chemotherapy (yes/no); number of positive lymph nodes (0/1-3/≥ 4); HR status (both positive/one positive) and site. PRIMARY OBJECTIVE: disease-free survival (DFS). Planned sample size: 2852 patients. RESULTS: The study has an early stop due to the financer decision with 870 patients (437 randomized to A and 433 to A + F). Patient characteristics were well balanced. After a median follow-up of 6.24y and 111 DFS events (62 in A and 49 in A + F) the Hazard Ratio for DFS (combination vs. anastrozole) was 0.84 (95% CI 0.58-1.22; p = 0.352). The proportion of patients disease-free in arms A and A + F at 5 year and 7 year were 90.8% versus 91% and 83.6% versus 86.7%, respectively. Most relevant G2-4 toxicities (≥ 5% in either arm) with A versus A + F were joint pain (14.7%; 13.7%), fatigue (2.5%; 7.2%), bone pain (3%; 6.5%), hot flushes (3.5%; 5%) and muscle pain (2.8%; 5.1%). CONCLUSIONS: The GEICAM/2006-10 study did not show a statistically significant increase in DFS by adding adjuvant F to A, though no firm conclusions can be drawn because of the limited sample size due to the early stop of the trial. ClinicalTrials.gov: NCT00543127.