Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer.

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study.

Preventing alpelisib-related hyperglycaemia in HR+/HER2-/-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/-mutated advanced breast cancer (ABC).

Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.

Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial.

Background: Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study.

Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial.

Importance: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population.

Objective: To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario.

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease.

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching.

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01).

Purpose: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC.

Patients And Methods: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy.

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.

Broad consensus on the optimal sequence for the systemic treatment of metastatic breast cancer: results from a survey of Spanish medical oncologists.

The aim of this survey conducted by 20 leading Spanish oncologists was to analyze the concurrence between Spanish clinical practice and the recently published definition of the optimal sequence for the systemic treatment of metastatic breast cancer (MBC) according to patient profiles. A self-administered questionnaire was developed, divided into five sections comprising 34 specific questions related to sequential treatments, plus three additional general questions. Respondents were asked to justify negative answers.

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer.

Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ tests determined the differences in variable distribution.

Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study.

Purpose: Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC.

Patients And Methods: Patients with operable node-positive BC (T1-3/N1-3) were eligible.

Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile.

Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel.

Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.

Background: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC).

Methods: Patients with diagnoses of CRC (n=2123) were included in the unselected group.

Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype.

Background: CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM).

Prospective evaluation of the conversion rate in the receptor status between primary breast cancer and metastasis: results from the GEICAM 2009-03 ConvertHER study.

The objective of this study was to determine the conversion rate of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) between primary tumors and metastatic lesions in advanced breast cancer. Patients with suspected diagnosis of locally recurrent or metastatic breast cancer, either at first relapse or after successive disease progressions, who had an appropriately preserved sample from a primary tumor and were scheduled for a biopsy of the recurrent lesion, were included. Blinded determinations of receptor status on paired samples were performed by immunohistochemistry and fluorescence in situ hybridization at a central laboratory and compared with those performed locally.

Influence of CYP2D6 polymorphisms on serum levels of tamoxifen metabolites in Spanish women with breast cancer.

Background: Estrogen receptor-positive breast cancer tumors depend on estrogen signaling for their growth and replication and can be treated by anti-estrogen therapy with tamoxifen. Polymorphisms of the CYP2D6 and CYP2C19 genes are associated with an impaired response to tamoxifen. The study objective was to investigate the impact of genetic polymorphisms in CYP2D6 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Spanish women with estrogen receptor-positive breast cancer who were candidates for tamoxifen therapy.

Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence.

During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spain), 310 mutations (155 in BRCA1 and 155 in BRCA2) in 1,763 hereditary breast (BC) and ovarian cancer (OC) families were identified. Of the mutations found 105 were distinct (53 in BRCA1 and 52 in BRCA2), eight new and 37 recurrent. Two of the novel mutations were frame-shift placed in exons 2 and 11 of BRCA1 and the remaining six were placed in BRCA2; four frame-shift (three in exon 11 and one in exon 23), one deletion of the entire exon 19 and one in the intervening sequence of exon 22.

Relationship of BRCA1 and BRCA2 mutations with cancer burden in the family and tumor incidence.

The aim of the present study is to analyze the relationship of the incidence of mutations in the two major genes BRCA1 and BRCA2 conferring risk of breast cancer (BC) and ovarian cancer (OC) with the cancer burden in families and with the presence and age of onset of BC/OC. We included 704 index patients (IP) and 668 family members of the IP who tested positive for BRCA1/BRCA2 who were studied in the Program of Genetic Counselling in Cancer of the Valencia Community (Spain). We found 129 IPs with deleterious mutations (18.

Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers.

Environmental or lifestyle factors are likely to explain part of the heterogeneity in breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers. We assessed parity as a risk modifier in 515 and 503 Spanish female carriers of mutations in BRCA1 and BRCA2, respectively. Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards regression, adjusted for year of birth and study centre.

CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers.

The polymorphic genetic differences among individuals may modify the high risk for breast cancer (BC) and/or ovarian cancer (OC) susceptibility conferred by BRCA1 and BRCA2 mutations. In the present study we investigate the relevance of RAD51 -135C > G, TP53 R72P, NQO1*2 and CASP8 D302H polymorphisms as potential modifiers of BC and/or OC susceptibility conferred by these mutations. The study group encompasses 390 BRCA1/BRCA2 mutation carriers (182 affected with BC and/or OC and 208 unaffected) of 131 unrelated families studied in the Program of Genetic Counselling on Cancer of Valencia Community.

[BRCA1 and BRCA2 mutations in families studied in the program of genetic counselling in cancer of the Valencian community (Spain)].

Background And Objective: The objective of the present study was to investigate the mutational spectrum of BRCA1 and BRCA2 in the Valencian Community, comparing this spectrum with that reported in Spain. We also analyze the association of the mutations with the family history of the selected families.

Patients And Method: We analyzed the mutations in the BRCA1 and BRCA2 in 147 families with history of breast and/or ovarian cancer.

Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families of Eastern Spain.

It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of breast and ovarian cancer. We here report 23 novel genetic variants of the BRCA1 and BRCA2 genes found in 349 cancer-prone unrelated families from Eastern Spain detected during the first 2 years of performance of the Program of Genetic Counseling of Valencia Community. Mutational screening was performed by pre-screening the heteroduplex formed in the PCR products obtained amplifying BRCA1 and BRCA2 genes by conformation sensitive electrophoresis.

Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family.

Background: Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian cancers. However, the frequency of detected germline mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations, but the large genomic rearrangements are commonly overlooked.