[Risk factors for cancer-related cognitive impairment in breast and colorectal cancer patients who undergo chemotherapy].

BACKGROUND: Our study aims to evaluate the impact of different factors on cancer-related cognitive impairment in patients who undergo chemotherapy. METHODOLOGY: Prospective longitudinal single-centre study that included patients with breast and colon carcinoma who underwent chemotherapy as part of their treatment. Clinical and genetic characteristics of the patients (single nucleotide polymorphisms, SNPs) were collected. Patients' neurocognitive status was assessed using eleven validated tests at three time points: before chemotherapy (M0 - baseline), between one and four weeks after completing chemotherapy (M1), and between 24-30 weeks after completing chemotherapy (M2). RESULTS: Sixty-two patients were included in this study; 82% were female, median age was 56 years (range 30-74), and 64.5% had been diagnosed with breast cancer. Overall, better cognitive results at M0 were associated with age < 55 years, higher educational level, absence of comorbidities, and the CC variant rs471692 (TOP2A). Significant decline was found between M0 to M1 in the Rey Auditory Verbal Learning Test and the Letter and Number test, with evidence of recovery in M2 compared to M0 regarding the following test: Visual Memory, Functioning Assessment Short Test (FAST), Digit Symbol Substitution and Cube. In the multivariate analysis, being =55 years of age, adjuvant chemotherapy, presence of comorbidities, tobacco and alcohol use, and GT variant rs1800795 were associated with cognitive decline between M0 and M1. CONCLUSION: Being =55 years of age, female, presence of comorbidities and basic education level are related to a higher risk of cognitive impairment after chemotherapy.

Long-term outcomes of high-risk HR-positive and HER2-negative early breast cancer patients from GEICAM adjuvant studies and El Álamo IV registry.

PURPOSE: The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib. METHODS: HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1-3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR). RESULTS: A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003-10 (210), and GEICAM-2006-10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%. CONCLUSIONS: This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted. TRIAL REGISTRATION: ClinTrials.gov: GEICAM/9906: NCT00129922; GEICAM/ 2003-10: NCT00129935 and GEICAM/ 2006-10: NCT00543127.

Impact of the 21-Gene Assay in Patients with High-Clinical Risk ER-Positive and HER2-Negative Early Breast Cancer: Results of the KARMA Dx Study.

BACKGROUND: The 21-gene Oncotype DX Breast Recurrence Score® assay is prognostic and predictive of chemotherapy benefit for patients with estrogen receptor-positive, HER2- early breast cancer (EBC). The KARMA Dx study evaluated the impact of the Recurrence Score® results (RS) on the treatment decision for patients with EBC and high-risk clinicopathological characteristics for whom chemotherapy (CT) was considered. METHODS: Eligible patients with EBC were candidates for the study if CT was considered standard recommendation by local guidelines. Three high-risk EBC cohorts were predefined: (A) pT1-2, pN0/N1mi, and grade 3; (B) pT1-2, pN1, and grades 1-2; and (C) neoadjuvant cT2-3, cN0, and Ki67 ≤ 30%. Treatment recommendations before and after 21-gene testing were registered, as well as treatment received and physicians' confidence levels in their final recommendations. RESULTS: A total of 219 consecutive patients were included from eight Spanish centers: 30 in cohort A, 158 in cohort B, and 31 in cohort C. Ten patients were excluded from the final analysis as CT was not initially recommended. After 21-gene testing, treatment decisions changed from CT + endocrine therapy (ET) to ET alone for 67% of the whole group. In total, 30% (95% confidence interval [CI] 15% to 49%), 73% (95% CI 65% to 80%), and 76% (95% CI 56% to 90%) of patients ultimately received ET alone in cohorts A, B, and C, respectively. Physicians' confidence in their final recommendations increased in 34% of cases. CONCLUSIONS: Use of the 21-gene test resulted in an overall 67% reduction in CT recommendation in patients considered candidates for CT. Our findings indicate the substantial potential of the 21-gene test to guide CT recommendations in patients with EBC considered to be at high risk of recurrence based on clinicopathological parameters, regardless of nodal status or treatment setting.

Facilitating Factors and Barriers in the Return to Work of Working Women Survivors of Breast Cancer: A Qualitative Study.

Several studies have identified the main barriers and facilitators that breast cancer survivors experience in the return to work (RTW). The authors conducted a qualitative study using focus group discussions with a group of female non-metastatic breast cancer survivors (n = 6), a group of health professionals from different medical specialties (n = 8), and a third group of company managers mainly composed of human resources managers (n = 7). The study was carried out between March and December 2021 in Zaragoza (Spain). Transcripts were analyzed using inductive content analysis to identify work-related barriers and facilitators and coded by the research team. Barriers identified included physical and cognitive symptoms, psychosocial problems, lack of knowledge and coordination (health professional, patients, and managers), legal vacuum, physical change, time constraints, work characteristics (lower skilled jobs), unsupportive supervisors and coworkers, family problems and self-demand. Facilitators included family and work support, physical activity and rehabilitation, personalized attention, interdisciplinary collaboration, legal advice for workers, knowledge about breast cancer in companies, positive aspects of work, elaboration of protocols for RTW in women with breast cancer. RTW in working women with breast cancer requires a personalized and holistic view that includes the perspectives of patients, healthcare professionals and company managers.

Association between missense variants of uncertain significance in the CHEK2 gene and hereditary breast cancer: a cosegregation and bioinformatics analysis.

Inherited mutations in the CHEK2 gene have been associated with an increased lifetime risk of developing breast cancer (BC). We aim to identify in the study population the prevalence of mutations in the CHEK2 gene in diagnosed BC patients, evaluate the phenotypic characteristics of the tumor and family history, and predict the deleteriousness of the variants of uncertain significance (VUS). A genetic study was performed, from May 2016 to April 2020, in 396 patients diagnosed with BC at the University Hospital Lozano Blesa of Zaragoza, Spain. Patients with a genetic variant in the CHEK2 gene were selected for the study. We performed a descriptive analysis of the clinical variables, a bibliographic review of the variants, and a cosegregation study when possible. Moreover, an in-depth bioinformatics analysis of CHEK2 VUS was carried out. We identified nine genetic variants in the CHEK2 gene in 10 patients (two pathogenic variants and seven VUS). This supposes a prevalence of 0.75% and 1.77%, respectively. In all cases, there was a family history of BC in first- and/or second-degree relatives. We carried out a cosegregation study in two families, being positive in one of them. The bioinformatics analyses predicted the pathogenicity of six of the VUS. In conclusion, CHEK2 mutations have been associated with an increased risk for BC. This risk is well-established for foundation variants. However, the risk assessment for other variants is unclear. The incorporation of bioinformatics analysis provided supporting evidence of the pathogenicity of VUS.

Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study.

The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon's design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2-37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

BACKGROUND: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. PATIENTS AND METHODS: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. RESULTS: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. CONCLUSIONS: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

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.

Survival impact of primary tumor resection in de novo metastatic breast cancer patients (GEICAM/El Alamo Registry).

The debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. We explored this approach's outcomes in patients included in a retrospective registry, named El Álamo, of breast cancer patients diagnosed in Spain (1990-2001). In this analysis we only included de novo MBC patients, 1415 of whom met the study's criteria. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Median age was 63.1 years, 49.2% of patients had single-organ metastasis (skin/soft tissue [16.3%], bone [33.8%], or viscera [48.3%]). PT surgery (S) was performed in 44.5% of the cases. S-group patients were younger, had smaller tumors, higher prevalence of bone and oligometastatic disease, and lower prevalence of visceral involvement. With a median follow-up of 23.3 months, overall survival (OS) was 39.6 versus 22.4 months (HR = 0.59, p < 0.0001) in the S- and non-S groups, respectively. The S-group OS benefit remained statistically and clinically significant regardless of metastatic location, histological type, histological grade, hormone receptor status and tumor size. PT surgery (versus no surgery) was associated with an OS benefit suggesting that loco-regional PT control may be considered in selected MBC patients. Data from randomized controlled trials are of utmost importance to confirm these results.

Double heterozygous mutation in the BRCA1 and ATM genes involved in development of primary metachronous tumours: a case report.

PURPOSE: Between 5 and 10% of cases of breast cancer (BC) are attributable to a genetic susceptibility. The BRCA1 and BRCA2 genes described in the late 1990s are associated with an increased risk of breast and ovarian cancer, and the clinical management of carriers of pathogenic variants in these genes is defined in several clinical guidelines (Paluch-Shimon et al. in Ann Oncol 27(suppl 5):v103-v110, 2016; Llort et al. in Clin Transl Oncol 17(12):956-961, 2015). However, the pathogenic variants in BRCA1 and BRCA2 represent only a third of the causes of hereditary BC (Easton et al. in N Engl J Med 372:2243-2257, 2015). The incorporation of NGS (Next Generation Sequencing) techniques in the genetic diagnosis of this pathology, in addition to minimising the cost and time of analysis, allows the simultaneous study of other genes of high and moderate penetrance (Easton et al. in N Engl J Med 372:2243-2257, 2015; Op. Cit.; Tung et al. in Cancer 121(1):25-33, 2015). To date, there are not many cases or series of patients that describe the co-occurrence of two pathogenic variants in these genes of BC. Cases of double heterozygosis have been described with the presence of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, BLM or NBN (Nomizu et al. in Breast Cancer 22(5):557-61, 2015; Heidemann et al. in Breast Cancer Res Treat 134(3):1229-1239, 2012; Zuradelli et al. in Breast Cancer Res Treat 124(1):251-258, 2010; Sokolenko et al. in Breast Cancer Res Treat 145(2):553-562, 2014). METHODS: We report the case of a patient diagnosed with multiple tumours who presented two pathogenic variants in heterozygosis. RESULTS: Two pathogenic variants, c.5123C > A (p.Ala1708Glu) in the BRCA1 gene and c.2413C > T (p.Arg805X) in the ATM gene were detected in heterozygosis. Said variants were confirmed by Sanger-type sequencing using specific primers. CONCLUSIONS: The implementation of gene panels using NGS in the study of hereditary cancer involves the detection of heterozygous double mutations in genes of high and moderate penetrance for cancer, although with a low frequency.

Effectiveness of biosimilar filgrastim vs. original granulocyte colony-stimulating factors in febrile neutropenia prevention in breast cancer patients.

PURPOSE: The purpose of this study is to describe the effectiveness of biosimilar filgrastim and original granulocyte colony-stimulating factors (G-CSFs), lenograstim and pegfilgrastim, in febrile neutropenia (FN) prevention in breast cancer patients receiving docetaxel/doxorubicin/cyclophosphamide (TAC) as adjuvant/neoadjuvant treatment and to analyze their treatment patterns. METHODS: A pharmacoepidemiology cohort study was developed in a university hospital (with 23 healthcare centers) with retrospective data collection (2012-2014). Effectiveness of G-CSFs was assessed by the FN incidence. Other parameters analyzed were as follows: moderate and severe neutropenia incidence, neutropenia-related hospitalizations, dosage, and duration. Data was analyzed using each cycle as a unit of analysis. RESULTS: We identified 98 patients representing 518 chemotherapy cycles, 215 with original G-CSFs (35 lenograstim and 180 pegfilgrastim) and 303 with biosimilar filgrastim. The FN incidence was similar in both groups (3.7% original vs. 3.3% biosimilar; p = 0.79). No statistically significant differences were found in moderate and severe neutropenia incidence (4.7 vs. 6.3%; p = 0.43) or neutropenia-related hospitalizations (3.3 vs. 3.6%; p = 0.19). When the three drugs were evaluated separately, a higher FN incidence was observed with lenograstim than with pegfilgratim or biosimilar (p = 0.024). The dosage and duration of biosimilar were lower than lenograstim (4.9 vs. 5.7 µg/kg/day; 5 vs. 7 days; p < 0.001). CONCLUSION: An abbreviated 5-day course of biosimilar filgrastim provided optimal primary prophylaxis against FN post-chemotherapy TAC in patients with breast cancer. The clinical relevance of the highest FN incidence in the lenograstim cohort needs further attention.

Frequency of breast cancer with hereditary risk features in Spain: Analysis from GEICAM "El Álamo III" retrospective study.

PURPOSE: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. METHODS: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. RESULTS: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. CONCLUSIONS: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.

Critically short telomeres and toxicity of chemotherapy in early breast cancer.

Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied.Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was "number of toxic episodes" during the 12 weeks of therapy.The percentage of CSTs ranged from 6.5%-49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial.

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432-41. ©2016 AACR.

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. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane.

A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.

Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.

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. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m(2), respectively, × four cycles), followed by docetaxel (100 mg/m(2) × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m(2), respectively, × four cycles), followed by capecitabine (1,250 mg/m(2) twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). RESULTS: After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). CONCLUSION: Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.

Role of surgery in patients with recurrent, metastatic, or unresectable locally advanced gastrointestinal stromal tumors sensitive to imatinib: a retrospective analysis of the Spanish Group for Research on Sarcoma (GEIS).

BACKGROUND: Recurrent, metastatic, and locally advanced gastrointestinal stromal tumors (GISTs) can be treated successfully with imatinib mesylate. Surgery for residual disease has been suggested for nonrefractory metastatic GISTs to reduce the probability of resistant recurrent clones, although no randomized Phase III trial has been performed to answer the question about its benefit. We carried out an analysis of the outcome of patients with recurrent unresectable locally advanced or metastatic imatinib-sensitive priamary GIST in 14 institutions in Spain. We compared two cohorts: treated or not treated with surgery after partial response or stabilization by imatinib. PATIENTS AND METHODS: Data were obtained from the online GIST registry of the Spanish Group for Research in Sarcomas. Selected patients were then divided into two groups: group A, treated initially only with imatinib, and group B, treated additionally with metastasectomy. Baseline characteristics between groups were compared, and univariate and multivariate analysis for progression-free survival and overall survival (OS) were performed. RESULTS: Analysis was undertaken in 171 patients considered nonrefractory to imatinib. The median follow-up time was 56.6 months. Focusing on OS, the Eastern Cooperative Oncology Group performance status different than 0, extent of disease limited to one metastatic organ, and comparison between groups A or B achieved statistical difference in the multivariate analysis. Median survival was 59.9 months in group A and 87.6 months in group B. CONCLUSIONS: Based in its benefit in OS, our study supports surgery of metastatic disease in GIST patients who respond to imatinib therapy.

Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study.

PURPOSE: Adding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer (BC). Currently, however, most patients with BC are node negative at diagnosis. The only pure node-negative study (Spanish Breast Cancer Research Group 9805) reported so far showed a docetaxel benefit but significant toxicity. Here we tested the efficacy and safety of weekly paclitaxel (wP) in node-negative patients, which is yet to be established. PATIENTS AND METHODS: Patients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence (according to St. Gallen 1998 criteria) were eligible. After primary surgery, 1,925 patients were randomly assigned to receive fluorouracil, doxorubicin, and cyclophosphamide (FAC) × 6 or FAC × 4 followed by wP × 8 (FAC-wP). The primary end point was disease-free survival (DFS) after a median follow-up of 5 years. Secondary end points included toxicity and overall survival. RESULTS: After a median follow-up of 63.3 months, 93% and 90.3% of patients receiving FAC-wP or FAC regimens, respectively, remained disease free (hazard ratio [HR], 0.73; 95% CI, 0.54 to 0.99; log-rank P = .04). Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died (one and seven from cardiovascular diseases, respectively; HR, 0.79; 95% CI, 0.49 to 1.26; log-rank P = .31). The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia (2.7% v 3.6%), fatigue (7.9% v 3.4%), and sensory neuropathy (5.5% v 0%). CONCLUSION: For patients with high-risk node-negative BC, the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy, in addition to manageable toxicity, especially regarding long-term cardiac effects.