HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer.

Background: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems. Trial design: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment. Clinical trial registration: www.soltihope.com, identifier NCT04497285.

Quality of life in Spanish postmenopausal breast cancer patients with localized disease who finish endocrine treatment: a prospective study.

OBJECTIVE: In this article, the quality of life (QOL) of Spanish postmenopausal early-stage breast cancer patients who have finished endocrine therapy (ET), QOL changes after endocrine therapy cessation, and the differences between two endocrine therapy modalities (tamoxifen or aromatase inhibitor [AI]) are studied. More QOL information after endocrine therapy cessation is needed. METHODS: A prospective cohort study was performed. Participating in the study were 158 postmenopausal patients who had received tamoxifen or AI for 5 years. In some cases, endocrine therapy may have changed during those 5 years.Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR45 questionnaires at baseline, after 6 months, and after 1 year of follow-up. Patients older than 65 years also completed the QLQ-ELD14. Linear mixed-effect models were used to evaluate longitudinal changes in QOL and differences in QOL between endocrine therapy modalities. RESULTS: QOL scores for the whole sample throughout follow-up were high (>80/100 points) in most QOL areas. Moderate limitations (>30 points) occurred in the QLQ-BR45 in sexual functioning and sexual enjoyment, future perspective, and joint symptoms. Moderate limitations also occurred in the QLQ-ELD14 in worries about others, maintaining purpose, joint stiffness, future worries, and family support. In those who had finished endocrine therapy, pain was reduced in all three assessments conducted during the 1-year follow-up period in both groups. Tamoxifen patients showed better QOL in functioning (role functioning, global QOL, financial impact), symptoms (pain), and emotional areas (future perspective and worries about others) than AI patients but worse QOL in skin mucosis symptoms. CONCLUSIONS: The results of this study show that postmenopausal early-stage breast cancer patients adapted well to their disease and endocrine therapy treatment. QOL improvements in the 1-year follow-up period appeared in one key area: pain. Differences between endocrine therapy modalities suggested QOL was better in the tamoxifen group than in the AI group.

Modification of Breast Cancer Milieu with Chemotherapy plus Dendritic Cell Vaccine: An Approach to Select Best Therapeutic Strategies.

BACKGROUND: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. METHODS: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. RESULTS: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). CONCLUSION: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.

A DNA Methylation-Based Gene Signature Can Predict Triple-Negative Breast Cancer Diagnosis.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype and lacks targeted treatment. It is diagnosed by the absence of immunohistochemical expression of several biomarkers, but this method still displays some interlaboratory variability. DNA methylome aberrations are common in BC, thereby methylation profiling could provide the identification of accurate TNBC diagnosis biomarkers. Here, we generated a signature of differentially methylated probes with class prediction ability between 5 non-neoplastic breast and 7 TNBC tissues (error rate = 0.083). The robustness of this signature was corroborated in larger cohorts of additional 58 non-neoplastic breast, 93 TNBC, and 150 BC samples from the Gene Expression Omnibus repository, where it yielded an error rate of 0.006. Furthermore, we validated by pyrosequencing the hypomethylation of three out of 34 selected probes (FLJ43663, PBX Homeobox 1 (PBX1), and RAS P21 protein activator 3 (RASA3) in 51 TNBC, even at early stages of the disease. Finally, we found significantly lower methylation levels of FLJ43663 in cell free-DNA from the plasma of six TNBC patients than in 15 healthy donors. In conclusion, we report a novel DNA methylation signature with potential predictive value for TNBC diagnosis.

Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up.

PURPOSE: This paper studies the Quality of Life (QL) of elderly early-stage breast cancer survivors. The aims are to compare the QL scores of these patients after follow-up with their scores before the start of radiotherapy (RT) and compare QL among different axillary treatment groups. METHODS: Of 173 patients over 65 who began treatment and completed the EORTC QLQ-C30 and QLQ-BR23 and the Interview for Deterioration in Daily Living Activities in Dementia (IDDD) before RT, 138 also completed these questionnaires three years after RT. Longitudinal changes in QL were assessed for the whole sample using linear mixed-effect models. Also assessed were differences in QL scores between axillary treatment groups (axillary node dissection ALND, sentinel lymph node biopsy SLNB, and no surgery) at the end of the follow-up (Anova or Kruskal-Wallis) and differences in the evolution of QL from baseline among these groups (linear regression models). RESULTS: QL scores in the follow-up were high (>70/100 points) in most QL areas, with moderate limitations (>30) in sexual functioning and enjoyment. Five areas (pain, nausea/vomiting, financial impact, breast symptoms and IDDD) improved significantly (<6 points) in the follow-up. The ALND group scored less for the future perspective item (15-20 points) in the follow-up than the other two axillary treatment groups. No differences between the pre-treatment and follow up assessments regarding treatment were found among the axillary treatment groups. CONCLUSIONS: Our results suggest that early-stage breast cancer patients adapted well both to their disease and treatments over the follow-up period and to the administration of RT. There were few QL differences between the axillary treatment groups.

CDH22 hypermethylation is an independent prognostic biomarker in breast cancer.

BACKGROUND: Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein involved in cell-cell adhesion and metastasis. Its role in cancer is controversial because it has been described as being upregulated in colorectal cancer, whereas it is downregulated in metastatic melanoma. However, its status in breast cancer (BC) is unknown. The purpose of our study was to determine the molecular status and clinical value of CDH22 in BC. RESULTS: We observed by immunohistochemistry that the level of CDH22 expression was lower in BC tissues than in their matched adjacent-to-tumour and non-neoplastic tissues from reduction mammoplasties. Since epigenetic alteration is one of the main causes of gene silencing, we analysed the hypermethylation of 3 CpG sites in the CDH22 promoter by pyrosequencing in a series of 142 infiltrating duct BC cases. CDH22 was found to be hypermethylated in tumoral tissues relative to non-neoplastic mammary tissues. Importantly, this epigenetic alteration was already present in adjacent-to-tumour tissues, although to a lesser extent than in tumoral samples. Furthermore, CDH22 gene regulation was dynamically modulated in vitro by epigenetic drugs. Interestingly, CDH22 hypermethylation in all 3 CpG sites simultaneously, but not expression, was significantly associated with shorter progression-free survival (p = 0.015) and overall survival (p = 0.021) in our patient series. Importantly, CDH22 hypermethylation was an independent factor that predicts poor progression-free survival regardless of age and stage (p = 0.006). CONCLUSIONS: Our results are the first evidence that CDH22 is hypermethylated in BC and that this alteration is an independent prognostic factor in BC. Thus, CDH22 hypermethylation could be a potential biomarker of poor prognosis in BC.

Quality of life in long-term premenopausal early-stage breast cancer survivors from Spain. Effects of surgery and time since surgery.

PURPOSE: More research is needed into Quality of Life (QoL) in young early-stage breast cancer patients in the long-term. Knowledge of long-term effects of surgery on QoL in breast cancer patients is limited. The purpose of this study was to assess QoL in premenopausal Spanish early- stage breast cancer patients over a long follow-up period and evaluate differences among surgery-treated groups and the influence of time on patient QoL. METHODS: 243 premenopausal stage I-III relapse-free breast cancer patients completed the EORTC QLQ-C30 and QLQ-BR23 questionnaire once during follow-up (5-20 years after surgery). Univariate and multivariate logistic regression analyses were performed to estimate the results. RESULTS: QoL mean scores were high in most areas (>80 points in functioning: <20 points in symptoms areas). Limitations were moderate (>30 points) in global QoL, sleep disturbance, future perspective, sexual areas, and hot flashes. Mastectomized patients had a 4-fold greater risk of low scores in body image. Patients with a longer follow-up showed lower systemic side effects, hot flashes and breast symptoms. CONCLUSIONS: QoL in Spanish premenopausal early-stage breast cancer patients in a long follow-up after surgery is high. Differences in QoL among surgery-treated groups are limited. Time since surgery influences treatment side effects.

An evaluation study of the determinants of future perspective and global Quality of Life in Spanish long-term premenopausal early-stage breast cancer survivors.

AIM OF THE STUDY: Quality of life (QL) is important in premenopausal long-term breast cancer survivors. In this study we assessed QL and factors associated with future perspective and global QL in premenopausal early-stage long-term breast cancer survivors from Spain. MATERIAL AND METHODS: 243 premenopausal stage I-IIIA relapse-free breast cancer patients who had received surgery 5-20 years previously completed EORTC QLQ-C30 and QLQ-BR23 questionnaires once during follow-up. Univariate and multivariate logistic regression analyses were performed. RESULTS: QL mean scores were high in most areas (> 80 in functioning; < 20 in symptoms). The main factors for future perspective were emotional and social functioning, fatigue, breast symptom, and body image. The main factors for global QL were fatigue, pain and physical functioning, and emotional and social functioning. The best logistic model to explain future perspective associated high emotional and social functioning and low breast symptoms with a lower risk of low future perspective (R(2) = 0.56). Higher scores in physical and emotional functioning and lower scores in fatigue were associated with a lower risk of low global QL (R(2) = 0.50). CONCLUSIONS: Psychological, social, and physical factors were found to be possible determinants of global QL and future perspective. QL in premenopausal early-stage long-term breast cancer survivors may benefit from multidisciplinary treatment.

Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis.

Breast cancer is a heterogeneous disease that can be subdivided into clinical, histopathological and molecular subtypes (luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive, and triple-negative). The study of new molecular factors is essential to obtain further insights into the mechanisms involved in the tumorigenesis of each tumor subtype. RASSF2 is a gene that is hypermethylated in breast cancer and whose clinical value has not been previously studied. The hypermethylation of RASSF1 and RASSF2 genes was analyzed in 198 breast tumors of different subtypes. The effect of the demethylating agent 5-aza-2'-deoxycytidine in the re-expression of these genes was examined in triple-negative (BT-549), HER2 (SK-BR-3), and luminal cells (T-47D). Different patterns of RASSF2 expression for distinct tumor subtypes were detected by immunohistochemistry. RASSF2 hypermethylation was much more frequent in luminal subtypes than in non-luminal tumors (p = 0.001). The re-expression of this gene by lentiviral transduction contributed to the differential cell proliferation and response to antineoplastic drugs observed in luminal compared with triple-negative cell lines. RASSF2 hypermethylation is associated with better prognosis in multivariate statistical analysis (P = 0.039). In conclusion, RASSF2 gene is differently methylated in luminal and non-luminal tumors and is a promising suppressor gene with clinical involvement in breast cancer.

Determinants of patient satisfaction with care in a Spanish oncology day hospital and its relationship with quality of life.

OBJECTIVE: This study evaluates satisfaction with care (SC) in cancer patients treated at a Spanish day hospital to identify SC determinants and assess the relationship between SC and quality of life. METHODS: One hundred seventy-six patients with different tumour sites and disease stages completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Cancer Outpatient Satisfaction with Care questionnaire for chemotherapy (OUT-PATSAT35 CT), the Oberst patients' perception of care quality and satisfaction scales, and an item on intention to recommend the hospital. Frequencies in the SC instruments, Spearman correlations between each scale of the OUT-PATSAT35 CT and overall satisfaction and between the subscales of OUT-PATSAT35 CT and of QLQ-C30 were calculated, and the determinants of patients' SC were calculated through multivariate regression models. RESULTS: Satisfaction with care was high: mean scores were >70 in all OUT-PATSAT35 CT areas except doctor availability and environment. These scores were in line with the other SC instruments. Correlation with overall satisfaction was high and statistically significant (p < 0.01) for all subscales, especially for the nurses domain, which also had higher SC scores. Correlations between the EORTC QLQ-C30 and the OUT-PATSAT35 CT were low (≤ 0.35). Younger patients and those with breast cancer showed significantly lower satisfaction in most subscales. Unmarried patients and patients that had undergone surgery reported lower satisfaction only in specific subscales. CONCLUSIONS: Satisfaction with care among cancer patients treated at the day hospital is high. Nurses play a key and successful role. Age and tumour location revealed stronger relationships with SC. Correlations between SC and quality of life indicate that these concepts are complementary.

Estilo de vida y factores biosocioculturales del adulto mayor del asentamiento humano San Juan - Chimbote, 2012 / Life style and sociocultural factors of the elderly people in the human settlemen San Juan - Chimbote, 2012

El presente trabajo de investigación de tipo cuantitativo, descriptivo correlacional, de corte transversal, tuvo como objetivo determinar la relación entre el estilo de vida y los factores biosocioculturales del adulto mayor del asentamiento humano "San Juan"-Chimbote, 2012. La muestra estuvo conformada por 84 personas adultas mayores de ambos sexos. La recolección de datos se efectuó a través de las visitas domiciliarias teniendo como instrumento la escala del estilo de vida y el cuestionario semi-estructurado sobre factores biosocioculturales. (El análisis de datos se efectuó mediante la prueba de independencia del Chi cuadrado (χ²) con el 95% confiabilidad y significancia de p<0,05. La mayoría de los adultos mayores tiene un estilo de vida no saludable; sin embargo, existe un porcentaje significativo con estilo de vida saludable. Respecto a los factores biosocioculturales, un poco más de la mitad fueron masculinos; la mayoría tiene grado de instrucción primaría completa e incompleta; cuentan con un ingreso económico de 100 a 599 Nuevos Soles; son viudos y con unión libre; más de la mitad son evangélicos. No existe relación significativa entre el estilo de vida y los factores biosocioculturales: sexo, grado de instrucción, religión estado civil e ingreso económico; pero sí existe relación significativa con el factor social de ocupación de los adultos mayores.

This non-experimental research of descriptive corelational desing aimed to establish the relationship between life style and sociocultural factors of the elderly people in the human settlemen San Juan - Chimbote. The sample consisted of 84 elderly people, males an females who were visited at home. The instruments used were the life style scale and sociocultural factors questionnaire. The data was statistically analyzed y means of the Chi Square test for independence with a 5% significance level and 95% of reliability. The study came to the followig conclusions: Most of elderly people present unhealthy lifestyle, however, a significant number of the present healthy one. Respect to the biosociocultural factors, most are male. Most have completed and non-completed primary education. Their salary range from 100and 599 Nuevos Soles monthly. Most of them are widowed and widowers. More than half are evangelists. There is no significant relationship between lifestyle and the sociocultural factors: sex, education level, religion, marital status, and income; but there is significant relation between elderly people's occupation.

The cancer outpatient satisfaction with care questionnaire for chemotherapy, OUT-PATSAT35 CT: a validation study for Spanish patients.

PURPOSE: The OUT-PATSAT35 CT questionnaire evaluates satisfaction with care expressed by cancer outpatients receiving chemotherapy. This study assesses the psychometric properties of the OUT-PATSAT35 CT when applied to a sample of Spanish patients. METHODS: One hundred seventy-six patients with different tumour sites and disease stages completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30, the OUT-PATSAT35 CT, the Oberst patients' perception of care quality and satisfaction scales (OS) and the item on intention to recommend the hospital (IR). Psychometric evaluation of the structure, reliability and validity of the questionnaire was conducted. RESULTS: Multitrait scaling analysis showed that 32 of 34 item-scale correlation coefficients met the standards for convergent validity and that many of them met the standards for discriminant validity. Cronbach's coefficients were good (0.78-0.97) for all scales except doctor availability and environment. Correlations between the QLQ-C30 and the OUT-PATSAT35 CT were low (≤0.40). Correlations between IR and the OUT-PATSAT35 CT were moderate, and correlations between this questionnaire and the OS were fairly low. Areas whose contents were more related had higher correlation coefficients (>0.50) and vice versa (<0.1). Male patients, elderly patients, those with higher education levels, those with higher scores in four OS and patients who had not received surgery showed higher satisfaction with care in several OUT-PATSAT35 CT areas. CONCLUSIONS: The OUT-PATSAT35 CT is a reliable and valid instrument when applied to a sample of Spanish cancer patients. These results are in line with those of the validation study conducted by the authors of the questionnaire and with the validation study for Spain of the OUT-PATSAT35 RT.

Sequential administration of dose-dense epirubicin/cyclophosphamide followed by docetaxel/capecitabine for patients with HER2-negative and locally advanced or node-positive breast cancer.

PURPOSE: Capecitabine is effective against metastatic breast cancer (MBC). We hypothesized that sequential treatment with dose-dense epirubicin/cyclophosphamide (EC) and docetaxel/capecitabine would be active and tolerable in the adjuvant/neoadjuvant setting. METHODS: In this prospective phase II clinical trial patients with HER2-negative and node-positive or locally advanced tumors were eligible to receive four cycles of EC (100/600 mg/m2) every 2 weeks with G-CSF on days 3-10, followed by four cycles of docetaxel/capecitabine (75/1,000 mg/m2 b.i.d., days 1-14) every 3 weeks. RESULTS: Fifty-five patients were enrolled with median age of 49, and 80% had hormone receptor-positive disease. The median tumor size was 2.5 cm, with a median of two axillary nodes involved. Seventy-five percent of the first 20 patients had grade 2/3 hand-foot syndrome (HFS). Dose reduction of capecitabine to 800 mg/m2 reduced the grade 2/3 HFS incidence to 31% in the remaining patients. No grade 4/5 toxicities were observed. All 20 patients treated preoperatively responded, with 5 (25%) pathologic complete responses and 3 additional pT0N1 tumors. At a median follow-up of 48 (range 28-60) months, the event-free and overall survival rates are 91 and 98%, respectively. CONCLUSIONS: Sequential treatment with dose-dense EC followed by docetaxel/capecitabine, using a lower capecitabine dose than that approved for MBC, has an acceptable toxicity profile and encouraging activity when used as neoadjuvant or adjuvant treatment of breast cancer.

Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy.

BACKGROUND: 5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron. PATIENTS AND METHODS: Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance. RESULTS: From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration-time curve for 0-12 hours (AUC(0-12h)) and higher levels at 12 hours, with similar values for AUC(0-24h). The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration. CONCLUSION: Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients.

Total remission of thymus carcinoma after treatment with intravenous immunoglobulin.

We report the case of a 42 year-old woman with myasthenia gravis associated with a malignant thymoma. Despite surgery, chemotherapy and radiotherapy, the thymoma showed soft tissues, pleural and mediastinic progression. Unexpectedly, a complete remission of the thymoma was confirmed by FDG-PET after four cycles of immunoglobulins, administered as treatment for a myasthenic crisis. To our knowledge this is the first case report of complete remission of a malignant thymoma with immunoglobulin therapy.