Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-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-/PIK3CA-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 [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Biopsia del ganglio centinela y disección axilar dirigida en mujeres con cáncer de mama y axila positiva en el momento del diagnóstico: caminando hacia el futuro / Sentinel node biopsy and targeted axillary dissection in women with positive axilla breast cancer at diagnosis: walking into the future

Objetivo: conocer la tasa de concordancia del ganglio marcado con semilla Magseed® con el ganglio centinela marcado mediante tecnecio, en las pacientes con enfermedad ganglionar en el momento del diagnóstico que han recibido tratamiento neoadyuvante. Pacientes y métodos: estudio descriptivo retrospectivo de 44 mujeres diagnosticadas de carcinoma de mama estadios cT1-4/cN1/cM0, que recibieron quimioterapia neoadyuvante entre enero 2016 y diciembre 2020, y que tras una reevaluación radiológica se realizaron una cirugía mamaria con ganglio centinela en el Hospital General Universitario de Alicante. En las pacientes cN1 con respuesta radiológica axilar completa, la detección del ganglio centinela se llevó a cabo mediante doble técnica, extrayéndose por lo menos 3 ganglios. Además, se realizó una disección axilar dirigida mediante semilla magnética Magseed®, para su correcta localización y escisión. Resultados: la tasa de concordancia al realizar la disección axilar dirigida fue del 93,2%. La tasa de respuesta completa tras la quimioterapia neoadyuvante fue del 45,45%. Conclusiones: la disección axilar dirigida mejora la estadificación axilar tras la quimioterapia neoadyuvante, ya que reduce la tasa de falsos negativos respecto a la biopsia selectiva del ganglio centinela de manera aislada. (AU)

Objectives:To know the concordance rate of the ganglion marked with Magseed® with the sentinel node marked by technetium, in patients with limph node disease at diagnosis, that had received neoadjuvant treatment. Patients and methods: Retrospective descriptive study of 44 women, diagnosed with stage cT1-4 / cN1 / cM0 breast carcinoma, who received neoadjuvant chemotherapy between January 2016 and December 2020, and who after radiological re-evaluation, have undergone breast surgery with sentinel node at the General University Hospital of Alicante. In cN1 patients with a complete axillary radiological response, detection of the sentinel node is performed using a double technique, removing at least 3 nodes. In addition, axillary dissection directed by Magseed® magnetic seed is performed, for its correct location and excision. Results: The concordance rate when performing targeted axillary dissection was 93.2%. The complete response rate after neoadjuvant chemotherapy was 45.45%. Conclusions: Targeted axillary dissection improves the axillary staging after neoadjuvant chemotherapy, since it improves the false negative rate with respect to sentinel lymph node biopsy in isolation. (AU)

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03).

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.

BACKGROUND: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. FINDINGS: Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). INTERPRETATION: Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. FUNDING: AbbVie.

Presence of human papillomavirus DNA in breast cancer: a Spanish case-control study.

BACKGROUND: Breast cancer is one of the most important neoplasia among women. It was recently suggested that biological agents could be the etiological cause, particularly Human Papilloma Virus (HPV). The aim of this study was to explore the presence of HPV DNA in a case-control study. METHODS: We performed our study including 251 cases (breast cancer) and 186 controls (benign breast tumors), using three different molecular techniques with PCR (GP5/GP6, CLART® and DIRECT FLOW CHIP®). RESULTS: HPV DNA was evidenced in 51.8% of the cases and in 26.3% of the controls (p < 0.001). HPV-16 was the most prevalent serotype. The odds ratio (OR) of HPV within a multivariate model, taking into account age and breastfeeding, was 4.034. CONCLUSIONS: Our study, with methodological rigour and a sample size not previously found in the literature, demonstrate a significant presence of HPV DNA in breast cancer samples. A possible causal relationship, or mediation or not as a cofactor, remains to be established by future studies.

Epidemiological pattern and time trends in testicular germ-cell tumors: a single institution 20-year experience.

INTRODUCTION: Recent studies have suggested a rise in the incidence of testicular germ-cell tumors (TGTs) in the last years, mainly due to an increase of early stage cases. We analysed the time trends in biological features of these patients in order to confirm this tendency in our environment. MATERIALS AND METHODS: The clinical records of 136 consecutive patients with TGTs treated at a single institution over a 20-year period (1984-2003) were retrospectively reviewed. Pathological, clinical, therapeutic and outcome data were collected. Patients were allocated into four consecutive 5- year intervals and their characteristics were compared by means of the chi-squared test. The survival analysis was performed with the method of Kaplan and Meier. RESULTS: A progressive increase in the incidence of new cases, and a more frequent diagnosis of stage I versus stage II-IV disease was confirmed within this time period. It was also observed a greater use of postorchiectomy chemotherapy, mainly due to an increase in the adjuvant indications. A significant decrease in the recurrence rate was noted. Ten-year overall survival was 86.5%. There was a trend for improved outcome, but the differences among the two decades were not statistically significant. CONCLUSIONS: A real increase in the incidence of TGTs and in the proportion of early stages was confirmed. This may be due to an epidemiological change or to an earlier diagnosis. This new pattern is associated with a more frequent use of adjuvant chemotherapy and with a reduction in the relapse rate.

Epidemiological pattern and time trends in testicular germ-cell tumors: a single institution 20-year experience

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Introduction. Recent studies have suggested a risein the incidence of testicular germ-cell tumors(TGTs) in the last years, mainly due to an increaseof early stage cases. We analysed the time trendsin biological features of these patients in order toconfirm this tendency in our environment.Materials and methods. The clinical records of136 consecutive patients with TGTs treated at asingle institution over a 20-year period (1984-2003)were retrospectively reviewed. Pathological, clinical,therapeutic and outcome data were collected.Patients were allocated into four consecutive 5-year intervals and their characteristics were comparedby means of the chi-squared test. The survivalanalysis was performed with the method ofKaplan and Meier.Results. A progressive increase in the incidence ofnew cases, and a more frequent diagnosis of stageI versus stage II-IV disease was confirmed withinthis time period. It was also observed a greater useof postorchiectomy chemotherapy, mainly due toan increase in the adjuvant indications. A significantdecrease in the recurrence rate was noted.Ten-year overall survival was 86.5%. There was atrend for improved outcome, but the differencesamong the two decades were not statistically significant.Conclusions. A real increase in the incidence of TGTsand in the proportion of early stages was confirmed.This may be due to an epidemiological change or toan earlier diagnosis. This new pattern is associatedwith a more frequent use of adjuvant chemotherapyand with a reduction in the relapse rate

[Extra-pulmonary small-cell cancer: is its outcome similar to small cell lung cancer?]. / Carcinoma microcítico de localización extrapulmonar: es su curso similar a los microcíticos pulmonares?

INTRODUCTION: Extra-pulmonary small cell carcinoma (ESCC) is as a pathologic entity distinct from small cell lung carcinoma (SCLC). ESCC is considered a systemic disease in its origin, so the therapeutic approach is similar to SCLC with chemotherapy being considered in case of extensive and local disease. We present a retrospective comparison of ESCC and SCLC in our institution. MATERIAL AND METHODS: Using the tumour registry database of Hospital Universitario La Fe we reviewed 24 ESCC cases receiving attention between 1987 and 2003, and these were compared with a series of 341 patients with SCLC in the same institution. RESULTS: Of the 24 patients with ESCC 19 were men and 5 were women with an average age of 58 years (range 23 to 85). The most frequent site was the mediastinum with 58% having extensive disease. All patients but one received treatment. The therapeutic approaches were local and systemic in 13 patients, systemic alone in 6 and local alone in 4. Schedules based on platinum and etoposide were used. The median follow-up was 53 months (range 4 to 211). Median survival was 18.9 months; 30 in patients with local disease and 8 in those with extensive disease. In the SCLC series of patients, there were 336 men and 5 women; 62% having extensive disease. The median survival was 10 months; 12 months in those patients with local disease and 8 in those with extensive disease. CONCLUSIONS: The overall survival of patients with ESCC was slightly better than patients with SCLC. ESCC with local disease had a better survival outcome than SCLC with local disease. Chemotherapy is the cornerstone of the treatment, but sometimes local treatment could be sufficient.

[Extra-cranial anaplastic oligoastrocytoma development from a low-grade glioma]. / Afectación extracraneal de oligoastrocitoma anaplásico desarrollado sobre un glioma de bajo grado.

Oligodendrogliomas are primary brain tumours derived from oligodendroglial cells, or precursors, and represent 2%-5% of brain tumours. This type of glioma has a favourable prognosis compared to other brain tumours. The treatment is multidisciplinary and is based on three therapeutic arms: surgery, radiotherapy and chemotherapy. We present a patient who had received treatment previously for a lowgrade glioma and who subsequently developed an anaplastic oligoastrocytoma in the same zone together with skull and extra-cranial involvement in the disease progression.

Afectación extracraneal de oligoastrocitoma anaplásico desarrollado sobre un glioma de bajo grado / Extra-cranial anaplastic oligoastrocytoma development from a low-grade glioma

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Oligodendrogliomas are primary brain tumours derived from oligodendroglial cells, or precursors, and represent 2%-5% of brain tumours. This type of glioma has a favourable prognosis compared to other brain tumours. The treatment is multidisciplinary and is based on three therapeutic arms: surgery, radiotherapy and chemotherapy. We present a patient who had received treatment previously for a lowgrade glioma and who subsequently developed an anaplastic oligoastrocytoma in the same zone together with skull and extra-cranial involvement in the disease progression

Carcinoma microcítico de localización extrapulmonar: ¿es su curso similar a los microcíticos pulmonares? / Extra-pulmonary small-cell cancer: is its outcome similar to small cell lung cancer?

Introducción. Los carcinomas microcíticos extrapulmonares (CMEP) se han reconocido como entidad diferenciada del carcinoma microcítico broncopulmonar (CMBP). Se consideran una enfermedad sistémica desde el inicio y esto hace que su abordaje sea similar al de los CMBP debiendo considerarse siempre el empleo de quimioterapia tanto en enfermedad localizada como diseminada. Presentamos un estudio retrospectivo sobre los CMEP y los comparamos con los CMBP atendidos en nuestro centro. Material y métodos. Usando la base de datos del servicio de Oncología Médica del Hospital Universitario La Fe se localizan 24 CMEP atendidos entre los años 1987 y 2004. Se realiza una comparación indirecta entre éstos y una serie publicada de nuestro servicio de 341 pacientes afectos de CMBP, durante los años 1981 a 1992 Resultados. De los 24 pacientes diagnosticados de CMEP 19 son hombres y 5 mujeres, con una media de edad de 58 años (extremos 23 a 85). Predomina la localización mediastínica. Un 58% presenta enfermedad diseminada. Todos los pacientes menos uno recibieron algún tipo de tratamiento. El abordaje terapéutico fue local y sistémico en 11 pacientes, sólo sistémico en 6, y sólo local en 4. Predomina el uso de quimioterapia basada en platino y etopósido. La mediana de seguimiento potencial de la serie es de 53 meses (extremos 4 y 211), la mediana de supervivencia es de 18,9 meses; 30,8 meses en el estadio localizado y 8 en el estadio diseminado. En cuanto a la serie de CMBP, existe un claro predominio de hombres (336) sobre mujeres (5). Un 62% presenta enfermedad diseminada al diagnóstico. La supervivencia global de la serie es de 10 meses, 12 en enfermedad limitada y 8 en enfermedad extendida. Conclusiones. La supervivencia global de la serie de CMEP es superior a la de CMBP. Los CMEP obtienen mejor supervivencia en enfermedad localizada. La quimioterapia es la piedra angular del tratamiento. En determinadas situaciones puede ser suficiente un tratamiento exclusivamente local

Introduction. Extra-pulmonary small cell carcinoma (ESCC) is as a pathologic entity distinct from small cell lung carcinoma (SCLC). ESCC is considered a systemic disease in its origin, so the therapeutic approach is similar to SCLC with chemotherapy being considered in case of extensive and local disease. We present a retrospective comparison of ESCC and SCLC in our institution. Meterial and methods. Using the tumour registry database of Hospital Universitario La Fe we reviewed 24 ESCC cases receiving attention between 1987 and 2003, and these were compared with a series of 341 patients with SCLC in the same institution. Results. Of the 24 patients with ESCC 19 were men and 5 were women with an average age of 58 years (range 23 to 85). The most frequent site was the mediastinum with 58% having extensive disease. All patients but one received treatment. The therapeutic approaches were local and systemic in 13 patients, systemic alone in 6 and local alone in 4. Schedules based on platinum and etoposide were used. The median follow-up was 53 months (range 4 to 211). Median survival was 18.9 months; 30 in patients with local disease and 8 in those with extensive disease. In the SCLC series of patients, there were 336 men and 5 women; 62% having extensive disease. The median survival was 10 months; 12 months in those patients with local disease and 8 in those with extensive disease. Conclusions. The overall survival of patients with ESCC was slightly better than patients with SCLC. ESCC with local disease had a better survival outcome than SCLC with local disease. Chemotherapy is the cornerstone of the treatment, but sometimes local treatment could be sufficient