Real-world clinical scenarios during introduction of trastuzumab biosimilar for HER2-positive breast cancer in the European Union.

Aim: Trastuzumab-anns is an intravenously administered biosimilar to trastuzumab approved by the EMA and US FDA for treatment of HER2+ early and metastatic breast cancer as well as metastatic gastric cancer. Lack of real-world characterization of biosimilar use has hindered uptake. Methods: This observational chart review characterizes 488 patients who received trastuzumab-anns in EU clinical practice settings. Results: Approximately 2/3rds of patients initiated trastuzumab-anns in adjuvant and neoadjuvant settings and most were naive new starters (70%). 30% were switchers from another trastuzumab, among whom 48% switched from trastuzumab iv. reference product. Common reasons for trastuzumab-anns discontinuation were a switch to another biosimilar product (34.8%, n = 85) or to trastuzumab reference product (15.6%, n = 38). Conclusion: Trastuzumab-anns was widely used in various treatment settings for HER2+ breast cancer.

Some patients have a type of breast cancer caused by abnormal amounts of a normal growth factor receptor. This growth factor receptor, known as human epidermal growth factor receptor-2 (HER-2), plays a role in normal life changes that occur in breast tissue, including during pregnancy. HER-2 exists on the surface of breast cells and sends a signal inside cells for growth and proliferation. Sometimes an abnormal amount of HER-2 appears on breast cell surfaces, which causes HER-2 to promote excessive growth and proliferation and leads to HER2+ breast cancer. HER2+ breast cancer can be treated with trastuzumab, a medicine that specifically blocks HER-2 signals, and stops cancer cell growth. Trastuzumab has greatly improved outcomes for women worldwide with HER2+ breast cancer but trastuzumab is not always available due, in part, to its high cost. Biosimilars are medicines that are highly similar, but not identical, to the brand name (original) product and have been shown in clinical trials to result in no meaningful difference in efficacy and safety compared with the original product. Trastuzumab-anns is an intravenously administered biosimilar to trastuzumab. Biosimilars are as effective and safe as original products, although more cost-effective, such that physicians and patients can benefit from more information about their use in the real world. This study provided information about trastuzumab-anns use from clinical oncology practices in seven European countries. The study provides real world evidence that trastuzumab-anns is used widely across different patients with HER2+ breast cancer, including those with metastatic disease.

The economic burden of metastatic breast cancer in Spain.

Objectives: The study aimed to estimate the burden of metastatic breast cancer (mBC) in Spain over 5 years. Methods: An incidence-based cost-of-illness model was developed in which a cohort of patients with mBC was followed from the diagnosis of metastatic disease over 5 years or death. Resource use data were collected through a physician survey conducted with 10 clinical experts in Spain. The model distinguished patients according to HER2 and hormonal receptor (HR) status, and followed the patient cohort in monthly cycles. Results: The incident cohort was estimated to be 2,923 patients with mBC, consisting of 1,575 HER2-/HR+, 520 HER2+/HR+, 324 HER2+/HR-, and 503 triple negative patients. The estimated mean survival over the 5-year time period was 2.51 years, on average, with longer survival of 3.36 years for HER2+/HR+, 2.41 years for HER2-/HR+, 2.82 years for HER2+/HR- and shortest mean survival of 1.74 years for triple negative patients. The total costs were €469,92,731 for the overall population, €190,079,787 for the HER2-/HR+, €151,045,260 for the HER2+/HR+, €80,827,171 for the HER2+/HR- and €47,540,512 for the triple negative subgroups over 5 years. Per patient total costs were €160,642 on average, €120,664 for HER2-/HR+, €290,346 for HER2+/HR+, €249,152 for HER2+/HR-and €94,572 for triple negative patients over 5 years. Conclusions: The economic burden of mBC in Spain is significant, but differs by HER2 and HR status. HER2-/HR +patients account for the highest burden due to the prevalence of this category, but HER2+/HR +patients have the highest per patient costs.

Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer.

The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.

Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients.

Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the "drug plus diet" approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body ß-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.

The C Allele of ATM rs11212617 Associates With Higher Pathological Complete Remission Rate in Breast Cancer Patients Treated With Neoadjuvant Metformin.

Background: The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We herein investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC). Methods: DNA was collected from 79 patients included in the intention-to-treat population of the METTEN study, a phase 2 clinical trial of HER2-positive BC patients randomized to receive either metformin combined with anthracycline/taxane-based chemotherapy and trastuzumab or equivalent regimen without metformin, before surgery. SNP rs11212617 genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction. Results: Logistic regression analyses revealed a significant relationship between the rs11212617 genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]genotype×arm = 10.33, 95% confidence interval [CI]: 1.29-82.89, p = 0.028). In the metformin-containing arm, patients bearing the rs11212617 C allele had a significantly higher probability of pCR (OR A/C,C/C = 7.94, 95%CI: 1.60-39.42, p = 0.011). Conversely, no association was found between rs11212617 and clinical response in the reference arm (OR A/C,C/C = 0.77, 95%CI: 0.20-2.92, p = 0.700). After controlling for tumor size and hormone receptor status, the rs11212617 C allele remained a significant predictor of pCR solely in the metformin-containing arm. Conclusions: If reproducible, the rs11212617 C allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients. Trial Registration: EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study.

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7-74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 µmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

Diagnóstico y tratamiento del dolor irruptivo oncológico: recomendaciones de consenso / Diagnosis and treatment of break-through cancer pain: Consensus recommendations

INTRODUCCIÓN Y OBJETIVOS: El dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los diferentes especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de 4 sociedades científicas implicadas en el manejo del paciente oncológico, han diseñado este documento de consenso. MÉTODOS: Tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO, se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan(R), donde se debatieron las recomendaciones a incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). RESULTADOS: El manejo del DIO requiere de una anamnesis completa, tanto del DIO como del dolor basal, y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio de acción, efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. CONCLUSIÓN: Este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO

INTRODUCTION OBJECTIVES: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved in its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. METHODS: After an initial search on the most relevant publications in BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan(R) methodology -a structured brainstorming technique- that produced a first version of the Consensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish Intercollegiate Guidelines Network) system. OUTCOMES: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain. CONCLUSION: This Consensus can be a very useful tool to improve the quality of life in cancer patients, because it guides the clinician towards a better diagnose and treatment of BTcP

Professional survey on knowledge and clinical patterns of pain management in Spanish medical oncology.

Cancer pain is still not treated adequately. The barriers impeding its appropriate treatment include lack of knowledge, erroneous beliefs and inappropriate attitudes with regard to pain, which are sustained by some or all of those involved in the problem. The present study shows the results of an exploratory survey using a large sample of specialists in clinical oncology. Its main objective is to evaluate daily analgesic practices and compliance with clinical guidelines in order to identify areas that should be improved in this particular therapeutic field. Information collection from the responders was in the form of a self-administered written questionnaire, structured in three thematic areas: clinical patterns and resources used in pain treatment in clinical practice, pain and pain-relief therapy, and theoretical knowledge and decision-making in clinical practice. The study identified those skills that most need improvement in the treatment of pain (scientific and technical knowledge and clinical decision-making capacity of professionals) in order to reduce the unjustified variability in current clinical practice.

Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer.

AIM: To retrospectively assess the efficacy and safety of bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients with recurrent ovarian cancer and prior treatment with platinum- and taxane-based chemotherapy were included. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks plus oral cyclophosphamide 50 mg daily until disease progression or unacceptable toxicity. Response rates (RR) were determined according to RECIST criteria and by monitoring the CA 125 serum tumor marker according to Rustin's criteria. The endpoints were progression-free survival (PFS), RR, overall survival (OS), and safety. RESULTS: Thirty-eight patients were treated; 79% were platinum resistant and 21% were platinum sensitive. The median number of previous treatments was 4 (range 1-8). Seventy-nine percent of patients had received more than 2 previous lines of treatment. Eighty-one percent of patients had received gemcitabine, 76% liposomal doxorubicin, and 50% topotecan. A median of 8 (range 1-70) cycles of bevacizumab were administered. The overall RR was a complete response (CR) in 3 patients (8.1%), a partial response (PR) in 12 (32.4%), and stable disease (SD) ≥6 months in 3 (8.1%). The median PFS and OS were 4.5 and 10.7 months, respectively. Thirty-nine percent of patients were progression free for at least 6 months. In an exploratory analysis there was a significant relation of prior platinum response and performance status with the risk of progression. Grade 3-4 toxicities included anemia (1), hypertension (2), hematuria (1), arterial thrombosis in the leg (1), dyspnea (1), and intestinal fistulae (1). There were no cases of gastrointestinal perforation (GIP) or treatment-related deaths. CONCLUSION: The combination of bevacizumab and metronomic cyclophosphamide was active and well-tolerated in heavily pretreated patients with recurrent ovarian cancer.

Metastatic prostate cancer with a normal prostate-specific antigen level.

Prostate-specific antigen (PSA) is the most commonly used tumour marker for prostate cancer, both in screening and in follow-up. However, there are many false positive increases in the presence of other prostate diseases and, currently, there is no consensus regarding sensitivity and specificity of the PSA test, nor what constitutes the upper limit of normality. We report a case of a 67-year-old patient with metastatic prostate cancer who, with increased level of alkaline phosphatase and normal PSA, showed clinical and radiological evidence of progression of the disease.

Metastatic prostate cancer with a normal prostate-specific antigen level

Prostate-specific antigen (PSA) is the most commonly used tumour marker for prostate cancer, both in screening and in follow-up. However, there are many false positive increases in the presence of other prostate diseases and, currently, there is no consensus regarding sensitivity and specificity of the PSA test, nor what constitutes the upper limit of normality. We report a case of a 67-year-old patient with metastatic prostate cancer who, with increased level of alkaline phosphatase and normal PSA, showed clinical and radiological evidence of progression of the disease