An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors.

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.

Evaluating everolimus for the treatment of breast cancer.

INTRODUCTION: Everolimus is an oral drug that inhibits mTOR with immunosuppressive and antiproliferative characteristics. It is commonly used in association with exemestane in hormone receptor (HR)-positive advanced breast cancer (ABC). AREAS COVERED: The current review summarizes the publications relating to everolimus from clinical research in breast cancer. Everolimus showed treatment efficacy and an acceptable safety tolerance with the prevention of side effects in Phase II/III studies. BOLERO-2 study showed a progression-free survival improvement in patients with HR - positive ABC previously treated with aromatase inhibitors (AI) and leading to its acceptance in this indication. The absence of a post-CDK4/6 inhibitor (CDK4/6i.) study and the arrival of new drugs may raise questions about its current place in the therapeutic strategy. EXPERT OPINION: Everolimus is relevant in the management of HR - positive ABC. Because of its efficacy, acceptable tolerability and the absence of drugs that have shown a greater benefit, it remains a second-line treatment option in HR-positive, HER2 negative (score 0) patients without BRCA mutation or visceral crisis and can be discussed with fulvestrant in second line after CDK4-6i. It is likely that within 5 years this treatment will be replaced in second-line HR-positive breast cancer by new emerging treatments: drug-conjugated antibodies, tyrosine kinase inhibitors or immunotherapy in combination with chemotherapy.

Cognitive change in breast cancer patients up to 2 years after diagnosis.

BACKGROUND: Using the large nationwide French, national, multicenter, prospective cancer and toxicities (CANTO) cohort, we assessed cognitive functioning change after cancer treatments in a subgroup of breast cancer (BC) patients. METHODS: We included patients with newly diagnosed invasive stage I-III BC enrolled in the CANTO substudy focused on cognitive evaluation and healthy control women matched for age and education. Episodic and working memory, executive functions, processing speed, attention, self-report cognitive difficulties (SRCD), fatigue, anxiety and depression were assessed with neuropsychological tests and self-report questionnaires before treatment (baseline) and approximately 1 (year 1) and 2 years (year 2) after diagnosis. We used linear mixed models to study changes in cognition and tested the effect of adjuvant chemotherapy. RESULTS: We studied 276 localized BC patients (62% chemotherapy) compared with 135 healthy controls (HC). After adjustment, patients had lower baseline working memory, processing speed, and attention scores than HC (P ≤ .001), and the difference remained statistically significant over follow-up for working memory and processing speed. Executive function scores were similar between groups at baseline but decreased at year 1 among patients compared with HC (Pchange = .006). This decrease in chemotherapy patients was statistically significant compared with HC scores (Pchange < .001). After adjustment, SRCD were similar between BC patients and HC at baseline but increased in patients after treatment at year 1 (Pchange = .002). CONCLUSIONS: Cognitive difficulties are an important concern in BC patients, starting at diagnosis. Cancer treatments induce executive function decline and SRCD, which decrease over follow-up.

[French translation and adaptation of the "Return to Work Self-Efficacy' Scale - 11 items" in patients diagnosed with a cancer]. / Traduction et adaptation française du « Return to Work Self-Efficacy' scale ­ 11 items ¼ chez des patients diagnostiqués d'un cancer.

INTRODUCTION: The self-efficacy to return to work is a major psychological factor of the return to work of patients diagnosed with a cancer. However, french investigations in this field do not take this dimension into account due to the lack of a suitable tool for its assessment. The objective of this study was to provide a french translation and adaptation of the "Return to Work Self-Efficacy' scale - 11 items" (RTWSE-11), validated in dutch language in its original version. METHODS: After translation-back translation steps, completed by experts' consensus meetings, interviews were conducted with thirteen patients diagnosed with cancer in order to evaluate the degree of clarity, simplicity and ambiguity or the various elements of the french version of the RTW-SE-11. RESULTS: The main modifications inherent to the french adaptation of the questionnaire concerned the modalities of the Likert scale and the inversion of three negative items into positive items. DISCUSSION: The french translation and adaptation of the RTWSE-11 was particularly faithful to the semantic, idiomatic, functional, experiential, conceptual and operational aspects of the original version. Future work can therefore focus on the psychometrics evaluations of the questionnaire. However, this tool can already be used in clinical practice to establish an initial assessment of the ability of patients diagnosed with cancer to return to work.

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy in primary or recurrent epithelial ovarian cancer: A pilot study of 31 patients.

BACKGROUND: The feasibility and safety of oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) associated with cytoreductive surgery (CRS) was assessed in patients with peritoneal carcinomatosis resulting from primary advanced or relapsing epithelial ovarian cancer (EOC). METHODS: Thirty-one patients received neoadjuvant platin-based chemotherapy followed by oxaliplatin-based HIPEC associated with CRS as consolidation of primary therapy (n = 19) or for relapsing disease (n = 12). Grade 3/4 complications were recorded according to National Cancer Institute definitions. RESULTS: Median peritoneal carcinomatosis index (PCI) was 2.7 after neoadjuvant chemotherapy. Mean duration of surgery was 352 min (range 105-614) and median hospital stay was 11 days (range 6-87). Grade 3 toxicity was observed in nine patients: five required repeat surgery, two an invasive procedure, four rehospitalization, and three a return to the ICU. No grade 4 toxicity occurred, excepted one hypokalemia. Median progression-free survival (PFS) for primary advanced EOC was 13.2 months and 1-year PFS was 59.3%. Median PFS for relapsing patients was 14.3 months and 1-year PFS was 54.4%. CONCLUSION: CRS with oxaliplatin-based HIPEC is feasible and relatively safe in recurrent and primary EOC. HIPEC after neoadjuvant chemotherapy reduces the PCI and decreases the number of surgical procedures and morbidity. Further evaluations of this procedure are required to assess the survival benefits.

Efficacy and Safety of First-line Single-Agent Carboplatin vs Carboplatin Plus Paclitaxel for Vulnerable Older Adult Women With Ovarian Cancer: A GINECO/GCIG Randomized Clinical Trial.

IMPORTANCE: Single-agent carboplatin is often proposed instead of a conventional carboplatin-paclitaxel doublet in vulnerable older patients with ovarian cancer. Such an approach could have a detrimental effect on outcomes for these patients. OBJECTIVE: To compare the feasibility, efficacy, and safety of single-agent carboplatin every 3 weeks, weekly carboplatin-paclitaxel, or conventional every-3-weeks carboplatin-paclitaxel in vulnerable older patients with ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: This international, open-label, 3-arm randomized clinical trial screened 447 women 70 years and older with newly diagnosed stage III/IV ovarian cancer by determining their Geriatric Vulnerability Score; 120 patients with a Geriatric Vulnerability Score of 3 or higher were stratified by country and surgical outcome. Enrollment took place at 48 academic centers in France, Italy, Finland, Denmark, Sweden, and Canada from December 11, 2013, to April 26, 2017. Final analysis database lock April 2019. Data analysis was performed from February 1 to December 31, 2019. INTERVENTIONS: Patients were randomized to receive 6 cycles of (1) carboplatin, area under the curve (AUC) 5 mg/mL·min, plus paclitaxel, 175 mg/m2, every 3 weeks; (2) single-agent carboplatin, AUC 5 mg/mL·min or AUC 6 mg/mL·min, every 3 weeks; or (3) weekly carboplatin, AUC 2 mg/mL·min, plus paclitaxel, 60 mg/m2, on days 1, 8, and 15 every 4 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was treatment feasibility, defined as the ability to complete 6 chemotherapy cycles without disease progression, premature toxic effects-related treatment discontinuation, or death. RESULTS: A total of 120 women were randomized. The mean and median age was 80 (interquartile range, 76-83; range, 70-94) years; 43 (36%) had a Geriatric Vulnerability Score of 4 and 13 (11%) had a Geriatric Vulnerability Score of 5; 40 (33%) had stage IV disease. During its third meeting, the independent data monitoring committee's recommendation led to the termination of the trial because single-agent carboplatin was associated with significantly worse survival. Six cycles were completed in 26 of 40 (65%), 19 of 40 (48%), and 24 of 40 (60%) patients in the every-3-weeks combination, single-agent carboplatin, and weekly combination groups, respectively. Treatment-related adverse events were less common with the standard every-3-weeks combination (17 of 40 [43%]) than single-agent carboplatin or weekly combination therapy (both 23 of 40 [58%]). Treatment-related deaths occurred in 4 patients (2 of 40 [5%] in each combination group). CONCLUSIONS AND RELEVANCE: This randomized clinical trial shows that compared with every-3-weeks or weekly carboplatin-paclitaxel regimens, single-agent carboplatin was less active with significantly worse survival outcomes in vulnerable older patients with ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02001272.

Clinical and survival impact of FDG PET in patients with suspicion of recurrent cervical carcinoma.

PURPOSE: The aim of this retrospective study was to evaluate the contribution of (18)F-FDG PET to the clinical management and survival outcome of patients suspected of recurrent cervical carcinoma and in line with the hypothesis that early diagnosis of recurrent cervical cancer may improve overall survival. METHODS: A total of 40 patients underwent conventional imaging (CI) and FDG PET/CT for suspected cervical cancer. Clinical management decisions were recorded with CI and additional PET/CT. Discordances and concordances between CI and PET/CT results were compared to the final diagnosis as based on histopathology analysis or follow-up considered as the gold standard. RESULTS: The final diagnosis was established pathologically (n = 25) or by median clinical follow-up for 48 months after the PET (n = 15). The PET/CT was positive in 76% (20/26) of patients compared to 19% (6/26) with CI. Globally PET/CT modified the treatment plan in 55% (22/40) of patients and in 75% (18/24) when the CI was negative prior to PET/CT. These changes led to the use of previously unplanned therapeutic procedures in 37.5% (15/40). When FDG PET was positive for recurrence (> 3 foci), the median overall survival was 12 months (2-70) compared to patients with PET findings with < or = 1 focus for which the median survival was not attained (p = 0.007). A multivariate analysis of prognostic factors demonstrated that abnormal FDG uptake (> 3 foci) was the most significant factor (p < 0.03) for death from cervical cancer. CONCLUSION: FDG PET is a valuable tool in the case of suspected recurrence of cervical cancer on account of its impact on treatment planning and especially in predicting patient outcome.

Pertuzumab for the treatment of breast cancer.

Introduction: Pertuzumab, a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), inhibits the heterodimerization of HER2 with other HER receptors. It has been approved both by the Food and Drug Administration and the European Medicine Agency in the metastatic, neoadjuvant and adjuvant setting.Areas covered: This review analyses and discusses preclinical and clinical studies of pertuzumab in breast cancer. In this article, we review the status of pertuzumab, the completed and ongoing trials, and its safety.Expert opinion: Pertuzumab is a key drug for the treatment of HER2-positive metastatic or early breast cancer. However, it is imperative to identify patients that will need dual-targeting and mechanisms of resistance. Moreover, the value of pertuzumab beyond progression needs to be evaluated.

Pharmacokinetic drug evaluation of abemaciclib for advanced breast cancer.

INTRODUCTION: The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.

Benefits versus risk profile of buparlisib for the treatment of breast cancer.

Introduction: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination. Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib. Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α-selective PI3K inhibitors for ongoing and future trials.

An Update on the Clinical Use of CDK4/6 Inhibitors in Breast Cancer.

Deregulated cell division, resulting in aberrant cell proliferation, is one of the key hallmarks of cancer. Cyclin-dependent kinases (CDKs) play a central role in cell cycle progression in cancer, and the clinical development of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has changed clinical practice in the setting of endocrine-receptor positive breast cancer. Results of pivotal phase II and III trials investigating these CDK4/6 inhibitors in patients with endocrine receptor-positive, advanced breast cancer have demonstrated a significant improvement in progression-free survival, with a safe toxicity profile. No validated biomarkers of sensitivity or resistance exist at the moment. Future development of CDK4/6 inhibitors in breast cancer should focus on the identification of predictive biomarkers, the development of drug combinations to overcome resistance, and the application of CDK4/6 inhibitors to other breast cancer subtypes.

Efficacy of buparlisib in treating breast cancer.

INTRODUCTION: Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different tumor types. Areas covered: Buparlisib is one of the most investigated PI3K inhibitors. Preclinical and clinical studies of buparlisib in breast cancer are analyzed and discussed. This article reviews the status of buparlisib, completed and ongoing trials, and its safety. Expert opinion: PI3K inhibitors show promising results in breast cancer. However, we raise a number of issues including the identification of biomarkers to predict treatment response and strategies to counteract resistance. Moreover, its toxicity profile could limit its extensive use.

Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy.

Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway. The strategy of combined hormone therapy with targeted agents has shown an improvement of progression-free survival (PFS) in several phase II or III trials, including three different classes of drugs: mTOR inhibitors, PI3K and CDK4/6 inhibitors. A recent phase III trial has shown that fulvestrant combined with a CDK 4/6 inhibitor doubles PFS in aromatase inhibitor-pretreated postmenopausal ER+ breast cancer. Other combinations are ongoing to disrupt the interaction between PI3K/AKT/mTOR and cyclin D/CDK4/6/Rb pathways. Despite these successful strategies, reliable and reproducible biomarkers are needed. Tumor genomics are dynamic over time, and blood-based biomarkers such as circulating tumor DNA represent a major hope to elucidate the adaptive mechanisms of endocrine resistance. The optimal combinations and biomarkers to guide this strategy need to be determined.

Taxanes in adjuvant breast cancer setting: which standard in Europe?

The clinical studies of cooperators groups (trials CALGB 9344, NSABP-B-28, BCIRG 001, PACS01 and CALGB 9741) demonstrated, in the adjuvant breast cancer setting, that taxanes (paclitaxel and docetaxel) improved both disease free and overall survival (trials CALGB 9344, BCIRG 001 and PACS 01). However, the debate remains open in Europe. Less than 50% of the expert present at the last St. Gallen Conference recommended the use of taxanes in adjuvant setting. The reasons for this are primarily related to the fact that the comparator arms of cooperators group (AC, FAC and FEC 100) are considered by some Europe groups as being less effective than the European standards (chemotherapy (CMF) and Epirubicine-CMF). Many questions remain unanswered, including whether the use of taxanes should be sequential or concomitant, and which population would benefit from such a treatment: patients with hormone-receptor negative disease and/or the HER-2 positive tumors?

[Cancer screening practices in elderly with dementia]. / Étude des pratiques de dépistage du cancer chez la personne âgée ayant une démence.

Current demographic trends and medical practices raise the question of cancer screening in the elderly, especially those with dementia. Furthermore, studies have suggested that patient with Alzheimer disease showed a reduced risk of cancer. However, this link may be biased by the absence of cancer screening. That's why we conducted a survey to poll general practitioners' (GP) opinion on screening cancer in the elderly. In this study, 304 general practitioners were asked, from May to March 2014, about their cancer screening practices and on the elements influencing it. Eighty-two physicians responded. The rate of response was 29.4%. Forty-nine (60%) GP said practicing cancer screening in the elderly, 60 (64%) thought that screening does not lead to treatment, 51 (62%) GP were not favorable to cancer screening in patients with dementia, 63 (77%) GP thought that there is a lack of recommendations to guide cancer screening in the elderly. Finally, this study shows that cancer screening is less performed in patients with dementia. Further, promote exchange between general practitioners and specialists, by strengthening Cancer and Geriatrics networks, could probably increase cancer screening in the elderly, with or without dementia.

[Her2 positive breast cancer: practices]. / Les cancers du sein HER2 : que devons-nous retenir dans notre pratique clinique quotidienne ?

The molecular classification of Perou and Sørlie breast tumors has to streamline, systematize and make effective use of targeted therapies against specific molecular subtypes, including breast HER2 positive. Trastuzumab and lapatinib are currently the two therapies targeting HER2, which have demonstrated their effectiveness in clinical practice. This literature review aims to make the data points on pertinent and useful data for physicians in daily.

NY-ESO-1-specific circulating CD4+ T cells in ovarian cancer patients are prevalently T(H)1 type cells undetectable in the CD25+ FOXP3+ Treg compartment.

Spontaneous CD4(+) T-cell responses to the tumor-specific antigen NY-ESO-1 (ESO) are frequently found in patients with epithelial ovarian cancer (EOC). If these responses are of effector or/and Treg type, however, has remained unclear. Here, we have used functional approaches together with recently developed MHC class II/ESO tetramers to assess the frequency, phenotype and function of ESO-specific cells in circulating lymphocytes from EOC patients. We found that circulating ESO-specific CD4(+) T cells in EOC patients with spontaneous immune responses to the antigen are prevalently T(H)1 type cells secreting IFN-γ but no IL-17 or IL-10 and are not suppressive. We detected tetramer(+) cells ex vivo, at an average frequency of 1:25,000 memory cells, that is, significantly lower than in patients immunized with an ESO vaccine. ESO tetramer(+) cells were mostly effector memory cells at advanced stages of differentiation and were not detected in circulating CD25(+)FOXP3(+)Treg. Thus, spontaneous CD4(+) T-cell responses to ESO in cancer patients are prevalently of T(H)1 type and not Treg. Their relatively low frequency and advanced differentiation stage, however, may limit their efficacy, that may be boosted by immunogenic ESO vaccines.

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

RATIONALE: Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. DESIGN AND METHODS: In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. RESULTS: Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. CONCLUSION: This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderly women <85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment.