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Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.Funding: Merck Sharp & Dohme. [ABSTRACT FROM AUTHOR]

Introduction The necessity of using granulocyte-colony stimulating factor (G-CSF) during dose-dense (DD) paclitaxel (T) after doxorubicin and cyclophosphamide (AC) is unclear. Methods This was a retrospective cohort study including patients with stage I-III breast cancer treated at Dana-Farber Cancer Institute with adjuvant DD-ACT between January 2011 and December 2013. Descriptive analyses evaluating patterns of G-CSF utilization during T were performed. Results Overall, 156 patients were treated with DD-ACT by 26 providers. The majority of patients (135, 87%) received at least one dose of G-CSF during T (group 1), 17% of these patients received it in only one cycle and 48% received it in all four cycles. Reasons for omitting G-CSF included high baseline absolute neutrophil count and pain. Twenty-one (13%) patients did not receive any G-CSF during T (group 2). Respectively, 94% and 90% of patients completed the treatment in groups 1 and 2. There were no cases of treatment cessation due to neutropenia. Six percent of patients in group 1 had at least one treatment delay. There were no treatment delays reported in group 2. Variation in the use of G-CSF by provider and by patient was found, with 11 providers choosing not to use G-CSF in at least one patient. Conclusions We identified substantial variation in the use of G-CSF within the practice. However, omission of G-CSF was not associated with treatment delays or adverse events. Prospective studies are warranted to formally test whether routine G-CSF is necessary during dose-dense T therapy. [ABSTRACT FROM AUTHOR]

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we investigated the relative benefits of adding rituximab to CHOP chemotherapy in diffuse large B-cell lymphoma (DLBCL) of extranodal origin, and found similar advantage for nodal and extranodal lymphomas. Hazard ratio for overall survival was 0.64 for nodal, and 0.70 for extranodal DLBCL. Hazard ratios for lymphoma-related death were 0.62 and 0.57, respectively. The advantage was largest for DLBCL of the spleen, liver and lung. Conversely, it was not evident for thyroid or testicular lymphomas. Compared with nodal DLBCL, spleen was the only site with significantly better prognosis after R-CHOP. [ABSTRACT FROM AUTHOR]

Abstract: Acute myeloid leukemia with inv3(q21q26.2)/t(3,3)(q21;q26.2) is a subtype of acute myeloid leukemia associated with significant dysmyelopoiesis and a poor prognosis. In more than a half of the cases, there is also monosomy 7. We present 2 young male patients with de novo acute myeloid leukemia with inversion 3 and monosomy 7 who had significant morphologic and immunophenotypical similarities. Both patients had circulating subsets of blasts with unusual intracytoplasmic basophilic granules and prominent bone marrow dysmegakaryopoiesis. The leukemic myeloid blasts were negative for myeloperoxidase and had aberrant coexpression of CD2 and CD31. Despite their morphologic and immunophenotypical similarities, only 1 of the patients achieved remission and remained free of disease 24 months after bone marrow transplant. The younger patient, who had also increased hemoglobin F and an associated FLT3 D835 variant, had an acute myeloid leukemia refractory to chemotherapy and died 4 months after his diagnosis. [Copyright &y& Elsevier]

Abstract: Objectives: Patients ≥65years old (“older”) are often not included in randomized clinical trials (RCT), but when they are, care in an RCT might improve quality of life (QoL). We conducted a prospective comparison of QoL among older women receiving standard chemotherapy from the same cooperative group physicians in an RCT vs. an observational study (“off-trial”). Methods: Older women with invasive, non-metastatic breast cancer (n=150 RCT; 530 off-trial) were included. Linear mixed-effects models tested associations between chemotherapy on- vs. off-trial and changes in EORTC (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) QoL scores over 24months, controlling for pre-treatment QoL, age, education, tumor factors, comorbidity, and other covariates. Results: Anthracycline regimens were used by 58% of women treated on-trial vs. 54% of those treated off-trial. Women in the RCT reported an adjusted mean increase of 13.7 points (95% CI 10.2, 17.1) in global QoL at 24months (vs. mid-treatment), while women treated off-trial had only an adjusted improvement of 7.0 points (95% CI 3.5, 10.4; p=.007 for difference in mean changes). Women in the RCT had significantly greater improvement in emotional function than those treated off-trial, controlling for baseline; they also had greater reductions in therapy side effects and fatigue at 24months than women off-trial, controlling for covariates. Conclusion: There may be different QoL trajectories for older women undergoing breast cancer chemotherapy on- vs. off-trial. If confirmed, the results suggest that the extra monitoring and communication within an RCT could provide the infrastructure for interventions to address symptoms and improve QoL for the growing older cancer population. [Copyright &y& Elsevier]

Abstract: Background: Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. Methods: 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan–Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. Results: Median OS was 3.5 years (95% CI 3.0–4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1–5.9, liver/lung: 3.2 years CI 2.5–4.2, other: 4.6 years CI 2.7–8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. Conclusions: The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy. [Copyright &y& Elsevier]

Abstract: In clinical practice, the surveillance and follow-up of patients with breast cancer (BC) is quite variable. At the 7th European Breast Cancer Conference, the ESO-MBC Task Force convened a series of lectures, followed by open debate, on the use of physical examination, imaging, and laboratory tests in patients with early-stage BC, and for restaging evaluations and follow-up among patients with MBC. Based on the available data, the Task Force recommends against intensive, routine radiologic or blood-based surveillance (with the exception of mammography) in patients with early-stage BC. As systemic therapies for MBC continue to improve, this question might be re-visited in the context of a carefully controlled clinical trial in specific BC subtypes. For patients with MBC, response to therapy should generally be assessed 2–3 months after initiation of treatment, and thereafter every 2–4 months for endocrine therapy or every 2–4 cycles for chemotherapy, depending on the dynamics of the disease, the location and extent of metastatic involvement, and type of treatment. Additional testing should be performed irrespective of the planned intervals if progression of disease is suspected (e.g. in the case of specific symptoms). Use of tumor markers is not recommended for surveillance of early-stage patients, but may be helpful in monitoring response to therapy in patients with metastatic disease. However, change in tumor markers alone should not be used for decision-making. Moving forward, enhanced efforts to document quality of life over time should be made in order to more fully evaluate the risk/benefit ratio of available options. [Copyright &y& Elsevier]

Abstract: Cardiovascular toxicity is a potential short- or long-term complication of anticancer therapy. Exposure to chemotherapy medications, primarily the anthracycline class, can lead to potentially irreversible clinically significant cardiac dysfunction. The advent of novel biologic agents, including monoclonal antibodies and tyrosine kinase inhibitors, has revolutionized the treatment of several types of malignancies. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare serious complications have been observed; and longer-term follow-up is needed to determine the exact profile of related cardiac adverse effects. Cardiac toxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes. Assessment of the prevalence, type, and severity of cardiac toxicity caused by various cancer treatments is a critical topic for patient management and specifically for new drug development. Guidelines for monitoring cardiac adverse effects have been formulated; however, appropriate supportive evidence remains limited. Given the rate of new drug development designed to fulfill unmet oncologic needs, efforts are needed to promote strategies for cardiac risk detection and management and to avoid unintended consequences potentially impeding development of, regulatory approval for, and patient access to novel therapies. These advances require ongoing research to assess and manage the cardiovascular safety of patients treated with anticancer agents, as well as a well-organized collaboration between oncologists and cardiologists. The aim of this review is to summarize potential cardiovascular toxicities for a range of cancer chemotherapeutics and to review general mechanisms of cardiovascular toxicity for each agent. [Copyright &y& Elsevier]

Abstract: Approximately 180,000 women are diagnosed with breast cancer in the United States annually. The majority of these women are postmenopausal and have endocrine-sensitive tumors. Over the last four decades, multiple clinical trials have been conducted in efforts to establish and advance adjuvant endocrine therapies. We review the available evidence for adjuvant endocrine therapies and current recommendations for therapy in postmenopausal women. Although we have made substantial progress in the treatment of endocrine-sensitive breast cancer, future study will require incorporation of biological and translational questions with the goal of enhancing treatment benefits and minimizing toxicity. [Copyright &y& Elsevier]

Since the approval of rituximab in 1997, monoclonal antibodies have come to play an important role in the therapy of hematological malignancies. Rituximab, gemtuzumab ozogamicin, and alemtuzumab are US Food and Drug Administration–approved for treatment of B-cell lymphomas, acute myeloid leukemia, and chronic lymphocytic leukemia, respectively. Multiple monoclonal antibodies directed against new and not-so-new cellular antigens are undergoing development and investigation all over the world. Most of these new compounds have undergone primatization or humanization, improving their specificity and decreasing their antigenicity when compared to earlier murine or chimeric products. This review will focus on three major aspects of monoclonal antibody therapy: 1) new therapeutic approaches with currently approved agents; 2) preclinical and clinical experience accumulated on new agents in the last few years; discussion will include available phase I, II, and III data on ofatumumab, epratuzumab, CMC-544, HeFi-1, SGN-30, MDX-060, HuM195 (lintuzumab), galiximab, lumiliximab, zanolimumab, and apolizumab; and 3) the role of naked and radiolabeled monoclonal antibodies in the hematopoietic stem cell transplantation setting. [Copyright &y& Elsevier]

Summary: Purpose: To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5mcg/kg/day) in this setting. Patients and Methods: Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000mg/m2/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175mg/m2 by 3h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected. Results: One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence). Conclusion: The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status. [Copyright &y& Elsevier]

Abstract: In the US, over 200,000 new cases of invasive breast cancer are diagnosed each year, with an additional 60,000 cases of ductal carcinoma in situ. The majority of these women will never experience a recurrence of their disease, and most will survive more than 5 years. Follow-up care for these women is focused on addressing long-term complications of therapy, and early detection of new primary cancers and locoregional recurrences. There is no evidence that early detection of distant metastases will lead to an increase in survival, and currently routine imaging studies are not recommended. With the growing number of breast cancer survivors, further studies should be undertaken to study the cost-effectiveness of surveillance strategies. [Copyright &y& Elsevier]

Summary: In the United States alone, over 200,000 women are diagnosed with invasive breast cancer each year, and another 50,000 are diagnosed with ductal carcinoma in situ. The vast majority of these women will survive for five or more years, and the majority will never experience a recurrence of their disease. Follow-up care is focused on the early identification of new primary cancer and locoregional recurrences. There is no clear evidence that early identification of distant metastases will lead to an extension in survival, and for this reason routine imaging studies such as CT and PET scans are not recommended. Comprehensive care for breast cancer survivors should also address late complications of treatment and ongoing psychosocial problems that may have arisen as a result of a breast diagnosis and treatment. Although subspecialists often provide follow-up care for breast cancer survivors, randomized trials have demonstrated that generalists can provide such care. As the number of breast cancer survivors continues to increase, guidelines and programs to provide comprehensive, compassionate, and cost-effective follow-up care will become ever more important. [Copyright &y& Elsevier]

Abstract: Introduction: Little is known about quality of life and symptoms of male breast cancer survivors. Patients and methods: We recruited men with stage 0–4 breast cancer for an on-line survey through www.outoftheshadowofpink.com, www.malebreastcancer.org, and www.malebreastcancer.ca. Surveys included Expanded Prostate Cancer Index Composite (EPIC) Hormonal/Sexual Scales, Hospitalized Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy-Breast (FACT-B), sociodemographic/disease-related, genetic, and fertility-related items. Results: Forty-two responded. Mean EPIC Sexual and Hormonal scores were 44.5 and 81.3, respectively, suggesting symptom burden. Mean FACT-B score was 111.1, consistent with impaired overall quality of life. Conclusions: Male survivors experience substantial sexual and hormonal symptoms. [Copyright &y& Elsevier]

A commentary about the use of adjuvant chemotherapy in women with estrogen receptor (ER)-negative or ER-positive tumors is presented. The authors explain how the biological characteristics of breast tumors could theoretically influence the benefit of chemotherapy in at least two ways. They believe the ER status is a real and important indicator of chemotherapy benefit. They claim that more studies are needed to determine the association between ER status and/or tumor subtypes and specific chemotherapy agents.

Cytotoxic chemotherapy remains the systemic therapy of choice for triple-negative breast cancer (TNBC), a poor-prognosis subtype of breast cancer. Growing data focusing on TNBC provides an opportunity to assess if we can tailor adjuvant chemotherapy based on patient and tumor characteristics. The standard of care for moderate-to-high risk TNBC remains a sequential anthracycline-taxane combination, with the potential for shorter and less toxic regimens in stage I disease. Platinums are promising in the neoadjuvant and metastatic settings but we await long-term outcome data before incorporation into standard regimens in the adjuvant setting. Specific subgroups within TNBC, such as BRCA mutation carriers, require special attention, and the role of platinums in these patients warrants further consideration. There is hope that in the future, further subdividing TNBC by gene expression profile, mutation, immune infiltrate, and others will reveal novel susceptibilities. [ABSTRACT FROM AUTHOR]

Summary: Luminal breast cancers are traditionally considered to comprise of tumors expressing estrogen receptor (ER) and represent the majority of breast cancers. These tumors are characterized by significant heterogeneity in phenotype, molecular signature, relapse patterns and therapeutic response to endocrine and chemotherapy. Whilst adjuvant endocrine therapy is standard of care in patients with tumors that express either ER and/or progesterone receptor (PR), the indication for adjuvant chemotherapy is less clear-cut. On average, ER-positive breast tumors derive less benefit from chemotherapy compared to ER-negative tumors, however there is still clearly a subset of patients with ER-positive tumors that are chemosensitive. The basis for the addition of chemotherapy to adjuvant endocrine therapy is usually guided by the clinician''s estimation of prognosis and assessment of the endocrine sensitivity of the tumor. The use of chemotherapy in this setting, however, is highly variable. There is tremendous value in identifying subgroups of patients who can expect favorable outcomes with endocrine therapy and who may not require any additional therapy. Similarly, it is equally important, if not more important, to characterize patients with ER-positive disease who will derive a substantial benefit from cytotoxic chemotherapy. In this article, we aim to discuss the utility of current biomarkers used to guide decisions regarding chemotherapy in ER-positive, HER2-negative breast cancers. [Copyright &y& Elsevier]

The risk of breast cancer-specific mortality (BCSM) persists for at least 20 years from diagnosis. Estimating the risk of BCSM over this extended period along with competing risks of death would aid clinical decision-making. We aimed to develop an interactive tool called 'ESTIMATE', to explore the Surveillance, Epidemiology, and End Results (SEER) registry to quantify residual risks of BCSM, non-BCSM and all-cause mortality in non-metastatic, hormone receptor (HR)-positive breast cancer patient subgroups at any given time after diagnosis, up to 20 years. Using SEER data, we included 264,237 women with invasive, non-metastatic, HR-positive breast cancer diagnosed from 1990 to 2006. We developed a tool that provides a nonparametric estimate of the residual cumulative risk of BCSM and non-BCSM by year 20 after any specified time from initial diagnosis, among patients defined by baseline clinical and pathologic variables, using Gray's subdistribution method. ESTIMATE allows the user to input patient and tumour characteristics and the preferred timeframe. For example, patients in the age group of 40–49 diagnosed with T1cN1, grade II breast cancer who survived 7 years, have a 14% (95% confidence interval [CI]: 11.9%–16.1%) residual cumulative risk of BCSM in the next 13 years, and a 6.4% (95% CI: 4.7%–8.1%) residual cumulative risk of non-BCSM over the same period. ESTIMATE provides population-based risks of BCSM, non-BCSM and all-cause mortality through 20 years after diagnosis of HR-positive breast cancer, based on patient and tumour characteristics. ESTIMATE can inform discussions about prognosis, a balance between competing risks and aid clinical decision-making. • The risk of BCSM persists for at least 20 years from diagnosis. • We developed a tool, 'ESTIMATE', for non-metastatic, HR-positive breast cancer. • The tool quantifies risks of BCSM, non-BCSM and all-cause mortality. • Risk estimates can be quantified at any given time after diagnosis, up to 20 years. • The tool can be used to understand competing risks and aid clinical decision-making. [ABSTRACT FROM AUTHOR]

Introduction During induction daunorubicin intensification from 45 mg/m 2 /day to 90 mg/m 2 /day has shown improved response and survival rates in AML patients. We retrospectively reviewed outcomes of daunorubicin 60 mg/m 2 /day (DNR60) versus daunorubicin 90 mg/m 2 /day (DNR90) in adult AML patients. Material and methods Newly diagnosed AML patients ≥18 years who received 7 + 3 with or without etoposide as frontline therapy from 1/1/2006 to 5/1/2013 were identified. Chi-square and Wilcoxon rank sum tests were used to compare characteristics. Kaplan–Meier curves were estimated for overall survival (OS). Univariate and multivariate Cox proportional hazard regression models were developed to determine independent predictors for survival. Results A total of 128 patients were included (DNR90 = 48 patients, DNR60 = 80 patients). The estimated 3-year OS rate in the DNR90 group was 56% (95% CI 38–70%), while in the DNR60 group was 34% (95% CI 23–44%). Multivariate analysis (MVA) in non-allotransplanted patients showed that unfavorable cytogenetics and worse performance status were associated with decreased OS while DNR intensification, etoposide use and site were associated with improved OS. In MVA of allotransplanted patients re-induction based on day-14 marrow was associated with worse OS. Conclusions Based on our retrospective study, initial DNR based induction chemotherapy intensification improved OS in non-allotransplanted patients. Prospective studies are needed to confirm this preliminary finding. [ABSTRACT FROM AUTHOR]

Purpose: Human epidermal growth factor receptor 2 (HER2)-directed therapy improves local control among women with HER2-positive breast cancer. This retrospective analysis evaluates the safety and efficacy of radiation therapy (RT) among patients receiving adjuvant trastuzumab emtansine (T-DM1) or paclitaxel (T) plus trastuzumab (H) in the ATEMPT (Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab) trial; Translational Breast Cancer Research Consortium (TBCRC) 033.Methods and Materials: Patients with stage I HER2-positive breast cancer were randomized 3:1 to receive adjuvant T-DM1 or TH after mastectomy or breast-conserving surgery (BCS). Breast RT was required after BCS and permitted after mastectomy. Patients receiving T-DM1 began RT after 12 weeks of therapy and received RT concurrently with T-DM1. Patients receiving TH began RT after paclitaxel, but concurrent with trastuzumab. RT records were retrospectively reviewed to determine details of radiation delivery and acute RT-related toxicity.Results: Protocol therapy was initiated by 497 patients. Among the 299 BCS patients, 289 received whole breast RT (WBRT) and 10 partial breast. Among WBRT patients, 40.2% in the T-DM1 arm and 41.5% of TH patients received hypofractionated (≥2.5 Gy/fraction) RT. Eight mastectomy patients received RT, all conventional fractionation. Skin toxicity (grade ≥2) was seen in 33.9% of patients in the T-DM1 arm and 23.2% in the TH arm (P = .11). In conventionally fractionated WBRT patients, 44.7% had a grade ≥2 skin toxicity compared with 17.9% of patients receiving hypofractionation (P < .001). Five patients experienced pneumonitis after RT (T-DM1: n = 4, 1.0%; TH: n = 1, 0.9%). Three-year invasive disease-free survival was 97.8% for T-DM1 (95% confidence interval, 96.3-99.3) and 93.4% for TH (95% confidence interval, 88.7-98.2). Among the 18 invasive disease-free survival events, 7 were isolated locoregional recurrences (2, T-DM1; 5, TH).Conclusions: RT was well-tolerated when given concurrently with either T-DM1 or TH. Among BCS patients, hypofractionation resulted in lower grade ≥2 acute skin toxicity even with concurrent anti-HER2 therapy. Although follow-up was short, local recurrences were uncommon, attesting to the efficacy of HER2-directed therapy combined with RT. [ABSTRACT FROM AUTHOR]

• Joint scRNA-seq and JAK2 genotyping were performed for patients with myeloproliferative neoplasms. • Interferon response genes are significantly more highly expressed in JAK2-V617F hematopoietic progenitors. • Monocytes with JAK2–V617F have a pro-inflammatory, intermediate monocyte phenotype. • JAK2–V617F monocytes express SLAMF7, which is associated with fibrosis in MPNs. The JAK2–V617F mutation is the most common cause of myeloproliferative neoplasms. Although experiments have revealed that this gain-of-function mutation is associated with myeloid blood cell expansion and increased production of white cells, red cells, and platelets, the transcriptional consequences of the JAK2–V617F mutation in different cellular compartments of the bone marrow have not yet been fully elucidated. To study the direct effects of JAK2–V617F on bone marrow cells in patients with myeloproliferative neoplasms, we performed joint single-cell RNA sequencing and JAK2 genotyping on CD34+-enriched cells from eight patients with newly diagnosed essential thrombocythemia or polycythemia vera. We found that the JAK2–V617F mutation increases the expression of interferon-response genes (e.g., HLAs) and the leptin receptor in hematopoietic progenitor cells. Furthermore, we sequenced a population of CD34– bone marrow monocytes and found that the JAK2 mutation increased expression of intermediate monocyte genes and the fibrocyte-associated surface protein SLAMF7 in these cells. [ABSTRACT FROM AUTHOR]

Purpose: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC.Methods and Materials: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD.Results: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort.Conclusions: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively. [ABSTRACT FROM AUTHOR]

Background: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.Methods: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).Findings: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.Interpretation: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.Funding: Pfizer. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.Findings: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).Interpretation: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.Funding: F Hoffmann-La Roche and Genentech. [ABSTRACT FROM AUTHOR]

Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55–39.3, p = 0.007). In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort. • Only 8 % of patients developed post-induction ARLVD. • Reduction in LVEF was the deciding factor in determining allo-SCT eligibility in only 14 % of patients with ARLVD. • Presence of a JAK2 mutation was associated with a significantly increased risk of ARLVD. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is associated with a high risk of breast cancer-specific mortality (BCSM). Estimating the risk of BCSM and non-BCSM in TNBC would aid clinical decision-making. We developed the tool 'ESTIMATE-TN', to assess BCSM, non-BCSM, and all-cause mortality in non-metastatic TNBC. Using Surveillance, Epidemiology, and End Results (SEER), we created an interactive tool that provides a nonparametric estimate of the cumulative risk of BCSM and non-BCSM between years 0 and 7 from diagnosis, accounting for baseline clinical and pathologic variables, using Gray's subdistribution method. We included 37,293 women with TNBC diagnosed during 2010–2017. Most patients were White (71.9%) and aged 50–69 years (51.3%). Most tumour characteristics were high-grade (78.6%), T2 (42.4%), and N0 (69.5%). ESTIMATE-TN allows to input patient and tumour characteristics, and the preferred timeframe. For example, patients aged 50–59 years with a new diagnosis of T2, N1, high-grade TNBC have a risk of BCSM at 7 years of 30.8% (95% confidence interval [CI]: 26.3–35.4%) and a risk of non-BCSM over the same period of 2.8% (95% CI: 1.3–4.3%). After 3 years from initial diagnosis, the residual cumulative risks of BCSM and non-BCSM at 7 years are 17.4% (95% CI: 12.6–22.2%) and 1.1% (95% CI: 0–2.5%), respectively. ESTIMATE-TN is an interactive tool for TNBC that can be used to integrate population-based risks of BCSM and non-BCSM based on patient and tumour characteristics, facilitating our understanding of competing risks of death, which can aid clinical decision-making. • TNBC is associated with a high risk of BCSM. • We developed a tool, 'ESTIMATE-TN', for non-metastatic TNBC. • The tool quantifies risks of BCSM, non-BCSM, and all-cause mortality. [ABSTRACT FROM AUTHOR]

1. Identify the name and role of the family caregivers involved in the oncology patient's care during the ambulatory care visit 2. Assemble a list of community-based and hospital-based resources that offer support for family caregivers to any family caregiver in need As cancer care has shifted from inpatient to ambulatory settings, family members assume additional caregiving responsibility without the same close attention of an inpatient care team. Family caregivers' needs in the ambulatory setting are often underaddressed, and little is known about what specific support is lacking. To identify the recommendations of family caregivers from diverse racial and ethnic backgrounds for improving their experience of providing care to ambulatory patients with newly diagnosed advanced cancer in community- and academic-based ambulatory settings. We conducted semistructured interviews in caregivers of adults with newly diagnosed advanced solid tumors and hematologic malignancies receiving outpatient oncology care (n = 20). Interviews were recorded, transcribed, and analyzed via open, line-by-line, and inductive coding until thematic saturation was reached. Three primary recommendations emerged from these family caregivers. First, they expressed a desire to feel acknowledged by both the clinical care team and people in their community. Therefore, family caregivers recommended that health systems establish routine check-ins to assess and support them throughout the illness trajectory. Second, they asked that clinicians facilitate their positive adaptation to poor prognosis, including how they might face and accept the reality of prognosis and be involved in care decisions. Finally, family caregivers recommended that clinicians share resources and information on who, when, and how to access support in advance of their need for these services. Family caregivers offered key recommendations to enhance caregiver wellbeing when caring for patients with advanced cancer in the ambulatory care setting. Institutions should consider routine check-ins to assess caregiver wellbeing and interventions to help caregivers adapt to prognosis and access information about support services. Family caregiver roles are rapidly evolving due to shifts in cancer care toward ambulatory settings. Increased efforts are needed to promote wellbeing in this unique caregiver population. [ABSTRACT FROM AUTHOR]

Background: Management of the axilla in stage II/III breast cancer undergoing neoadjuvant systemic therapy (NST) is controversial. To understand current patterns of care, we collected axillary data from 2 NST trials: HER2-positive (Cancer and Leukemia Group B [CALGB] 40601) and triple-negative (CALGB 40603).Study Design: Axillary evaluation pre- and post-NST was per the treating surgeon and could include sentinel node biopsy. Post-NST, node-positive patients were recommended to undergo axillary lymph node dissection (ALND). We report pre-NST histopathologic nodal evaluation and post-NST axillary surgical procedures with correlation to clinical and pathologic nodal status.Results: Seven hundred and forty-two patients were treated, 704 had complete nodal data pre-NST and post-NST. Pre-NST, 422 (60%) of 704 patients underwent at least 1 procedure for axillary node evaluation (total of 468 procedures): fine needle aspiration (n = 234; 74% positive), core needle biopsy (n = 138; 72% positive), and sentinel node biopsy (n = 96; 33% positive). Pre-NST, 304 patients were considered node-positive. Post-NST, 304 of 704 patients (43%) underwent sentinel node biopsy; 44 were positive and 259 were negative (29 and 36 patients, respectively, had subsequent ALND). Three hundred and ninety-one (56%) patients went directly to post-NST ALND and 9 (1%) pre-NST node-positive patients had no post-NST axillary procedure. Post-NST, 170 (24%) of the 704 patients had residual axillary disease. Agreement between post-NST clinical and radiologic staging and post-NST histologic staging was strongest for node-negative (81%) and weaker for node-positive (N1 31%, N2 29%), with more than half of the clinically node-positive patients found to be pathologic negative (p < 0.001).Conclusions: Our results suggest there is no widely accepted standard for axillary nodal evaluation pre-NST. Post-NST staging was highly concordant in patients with N0 disease, but poorly so in node-positive disease. Accurate methods are needed to identify post-NST patients without residual axillary disease to potentially spare ALND. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) are essential for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and have allowed for effective, low intensity induction regimens including no or minimal chemotherapy. Whether the use of low intensity induction regimens impacts outcomes after allogeneic hematopoietic stem cell transplant (alloHCT) is less understood. We identified consecutive adult patients with Ph+ ALL undergoing alloHCT in first complete remission (CR1) at our center from 2010 to 2021 and examined the impact of pre-transplant induction intensity on outcomes. Among the 87 identified patients, 44 (51%) received low intensity induction and 43 (49%) received induction with high intensity chemotherapy. Patients receiving low intensity induction were older (median age 60 vs. 47 years, p < 0.01). Following induction, measurable residual disease (MRD) negativity by BCR::ABL1 RT-PCR was similar in the low and high intensity induction cohorts (54% and 52% respectively). Receipt of reduced intensity transplant conditioning was not associated with intensity of induction regimen (39% vs. 19% in low vs. high, respectively, p = 0.06). At a median follow-up of 21 months from transplant, there was no difference between low and high intensity induction with respect to 2-year disease-free survival (58% vs. 56%), 2-year overall survival (62% vs. 63%), 2-year cumulative incidence of relapse (9% vs. 17%), and 2-year non-relapse mortality (33% vs. 29%). We also found no difference in outcomes when patients were segmented by both induction and conditioning regimen intensities. Our retrospective analysis suggests that induction intensity does not impact post-transplant outcomes among patients with Ph+ ALL transplanted in CR1. [Display omitted] • TKIs have enabled the use of low intensity induction chemotherapy for Ph+ ALL. • Low intensity induction induces CR with less toxicity than conventional induction. • Induction intensity does not impact overall outcomes in Ph+ ALL transplanted in CR1. • Low intensity induction with reduced intensity conditioning is effective in Ph+ ALL. [ABSTRACT FROM AUTHOR]

Background: Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer.Methods: In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566.Findings: In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9-9·8]) and placebo (5·1 months [3·6-7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52-1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7-9·8] vs placebo 5·1 months [2·6-10·4]; HR 0·73 [95% CI 0·42-1·28]; p=0·268) or absence (5·8 months [3·6-11·1] vs 3·6 months [2·8-7·3]; HR 0·72 [0·42-1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8-8·3] vs 10·0 months [3·6-13·0]; HR 1·07 [95% CI 0·53-2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group.Interpretation: Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Summary Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Summary Background Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1 /2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov , number NCT01116648 . Findings Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7–not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7–16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). Interpretation Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. Funding American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) ( 3 U01 CA062490-16S2 ); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH. [ABSTRACT FROM AUTHOR]