Effects of an 18-Week Integrated Yoga Program on Cardiac Autonomic Function in Breast Cancer Patients Undergoing Adjuvant Chemotherapy: A Randomized Controlled Trial.

BACKGROUND: Cardiotoxicity is a commonly observed adverse effect seen in breast cancer (BC) patients undergoing chemotherapy with attributes toward cardiac autonomic dysfunction (CAD). Yoga, a mind-body system of medicine that has been shown to improve cardiac autonomic nervous system (ANS) activity in various health conditions, could be an effective adjuvant approach in addressing CAD. OBJECTIVE: This study aims to investigate the protective effects of Integrated Yoga Therapy (IYT) on ANS functioning, assessed using Heart rate variability (HRV) in breast cancer patients undergoing chemotherapy. METHODS: A total of 68 (stage I-III) BC patients were randomly assigned into 2 groups: Treatment as Usual group (TAU) and TAU with Yoga Therapy group (TAUYT). All patients underwent anthracycline-based adjuvant chemotherapy for a total of 6 cycles with 21 days/cycle. During chemotherapy, the TAUYT group received IYT 5 days a week for 18 weeks, compared with usual care alone in the TAU group. Resting heart rate (RHR) and HRV, measured in both the time and frequency domains, were used to assess the cardiac ANS function of each patient before and after 6 cycles of chemotherapy. RESULTS: A total of 30 subjects in the TAU group and 29 subjects in the TAUYT group were included in the analysis. At baseline (before chemotherapy), there were no significant differences between the TAU and TAUYT groups in terms of RHR and HRV indices. However, after chemotherapy, patients in the TAU group had a significantly higher average RHR (P < .02) and lower HRV indices with reduced parasympathetic indices: RMSSD (P < .01), pNN50% (P < .04), high-frequency power (P < .001) and increased sympathetic indices: low-frequency power (P < .001) with sympathovagal imbalance: LF/HF (P < .001) compared with patients in the TAUYT group. CONCLUSION: The study showed the protective effects of yoga therapy on CAD in patients receiving anthracycline-based chemotherapy for BC, proposing yoga as a potential adjuvant intervention in improving cardiac health and preventing cardiovascular-related morbidities. TRIAL REGISTRATION: This trial is registered with the Clinical Trials Registry-India (CTRI) database (CTRI/2020/10/028446; October 16, 2020).

Clinicopathologic characteristics, outcomes, and prognostic factors of angioimmunoblastic T-cell lymphoma in China.

BACKGROUND: This study aimed to better characterize the clinicopathologic characteristics, outcomes, and prognostic factors of AITL in China. METHODS: We retrospectively analyzed 312 patients with AITL enrolled between January 2011 and December 2020 from five institutions in China. RESULTS: The median age was 65 years, with 92.6% advanced stage, 59.7% elevated LDH, 46.1% anemia, and 44.0% hypergammaglobulinemia. The majority of patients (84.9%) received anthracycline-based regimens with or without etoposide, and only 6.1% underwent autologous stem cell transplantation following first remission. The 5-year OS and PFS estimates were 43.4% and 25.0% with no significant improvement of survival between patients treated during 2011-2015 and 2016-2020, respectively. Both the International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT), were predictive for OS. In multivariate analysis, age >70 years, elevated LDH, and albumin level <35 g/L were independent prognostic factors for OS. Combining these three factors, a novel prognostic model (the Chinese AITL score) was constructed, which stratified patients into low-, intermediate-, and high-risk groups, with 5-year OS rates of 69.0%, 41.5%, and 23.7%, respectively. This new model was successfully validated in an independent cohort. CONCLUSIONS: Patients with AITL were mainly treated with anthracycline-based regimens, and the outcomes were still unsatisfactory in China. Our novel prognostic model may improve our ability to identify patients at different risks for alternative therapies.

Impact of body mass index on survival in women receiving chemotherapy for early breast cancer.

PURPOSE: The impact of elevated body mass index (BMI) on overall survival (OS) in patients receiving modern anthracycline-taxane chemotherapy for early breast cancer (EBC) has not yet been well established. The purpose of our study was to examine overall survival (OS) by BMI category in women with EBC receiving either doxorubicin (A), cyclophosphamide (C) + paclitaxel (P) or fluorouracil (F), epirubicin (E), cyclophosphamide (C) + docetaxel (D). METHODS: This was a retrospective cohort study in patients ≥ 18 years with resected stage I-III BC diagnosed between 2007 and 2017 in Ontario, identified through linkage of administrative databases. Patients were classified according to baseline BMI into underweight (< 18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥ 30 kg/m2) World Health Organization (WHO) categories. The primary outcome was OS. Univariable and multivariable analyses were used to examine the association between clinico-pathologic characteristics and OS among BMI categories. RESULTS: Our cohort included 11,601 women, of whom 3890 (33.5%) were normal weight, 3696 (31.9%) overweight, and 3847 (33.1%) obese. Median OS was 7.9 years. There were no statistically significant differences in OS according to BMI (p = 0.66) in the overall study cohort or among the BMI categories after adjusting for age, nodal status, stage, grade, ER and HER2 status for either AC-P or FEC-D- treated patients (p = 0.45 and p = 0.97, respectively). CONCLUSIONS: Our large population-based retrospective cohort analysis of EBC patients receiving adjuvant anthracycline-taxane chemotherapy found no significant impact of BMI on OS. Further investigation is warranted to confirm these findings in prospective patient cohorts.

A multiparametric niche-like drug screening platform in acute myeloid leukemia.

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.

Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology).

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.

Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

A Retrospective Analysis of Metronomic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) Versus Docetaxel and Cyclophosphamide (TC) as Adjuvant Treatment in Early Stage, Hormone Receptor Positive, HER2 Negative Breast Cancer.

BACKGROUND: Anthracycline and taxane-based doublets have largely replaced cyclophosphamide, methotrexate, and fluorouracil (CMF) as preferred regimens in the adjuvant treatment of breast cancer. Metronomic CMF is associated with improved tolerability over anthracycline or taxane-based regimens. Previously, there have been no direct comparisons between taxane-based regimens and CMF. MATERIALS AND METHODS: We performed a retrospective review of 98 breast cancer patients treated at the Seattle Cancer Care Alliance from February 2015 through December 2018 that received either metronomic CMF or docetaxel and cyclophosphamide (TC) as adjuvant therapy for early-stage, hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2-) breast cancer. The primary outcome assessed was disease-free survival (DFS). Secondary outcomes included overall survival (OS), dose intensity, and adverse effects. RESULTS: With an average follow-up of 35.9 and 28.2 months for CMF and TC, respectively, there was no significant difference in DFS or OS between the chemotherapy regimens. DFS at 3 years was 96.7% vs. 94.3% and OS 96.7% vs. 100% for CMF and TC, respectively. There were more dose delays in the CMF group, but on average, patients receiving either regimen achieved a dose intensity ≥85%. There was a trend towards increased hospitalization or emergency department utilization (23.1% vs. 10.6%) and Grade 4 toxicities (9.6% vs. 4.3%) with TC vs. CMF. CONCLUSION: Metronomic CMF offers equivalent survival outcomes to TC and remains a viable option in the adjuvant treatment of HR+/HER2- breast cancer. There was a trend towards increased Grade 4 toxicities and hospitalizations with TC, suggesting that metronomic CMF may offer a more tolerable treatment option while maintaining excellent disease outcomes.

Cardioprotective effect of saffron total glycoside tablets in patients with breast cancer receiving anthracycline-based chemotherapy: study protocol for a multicentre, randomised, parallel, double-blind, placebo-controlled clinical trial.

BACKGROUND: Breast cancer is the most common cancer worldwide. Anthracyclines, alone or in combination with other chemotherapeutic agents, are the most effective chemotherapy agents against breast cancer. However, the dose-dependent cardiotoxicity of anthracyclines is a serious drawback in clinical treatment. Considerable efforts have been made to establish suggestions to avoid anthracycline-induced cardiotoxicity. Crocin extracted from saffron has potential cardioprotective effects against anthracycline-induced cardiotoxicity. The aim of this study was to estimate the cardioprotective effects and safety of saffron total glycoside tablets relative to placebo in patients with breast cancer undergoing anthracycline-based chemotherapy. METHODS: This is a multicentre, randomised, double-blind, placebo-controlled clinical trial. A sample of 200 participants (100 per group) with breast cancer will be randomly assigned to receive either saffron total glycoside tablet or placebo (four tablets each time, three times each day) for 6 months. Each participant will be interviewed three times: baseline (visit 1), after 3 months (visit 2), and after 6 months (visit 3). The primary outcome is to confirm if administration of saffron total glycoside tablets reduces the rate of cardiotoxicity relative to that with placebo. Secondary outcomes include new arrhythmic events, and cardiac troponin I and N-terminal pro-B-type natriuretic peptide levels. The quantity, quality, and severity of the adverse events will be carefully documented. DISCUSSION: We look forward to obtaining high-quality evidence that can be used to formulate clinical practice guidelines. Thus, the findings of this study are expected to help fill the current gap in cardiotoxicity prevention drugs. TRIAL REGISTRATION: This trial was published in the Chinese Clinical Trial Registry (No. ChiCTR2000041134, registered on 19th December 2020).

Neoadjuvant chemotherapy-induced decrease of prognostic nutrition index predicts poor prognosis in patients with breast cancer.

BACKGROUND: The prognostic nutritional index (PNI), which is an easily calculated nutritional index, is significantly associated with patient outcomes in various solid malignancies. This study aimed to evaluate the prognostic impact of PNI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). METHODS: We reviewed patients with breast cancer who underwent NAC and a subsequent surgery for breast cancer between 2005 and 2016. PNI before and after NAC were calculated using the following formula: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count/mm3. The relationship between PNI and prognosis was retrospectively analyzed. RESULTS: In total, 191 patients were evaluated. There was no significant difference in disease-free survival (DFS) between the pre-NAC PNI high group and the pre-NAC PNI low group (cutoff: 53.1). However, PNI decreased in 181 patients (94.7%) after NAC and the mean PNI also significantly decreased after NAC from 52.6 ± 3.8 pre-NAC to 46.5 ± 4.4 post-NAC (p < 0.01). The mean ΔPNI, which was calculated as pre-NAC PNI minus post-NAC PNI, was 5.4. The high ΔPNI group showed significantly poorer DFS than the low ΔPNI group (cut off: 5.26) (p = 0.015). Moreover, high ΔPNI was an independent risk factor of DFS on multivariate analysis (p = 0.042). CONCLUSIONS: High decrease of PNI during NAC predicts poor prognosis. Thus, maintaining the nutritional status during NAC may result in better treatment outcomes in patients with breast cancer.

Neoadjuvant Chemotherapy With Anthracycline-Based Regimen for BRCAness Tumors in Triple-Negative Breast Cancer.

BACKGROUND: A subgroup of triple-negative breast cancer (TNBC) shows impaired BRCA1 function owing to causes other than mutation, which is called "BRCAness." DNA-damaging agents are known to have more efficacy in BRCA1-mutant tumors than mitotic poisons. We conducted a prospective single-arm clinical trial of neoadjuvant chemotherapy (NAC) using an anthracycline-based regimen without taxanes for BRCAness TNBCs. MATERIALS AND METHODS: BRCAness was examined using the multiplex ligation-dependent probe amplification (MLPA) method in TNBC cases. For BRCAness cases, NAC was performed with anthracycline-based regimens without additional taxanes. RESULTS: A total of 30 patients with TNBC were enrolled. MLPA was successfully performed in 25 patients. Eighteen patients (72%) showed BRCAness. Twenty-three patients received NAC as per the protocol. On analysis, the clinical response rate (complete response plus partial response) was 76.4%, and the pathological complete response rate was 35.3%. CONCLUSIONS: The interim analysis revealed that the pathological complete response rate was lower than estimated. Therefore, BRCAness by MLPA was not sufficient to predict the therapeutic response to anthracycline-based regimens in TNBC.

Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial.

Importance: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. Objective: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. Design, Setting, and Participants: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. Interventions: The adjuvant chemotherapy regimen was selected by the treating physician. Main Outcomes and Measures: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). Results: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). Conclusions and Relevance: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. Trial Registration: ClinicalTrials.gov identifier: NCT00310180.

Anthracycline could be essential for triple-negative breast cancer: A randomised phase II study by the Kanagawa Breast Oncology Group (KBOG) 1101.

BACKGROUND: It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. METHODS: The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. RESULTS: Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). CONCLUSION: TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

The pivotal role of microRNA-21 in osteoclastogenesis inhibition by anthracycline glycoside aloin.

Osteopenic disorders such as osteoporosis and rheumatoid arthritis are characterized by excessive bone resorption by osteoclasts relative to bone formation by osteoblasts. MicroRNAs are emerging as key players in bone remodeling, modulating the functions of both osteoblasts and osteoclasts. Among them, miR-21 is highly expressed in osteoclast precursors and is known to regulate genesis, differentiation, and apoptosis of osteoclasts. The pro-osteoclastogenic nature of miR-21 makes it a potential candidate as a therapeutic target to treat bone disorders. We had previously demonstrated that anthroglycoside aloin derived from Aloe vera was effective in promoting osteoblastogenesis and inhibiting osteoclastogenesis. The present study investigated the role of miR-21 in aloin's inhibitory effect on osteoclast differentiation. Aloin effectively suppressed receptor activator of nuclear factor kappa-B (NFĸB) ligand (RankL)-induced miR-21 expression via repression of NFĸB activation. MiR-21 suppression resulted in upregulation of osteoclast suppressor programmed cell death protein 4 (PDCD4), and downregulation of osteoclast marker cathepsin K. Knockdown or gain-of-function studies revealed that miR-21 was pivotal to aloin's inhibitory effect on osteoclastogenesis. This study also highlights the dynamic potential of aloin as a therapeutic agent to treat osteopenic disorders.

Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: the PRADA trial.

Aims: Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta-adrenergic blockade. Methods and results: PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial, placebo-controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 ± 2.7% to 28.6 ± 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003). Conclusions: Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer.

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

Beyond Anthracyclines: Preemptive Management of Cardiovascular Toxicity in the Era of Targeted Agents for Hematologic Malignancies.

Advances in drug discovery have led to the use of effective targeted agents in the treatment of hematologic malignancies. Drugs such as proteasome inhibitors in multiple myeloma and tyrosine kinase inhibitors in chronic myeloid leukemia and non-Hodgkin lymphoma have changed the face of treatment of hematologic malignancies. There are several reports of cardiovascular adverse events related to these newer agents. Both "on-target" and "off-target" effects of these agents can cause organ-specific toxicity. The need for long-term administration for most of these agents requires continued monitoring of toxicity. Moreover, the patient population is older, often over 50 years of age, making them more susceptible to cardiovascular side effects. Additional factors such as prior exposure to anthracyclines often add to this toxicity. In light of their success and widespread use, it is important to recognize and manage the unique side effect profile of targeted agents used in hematologic malignancies. In this article, we review the current data for the incidence of cardiovascular side effects of targeted agents in hematologic malignancies and discuss a preemptive approach towards managing these toxicities.

NCCN Consensus Guidelines for the Diagnosis and Management of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Published case series demonstrate a lack of treatment standardization for breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) with a wide variety of therapeutic strategies being employed at all stages of disease. The National Comprehensive Cancer Network (NCCN) annually publishes Clinical Practice Guidelines for Non-Hodgkin Lymphomas. For the first time, BIA-ALCL management will be included which signifies an important and needed guideline addition. The new BIA-ALCL guideline was achieved by a consensus of lymphoma oncologists, plastic surgeons, radiation oncologists, and surgical oncologists. NCCN guidelines focus on the diagnosis and management throughout the stages of many lymphoma subtypes based upon the most current data available. This article summarizes the essential recommendations and optimal therapeutic strategies of the NCCN guidelines critical to the plastic surgery community. We encourage international adoption of these BIA-ALCL treatment standards by our specialty societies across the oncology and surgery disciplines.

The Impact of Age on Quality of Life in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Comparative Analysis From the Prospective Multicenter Randomized ADEBAR trial.

BACKGROUND: Elderly breast cancer patients are affected by poorer quality of life (QoL) compared to younger patients. Because QoL has a relevant impact on guideline-adherent treatment, elderly breast cancer patients are often undertreated, especially with regard to adjuvant chemotherapy, and overall survival is decreased. Thus, understanding the impact of chemotherapy on QoL in elderly patients is crucial. This study compared QoL in patients aged < 65 years and 65 to 70 years receiving adjuvant chemotherapy as a secondary outcome in the prospective randomized multicenter ADEBAR trial. PATIENTS AND METHODS: Patients with lymph node-positive breast cancer were prospectively randomized for either sequential anthracycline-taxane or epirubicin/fluorouracil/cyclophosphamid chemotherapy (FEC) therapy. QoL was assessed at baseline (t1), before cycle 4 FEC, and cycle 5 epirubicin/cyclophosphamid-docetaxel (EC-DOC) (t2), 4 weeks after chemotherapy (t3), and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23). We compared patients aged < 65 years and 65 to 70 years with respect to QoL and discontinuation of chemotherapy. RESULTS: A total of 1363 patients were enrolled onto the ADEBAR trial, with 16.7% of the patients aged 65 to 70 years. In elderly patients, Eastern Cooperative Oncology Group performance status was higher and global health status and physical functioning were lower at baseline. Global health status decreased between t1 and t3 by 7 points in patients < 65 years and by 11 points in patients 65 to 70 years, and physical functioning decreased in the same period by 13.4 points in patients aged < 65 years and by 15.9 points in patients 65 to 70 years. In both groups, at t4 global health status exceeded baseline by 6 points, and physical functioning was 1.3 points under baseline in patients < 65 years old and 3 points under baseline in patients 65 to 70 years. There was a trend to more fatigue in elderly patients and to more nausea and vomiting while receiving chemotherapy in younger patients at t3. There was a higher dropout rate in patients aged 65 to 70 years (25.7%) than in patients aged < 65 years (16.2%). CONCLUSION: There were only small or trivial differences in QoL in patients aged < 65 years versus 65 to 70 years who were receiving adjuvant chemotherapy, although the dropout rate from chemotherapy was notably higher in elderly breast cancer patients.

Anthracycline-Induced Cardiotoxicity in Young Cancer Patients: The Role of Carnitine.

While the increased rates of survival in childhood cancers have increased progressively in recent decades, many childhood cancer survivors will have at least one chronic health condition within 40 years of age. In this regard, cardiovascular complications have emerged as a leading cause of long-term morbidity and mortality in long-term survivors of childhood cancer, likely due to exposure to anthracycline chemotherapy, and outcomes in patients with anthracycline-related cardiomyopathy remain poor. Some progress has been made in understanding the mechanisms at the basis of anthracycline-related cardiomyopathy, which appear to involve generation of reactive oxygen species, leading to mitochondrial dysfunction, followed by myocyte apoptosis and maladaptive left ventricular remodeling. Even if several guidelines currently exist for monitoring cancer patients treated with cardiotoxic therapies who are at high risk for heart failure, much work remains to be done in finding reliable markers for screening for cardiac dysfunction. Studies from our group have identified alterations in L-carnitine in cancer survivors. While additional investigations are needed, preliminary studies suggest a role for carnitine in primary prevention (during treatment) and secondary prevention (to improve function after treatment).

A four gene signature of chromosome instability (CIN4) predicts for benefit from taxanes in the NCIC-CTG MA21 clinical trial.

Recent evidence demonstrated CIN4 as a predictive marker of anthracycline benefit in early breast cancer. An analysis of the NCIC CTG MA.21 clinical trial was performed to test the role of existing CIN gene expression signatures as prognostic and predictive markers in the context of taxane based chemotherapy.RNA was extracted from patients in cyclophosphamide, epirubicin and flurouracil (CEF) and epirubicin, cyclophosphamide and paclitaxel (EC/T) arms of the NCIC CTG MA.21 trial and analysed using NanoString technology.After multivariate analysis both high CIN25 and CIN70 score was significantly associated with an increased in RFS (HR 1.76, 95%CI 1.07-2.86, p=0.0018 and HR 1.59, 95%CI 1.12-2.25, p=0.0096 respectively). Patients whose tumours had low CIN4 gene expression scores were associated with an increase in RFS (HR: 0.64, 95% CI 0.39-1.03, p=0.06) when treated with EC/T compared to patients treated with CEF.In conclusion we have demonstrated CIN25 and CIN70 as prognostic markers in breast cancer and that CIN4 is a potential predictive maker of benefit from taxane treatment.