Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.

BACKGROUND: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. FINDINGS: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. INTERPRETATION: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. FUNDING: Daiichi Sankyo and AstraZeneca.

Prognostic significance of abdominal obesity and its post-diagnosis change in a Chinese breast cancer cohort.

PURPOSE: It is well-known that obesity has an adverse impact on breast cancer prognosis; nonetheless, the prognostic role of abdominal obesity, especially its post-diagnosis change, has been understudied. This study aims to examine the prospective associations of general and abdominal obesity and their post-diagnosis changes with all-cause mortality, breast cancer-specific mortality, and breast cancer recurrence in Chinese breast cancer patients. METHODS: From 2011 to 2014, 1460 Chinese breast cancer patients were recruited and followed up at 18, 36, and 60 months after diagnosis. Body mass index (BMI), waist-to-hip ratio (WHR), and their changes between baseline and 18-month follow-up were derived. Clinical records on diagnosis, treatment, and death were also obtained. In total, 1309 women who completed the 18-month follow-up were included for Cox regression analyses, stratified by follow-up periods. RESULTS: Within 18-48 months post-diagnosis, substantial WHR loss (5% or above) had reduced risk of all-cause (HR = 0.21 [95% CI 0.06-0.75]) and breast cancer-specific mortality (0.21 [0.06-0.77]) relative to stable WHR; whereas after 48 months post-diagnosis, substantial WHR gain showed elevated risks of all-cause mortality (2.67 [1.22-5.85])). Higher baseline WHR was also associated with both mortality outcomes. Nonetheless, no such associations were observed for BMI measures. Also, the effects of obesity measures on breast recurrence were less apparent. CONCLUSION: Abdominal obesity, rather than general obesity, was linked to worse survival in Chinese breast cancer patients. Prevention on abdominal obesity and waist gain following breast cancer diagnosis may have a beneficial effect on longer-term survival over and above conventional weight management. Waist assessment and abdominal obesity control should therefore be incorporated as a vital component of the evaluation and interventions of breast cancer prognosis.

Association of high adherence to vegetables and fruits dietary pattern with quality of life among Chinese women with early-stage breast cancer.

PURPOSE: Dietary intake and patients' quality of life (QoL) are important supportive care issues in breast cancer survivorship. This study aimed to identify dietary pattern before and after breast cancer diagnosis. In addition, the association between dietary patterns and QoL were cross-sectionally and longitudinally investigated. METHODS: A breast cancer cohort which included 1462 Chinese women were longitudinally interviewed at four time-points, namely baseline, 18-, 36-, and 60 months after diagnosis. At each follow-up, validated food frequency questionnaires (FFQ) were used to assess patients' dietary intake, and factor analysis was used to derive dietary patterns. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) were used to measure QoL at each follow-up. This study included 1368, 1226, 1079 and 1095 patients with invasive disease who completed assessment at baseline, 18-, 36- and 60-month follow-up and had detailed data of dietary intake and QoL. RESULTS: Based on data obtained at 18-month follow-up, two major dietary patterns were identified: "grain and animal food pattern" and "vegetables and fruits pattern". Similar dietary patterns were obtained at baseline, 36- and 60- month follow-up. Generalized Estimating Equations (GEE) were used to analyze the longitudinal associations between dietary patterns and QoL over the four follow-ups. High intake of grain and animal food was inversely associated with scores for role functioning (B = - 0.744; 95%CI - 0.147 to - 0.017), dyspnea (B = - 0.092; 95%CI - 0.092 to - 0.092) and constipation (B = - 1.355; 95%CI - 2.174 to - 0.536). Vegetables and fruits intake were positively associated with scores for global health status/QoL (B = 1.282; 95%CI 0.545-2.019), physical functioning (B = 0.545; 95%CI: 0.037-1.053), emotional functioning (B = 1.426; 95%CI 0.653-2.200) and cognitive functioning (B = 0.822; 95%CI 0.007-1.637), while inversely associated with scores for nausea and vomiting (B = - 0.382; 95%CI - 0.694 to - 0.071), dyspnea (B = - 0.570; 95%CI - 0.570 to - 0.570), insomnia (B = - 1.412; 95%CI - 2.647 to - 0.177), loss of appetite (B = - 0.722; 95%CI - 1.311 to - 0.132), constipation (B = - 2.028; 95%CI - 2.775 to - 1.281) and diarrhea (B = - 0.929; 95%CI - 1.481 to - 0.377). CONCLUSION: This study suggested that high adherence to "grain and animal food pattern" or "vegetables and fruits pattern" was significantly associated with several aspects of QoL. For instance, vegetables and fruits pattern appears to have beneficial effect on global health status/QoL among Chinese breast cancer patients. Prospective follow-up data could further confirm whether a specific dietary pattern has impact on cancer outcomes.

Quality of Life Associated with Nausea and Vomiting from Anthracycline-Based Chemotherapy: A Pooled Data Analysis from Three Prospective Trials.

BACKGROUND: There is limited work on the impact of chemotherapy-induced nausea and vomiting (CINV) on quality of life (QoL) in adriamycin-cyclophosphamide (AC)-treated patients with breast cancer. The objectives of the study were the following: (a) to confirm if symptoms of CINV led to lower QoL during AC; (b) to evaluate the pattern of changes in patients' QoL during multiple cycles of AC; and (c) to assess if the QoL in an earlier cycle affected the QoL in subsequent cycles of AC. MATERIALS AND METHODS: This is a secondary pooled data analysis that included 303 Chinese patients with breast cancer who received 1,177 cycles of adjuvant AC in three prospective antiemetic studies. QoL data were based on Functional Living Index-emesis (FLIE) scored over three to four AC cycles. CINV symptoms assessed included "no significant nausea" (NSN), "significant nausea" (SN), "no vomiting" (NoV), "vomiting" (V), and complete response (CR). RESULTS: Across all AC cycles, the mean scores for the FLIE nausea domain for patients who experienced NSN versus SN were 10.92 versus 53.92, respectively (p < .0001), with lower scores indicating better QoL; the mean scores for the FLIE vomiting domain for patients who experienced NoV versus V were 1.44 versus 19.11, respectively (p < .0001), with similar results across subsequent cycles. Analysis of the effect of the QoL in cycle 1 on the QoL of subsequent cycles revealed the following: for the nausea domain, among patients who had cycle 1 FLIE scores ≥ versus < the mean, the corresponding scores in cycle 2 were 6.87 versus 36.71 (p < .0001); whereas those for cycle 3 were 7.07 versus 36.87 (p < .0001); and those for cycle 4 were 5.92 versus 21.48 (p < .0001). Similar findings were observed for the vomiting domain. Netupitant + palonosetron- or aprepitant/olanzapine-based antiemetics had significantly better QoL outcomes. CONCLUSION: CINV had a significant impact on the QoL of patients with breast cancer treated with AC over multiple cycles. IMPLICATIONS FOR PRACTICE: In this post-hoc analysis of three prospective studies on chemotherapy-induced nausea and vomiting (CINV), quality of life (QoL) using contemporary antiemetic regimens in Chinese breast cancer patients receiving doxorubicin-cyclophosphamide (AC) was evaluated. During the first and subsequent AC cycles, QoL was significantly better for patients who did not experience vomiting or significant nausea. QoL in an earlier cycle affected the QoL in subsequent AC cycles. Furthermore, recent regimens involving olanzapine/aprepitant or netupitant-palonosetron were associated with a positive impact in QoL. Antiemetic guideline-consistent practice and higher clinician awareness of the impact of CINV on QoL can further mitigate the negative effects of CINV on QoL.

A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma.

BACKGROUND: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC). METHODS: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC. RESULTS: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9-6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3-78.0 weeks) vs. 15.14 weeks (95% CI: 13.4-15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes. CONCLUSIONS: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. TRIAL REGISTRATION NUMBER: NCT01092091. Date of registration: March 23, 2010.

Weight and waist-to-hip ratio change pattern during the first five years of survival: data from a longitudinal observational Chinese breast cancer cohort.

BACKGROUND: Body weight management was an important component in breast cancer survivorship care. The present study described the change patterns of body weight and waist-to-hip ratio (WHR) during the first 5 years of survival, and investigated potential factors associated with very substantial changes. PATIENTS AND METHODS: Based on a longitudinal cohort with 1462 Chinese women with breast cancer, anthropometric measurements including body weight, height, waist and hip circumferences were measured by trained interviewers following standard protocol at four time-points: baseline at study entry, 18-, 36- and 60-months follow up assessments (termed as T0, T1, T2 and T3, respectively). Body height was measured at baseline and body weight at cancer diagnosis were retrieved from medical record. RESULTS: Compared to weight at breast cancer diagnosis, the median weight change was - 0.5 kg, 0 kg, + 0.5 kg, and + 1 kg at T0, T1, T2 and T3, respectively. During the first 5 years of survival, the proportion of women who were obese have slightly increased. At 60-months after diagnosis, only 14.3% of women had weight gain by > 5 kg; and the percentage of women who had weight gain by > 10% was 10.7%. Nearly half of patients had abdominal obesity at study entry, and this proportion were gradually increased to nearly 70% at 60-months follow-up. Multivariate analysis indicated that older age, and frequent sports participation during the first 5 years of survival were related to lower risk of very substantial weight gain (> 10%) at 60-month follow-up; patients aged 40-49 years, having ≥2 comorbidities and ER negative were associated with less likelihood of very substantial WHR substantial increase (> 10%) at 60-month follow-up. CONCLUSION: Weight gain was modest in Chinese breast cancer survivors during the first 5 years of survival, while central adiposity has become a contemporary public health issue. The incorporation of healthy weight and abdominal circumference patient education and management has a potential to improve cancer survivorship.

Longitudinal change of quality of life in the first five years of survival among disease-free Chinese breast cancer survivors.

PURPOSE: This study aimed to investigate changes of QoL during the first 5 years of survival among disease-free Chinese breast cancer survivors. METHODS: A prospective cohort study enrolled 1462 Chinese women with early-stage breast cancer, and longitudinally visited those patients at four time-points, namely baseline (T0), 18- (T1), 36- (T2), and 60-month (T3) after diagnosis. This study included 992 patients who were disease-free during the first 5 years of survival and who had completed QoL assessments at all four time-points. RESULTS: The score of global health status/QoL improved gradually (T1, T2, T3 > T0; P < 0.001 for overall comparisons). Social functioning score significantly improved when compared to that of T0 (T1, T2, T3 > T0; P < 0.001 for overall comparisons). In contrast, cognitive functioning score decreased (T0 > T1, T2, T3; P < 0.001 for overall comparisons). Scores of physical functioning, role functioning and emotional functioning showed a fluctuated picture, with the highest score achieved at T1. In symptoms profile, most of them scored lowest at T1 (best QoL). Multivariate analysis showed that several characteristics significantly correlated to changes in QoL from T0 to T3. For instance, patients with higher education had better recovery of physical functioning, role functioning, and social functioning. CONCLUSION: During the first 5 years of survival, patients' global health status/QoL improved over time, social functioning consistently improved, but cognitive functioning steadily deteriorated. Most of functioning domains and symptoms improved at 18-month follow-up, but such improvements were not maintained and even deteriorated at 36- and 60-month post-diagnosis. This study suggested that some interventions should be investigated during such period.

The association between soy isoflavone intake and menopausal symptoms after breast cancer diagnosis: a prospective longitudinal cohort study on Chinese breast cancer patients.

PURPOSE: This study investigated the association between soy isoflavone intake and menopausal symptoms (MPS) among Chinese women with early stage breast cancer in a prospective cohort study. METHODS: In an on-going prospective cohort study that involved 1462 Chinese women with early stage breast cancer, MPS were assessed at 18, 36 and 60 months after cancer diagnosis using the validated menopausal rating scale (MRS) questionnaire. Daily soy food intake for the previous 12 months was assessed at the same time using a validated food frequency questionnaire. The associations between MPS and soy isoflavone intake were evaluated in multivariable logistic regression analyses. RESULTS: The prevalence of MPS was almost the same during the first 60 months after cancer diagnosis, which were 64.5%, 65.2%, and 63.9% at 18, 36, and 60 months, respectively. Patients with MPS tended to be younger than those without MPS. The intake of soy isoflavones was not associated with the total score of MRS at 18-month follow-up [highest vs lowest tertile, odds ratio (OR) = 1.00, 95% CI 0.75-1.34]. Similarly, no significant association was noted at 36-month (OR = 1.25, 95% CI 0.92-1.69) and 60-month (OR = 1.21, 95% CI 0.84-1.74) follow-up. With regards to specific domain within MRS, the risk of symptoms presenting in somatic domain was higher among breast cancer patients who were in the highest tertile of soy isoflavone intake at 36 months post-diagnosis (OR = 1.44, 95% CI 1.07-1.94, P-trend = 0.02), compared with the lowest tertile, where a stronger significant association was noted among patients who were younger than 60 years (OR = 1.52, 95% CI 1.05-2.20, P-trend = 0.03) and pre-menopausal (OR = 3.81, 95% CI 1.85-8.11, P-trend < 0.01). CONCLUSION: The present study provided further evidence that soy isoflavone consumption was not associated with MPS among Chinese breast cancer patients. In fact, patients with higher intake of soy isoflavone have increased risk of experiencing somatic symptoms.

Longitudinal changes in sports activity from pre-diagnosis to first five years post-diagnosis: a prospective Chinese breast cancer cohort study.

BACKGROUND: To compare change in level of physical activity between pre-and post- diagnosis of breast cancer in Chinese women. METHODS: Based on an on-going prospective study consisting of a sample of Chinese women with breast cancer, a validated modified Chinese Baecke questionnaire was used to measure physical activity at baseline (12 months before cancer diagnosis), 18-, 36- and 60-months after diagnosis (over the previous 12 months before each interview). RESULTS: In our cohort of 1462 Chinese women with a mean age of 52 years, the mean level of physical activity at post-diagnosis was 9.6 metabolic equivalent of task (MET)-hours/week, which was significantly higher than that at pre-diagnosis with mean level of 5.9 MET-hours/week (P < 0.001). The mean levels of physical activity at 18-, 36- and 60-months follow-up were 9.9, 9.8 and 9.3 MET-hours/week, respectively. There was no significant difference between any two of the three follow-ups at post-diagnosis. The proportions of participant who met World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) recommendation before and after cancer diagnosis were both low, being 20.7 and 35.1%, respectively. Compared to pre-diagnosis, most of the patients improved or had no change on level of physical activity at post-diagnosis, with the respective proportion being 48.2 and 43.8%. CONCLUSIONS: Adherence to current lifestyle recommendation for cancer survivors, Chinese women with breast cancer significantly increased level of physical activity level after cancer diagnosis, and such improvement was sustained to 5 years post-diagnosis. The proportion of patients who met the exercise recommendation for cancer survivors was still low. Encouraging patients on the importance of durable high level of physical activity in breast cancer survivorship is warranted.

Menopausal symptoms in relationship to breast cancer-specific quality of life after adjuvant cytotoxic treatment in young breast cancer survivors.

INTRODUCTIONS: For young premenopausal breast cancer patients, adjuvant chemotherapy may cause menstrual disruptions and premature menopause, which may in turn impair their quality of life (QoL). In this study among young breast cancer survivors who have undergone adjuvant chemotherapy, the objectives were to assess post-treatment menopausal symptoms and their associated factors, and to correlate these symptoms with breast cancer-specific QoL. METHODS: The study population included premenopausal young Chinese women with early-stage breast cancer who had undergone adjuvant chemotherapy between 3 and 10 years prior to enrolling into this study. At study entry, patients' characteristics and clinical features were collected; each patient had detail menstrual history collected and each filled in MENQOL and FACT-B + 4 questionnaires. RESULTS: Two hundred eighty eligible patients were recruited. For adjuvant chemotherapy, 92% received anthracyclines and 28% received taxanes; 76% received adjuvant tamoxifen. At a median of 5.0 years from initial cancer diagnosis, 49 and 11% had become post- and peri-menopausal respectively. MENQOL at study entry revealed that physical domain score was worse in overweight/obese patients (mean scores for underweight/normal vs overweight/obese: 2.65 vs 2.97, p = 0.0162). Vasomotor domain score was worse in those who received taxanes or tamoxifen (taxane vs non-taxane: 2.91 vs. 2.35, p = 0.0140; tamoxifen vs no tamoxifen: 2.75 vs. 2.34, p = 0.0479). Sexual domain score was worse among those who had become peri/post-menopausal (peri/postmenopausal vs premenopausal: 2.82 vs. 2.29, p = 0.0229). On the other hand, patients who utilized traditional Chinese medicine had significantly worse scores for vasomotor, psychosocial and physical domains. Further, there was a significant association between MENQOL scores and FACT-B + 4 scores; less severe symptoms in the MENQOL domains were associated with better QoL scores in FACT-B + 4 physical, functional, psychosocial and emotional well-being, Breast Cancer Subscale, Arm Subscale and FACT-B total score. CONCLUSION: Among premenopausal breast cancer women who had undergone adjuvant chemotherapy, those who had received taxanes or tamoxifen, were overweight/obese and utilized traditional Chinese medicine had more severe menopausal symptoms. Patients who experienced worse menopausal symptoms were found to have worse breast cancer-specific QoL. Interventional studies with an aim to alleviate menopausal symptoms are warranted to assess if overall QoL of these patients could be improved. TRIAL REGISTRATION: Not applicable.

Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.

BACKGROUND & AIMS: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. METHODS: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. RESULTS: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. CONCLUSION: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. LAY SUMMARY: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Treating HR+/HER2- breast cancer in premenopausal Asian women: Asian Breast Cancer Cooperative Group 2019 Consensus and position on ovarian suppression.

PURPOSE: Breast cancer in young Asian women has distinctive clinicopathological characteristics; hence, we question the universal generalizability of treatment recommendations based on data from predominantly non-Asian postmenopausal women. METHODS: The Asian Breast Cancer Cooperative Group (ABCCG) reviewed current ESO-ESMO and St. Gallen recommendations for treating hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer in premenopausal women. Points disputed by ≥ 3/12 members were discussed, and statements on contentious issues formulated for anonymous voting; consensus required a ≥ 75% majority. RESULTS: The ABCCG contends that: (1) Trials in premenopausal women are not only necessary, but also worthwhile if performed separately from others that also enroll postmenopausal participants. (2) Not all premenopausal women with HR+ early breast cancer need adjuvant ovarian function suppression (OFS). (3) Certain clinical factors might influence decision-making about prescribing OFS. (4) For early HR+/HER2- breast cancer in premenopausal patients with OFS, tamoxifen is preferred for intermediate-risk cases; for high risk, near-consensus supported aromatase inhibitor, despite no clear overall survival benefit versus tamoxifen. (5) Oncotype DX Breast Recurrence Score® has different treatment implications in patients aged ≤ 50 versus > 50 years. (6) High-risk patients (if premenopausal after chemotherapy) should receive adjuvant chemotherapy and OFS plus aromatase inhibitor. (7) For patients with advanced disease receiving OFS on a backbone of tamoxifen, gonadotrophin-releasing hormone agonists may be given 12-weekly. (8) For premenopausal women who decline OFS or oophorectomy, tamoxifen alone is still an option but is considered less effective; other monotherapies are also less effective than OFS plus such treatments. CONCLUSION: Premenopausal Asian women with breast cancer have unique disease characteristics and may benefit from treatment that differs somewhat from international guidelines. Given the great diversity of patients and clinical settings worldwide, the ABCCG advocates evidence-based yet flexible and individualized use of all potential options to improve breast cancer outcomes.

The association of liver function and quality of life of patients with liver cancer.

BACKGROUND: Quality of life (QOL) assessments with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-HCC18, C30 and HCC18 index scores have been shown to be prognostic factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC), independent of disease stage and liver function. Liver function parameters (including bilirubin, albumin, international normalized ratio [INR], Child-Pugh class, ALBI grade, MELD, alkaline phosphatase [ALP]-to-platelet ratio, albumin-to-ALP ratio) have also been found to be independent prognostic factors for OS in HCC patients. There has been scanty data on whether QOL and baseline liver function per se are correlated in HCC patients. This study investigates the correlations between baseline QOL data and liver function variables in HCC patients. METHODS: From 2007 to 2011, 517 patients were enrolled. Baseline QOL was assessed at diagnosis using the EORTC QLQ-C30 and QLQ-HCC18; thereafter C30 and HCC18 index scores were derived. Clinical and laboratory data were collected. For liver function assessment, Child-Pugh class, ALBI grade, MELD, ALP-to-platelet ratio and albumin-to-ALP ratio were derived. Correlation analyses were performed between QOL and liver function data. RESULTS: Complete QOL data were available in 472 HCC patients. After adjusting for clinical variables, significant correlations were found between QOL (QLQ-C30 and QLQ-HCC18) and dichotomized liver function variables (including Child-Pugh class, ALBI grade and the presence of ascites). It was demonstrated that QOL had significant and potentially clinically important correlations with continuous liver function variables (albumin, bilirubin, ALP and albumin-to-ALP ratio), with the highest Spearman's rank correlation coefficient (rho) exceeding 0.4. HCC18 and C30 index scores were also significantly correlated with these liver function variables. HCC18 index score, which had rho up to 0.37, generally performed better than C30 index score, which had rho up to 0.33. CONCLUSIONS: In HCC patients, baseline QOL assessment (using EORTC QLQ-C30, QLQ-HCC18, C30 index-score or HCC18 index-score) is significantly correlated with liver function. Based on the findings of this study, future trials are warranted to assess whether treatment to enhance liver function could improve HCC patients' QOL.

Status of inflammation in relation to health related quality of life in hepatocellular carcinoma patients.

PURPOSE: Both Inflammation and health-related quality of life (HRQoL) are independent prognosticators in HCC patients. We hypothesized that inflammation can cause impairment in HRQoL and investigated the correlation between inflammatory status and HRQoL in HCC patients. METHODS: Clinical, laboratory and HRQoL (using EORTC QLQ-C30, QLQ-HCC18, C30 and HCC18 index-scores) data were prospectively collected from HCC patients at diagnosis. Correlation analyses were performed between HRQoL and inflammation-based markers including C-reactive protein (CRP), CRP/albumin ratio (CRP/alb), Glasgow Prognostic Score (GPS), Inflammation-Based Index (IBI) and Prognostic Index (PI). RESULTS: Among 445 HCC patients, higher inflammatory states were significantly correlated with worse HRQoL. For CRP and CRP/alb ratio, the HRQoL factors with higher correlations included C30 and HCC18 index-scores, certain QLQ-C30 domains and items ('physical functioning', 'role functioning', 'fatigue', 'pain', 'appetite loss') and QLQ-HCC18 items ('fatigue', 'body image', 'nutrition' and 'abdominal swelling'), where the Pearson's correlation coefficients were up to 0.416. Multivariate analyses indicated that worse HRQoL factors were significantly correlated with worse scores in GPS, IBI and PI. CONCLUSION: In HCC patients, inflammatory status correlates with HRQoL at presentation. In particular, relatively stronger correlations with CRP-based markers have been observed in HRQoL scales that assess constitutional symptoms (QLQ-C30 'physical functioning', 'role functioning', 'fatigue', 'appetite loss' and QLQ-HCC18 'fatigue' and 'nutrition') and tumor burden (QLQ-C30 'pain' and QLQ-HCC18 'abdominal swelling' and 'body image'). Future studies are warranted to evaluate whether intervention that reduces inflammation could improve HRQoL in HCC patients.

Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma?

BACKGROUND: Irrespective of the underlying aetiology, 90% of hepatocellular carcinomas arise and progress on a background of chronic inflammation. We have explored the independent prognostic value of circulating inflammatory cells. METHODS: Peripheral blood count data sets from 583 consecutive patients presenting to a single UK centre (2000-2010) were analysed for associations with tumour stage, liver function, performance status (PST) and survival. Validation was in an independent Hong Kong cohort (585 patients; 2007-2013). RESULTS: In both UK and Hong Kong cohorts, neutrophils, platelets, lymphocytes, the neutrophil/lymphocyte ratio (NLR) and the Systemic Immune-Inflammation Index (SII) correlated stepwise, either increasing or decreasing (lymphocytes), with tumour node metastasis (TNM) and Childs-Pugh stage, PST and consequently with the combined Barcelona Clinic for Liver Cancer stage. Survival analyses confirmed the NLR and SII as highly significant prognostic biomarkers. Focused on individual cell types, only the neutrophil count was independently associated with both TNM stage and PST, as well as being significantly and independently associated with poorer survival. CONCLUSIONS: In this study of 1168 patients, neutrophils alone, rather than lymphocytes or platelets, were independently associated with outcome. These data support further characterisation of a potentially distinctive role for neutrophils as facilitators of tumour progression and deteriorating performance.

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.

BACKGROUND: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. METHODS: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. FINDINGS: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. INTERPRETATION: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. FUNDING: Bristol-Myers Squibb.

Ablative Chemoembolization for Hepatocellular Carcinoma: A Prospective Phase I Case-Control Comparison with Conventional Chemoembolization.

Purpose To evaluate the feasibility, safety, and treatment effectiveness of ablative chemoembolization (ACE) in the treatment of hepatocellular carcinoma (HCC) and compare with a similar patient cohort who underwent conventional transarterial chemoembolization (cTACE). Materials and Methods This was a prospective phase I nonrandomized study conducted between March 2013 and October 2016 in accordance to the Declaration of Helsinki and Declaration Good Clinical Practice with written informed consent. There were 36 men and eight women (median age, 64 years [interquartile range, 58-74] and 74.5 years [interquartile range, 70-80], respectively). The primary end points were treatment safety and tumor response. The secondary end points were time to progression, progression-free survival, conversion to partial hepatectomy, and viable HCC within the tumor specimen. The end points of the study group (n = 22) were compared with those of a case-matched control group (n = 22) of patients who underwent conventional cTACE during the same period by using a Pearson χ2 test. Results Treatment with ACE was successfully completed in all patients without adverse effects. The complete response (CR) rates by patient or by tumor were both 100%. The median time to progression and median progression-free survival were significantly longer in the study group than in the control group (both were 28 months vs 10 months, respectively; P < .001). The number of patient conversions to hepatectomy was seven for ACE and three for cTACE. In the tumor specimens, viable tumor was found in two of eight specimens that underwent ACE and three of three that underwent cTACE. Conclusion ACE is a feasible, safe, and well-tolerated treatment for patients with HCC; it is highly effective and may be more effective than cTACE in achieving CR. © RSNA, 2017 Online supplemental material is available for this article.

Factors predicting patient satisfaction in women with advanced breast cancer: a prospective study.

BACKGROUND: The present study (1) examined patient satisfaction with care over the first year following the diagnosis of advanced breast cancer and (2) tested if unmet health system and information needs, physical symptom distress, and psychological distress predicted patient satisfaction. METHODS: Prospective study of 213 Chinese women with advanced breast cancer assessed while awaiting or receiving initial chemotherapy (baseline), then again at 1.5-, 3-, 6-, and 12-months post-baseline. Health system and information unmet (HSI) needs, psychological distress, physical symptom distress, and patient satisfaction were assessed at baseline; patient satisfaction was reassessed at each follow-up assessment. Latent growth curve analysis assessed changes in patient satisfaction over the 12 months follow-up; hierarchical multiple regression analysis tested if baseline health system information needs, physical symptom distress, anxiety and depression predicted patient satisfaction at one-year post-baseline. RESULTS: The level of patient satisfaction was high and did not change significantly over time. Only HSI needs (ß = - 0.27, p < 0.005) significantly associated with baseline patient satisfaction. Patient satisfaction at one-year post-baseline was predicted by HSI needs (ß = - 0.26, p < 0.005), Anxiety (ß = 0.23, p < 0.05) and Depression (ß = - 0.28, p < 0.005), adjusting for the effect of baseline patient satisfaction (ß = 0.22, p < 0.005). CONCLUSIONS: Unmet health information needs and greater depressive symptoms at initial treatment phased predicted subsequent poorer patient satisfaction. This highlights a need to reinforce the importance of patient-centered care model in managing advanced breast cancer.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research Guideline Is Associated With Better Health-Related Quality of Life Among Chinese Patients With Breast Cancer.

Background: The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guideline provides recommendations for cancer prevention among cancer survivors. Limited data have examined whether guideline adherence is related to health-related quality of life (HRQoL) among Chinese patients with breast cancer. Methods: An ongoing prospective cohort study involving 1,462 Chinese women with early-stage breast cancer assessed exercise, diet, and body mass index (BMI) at baseline and at 18-months follow-up after diagnosis. Each assessment recorded patient habits within the previous 12 months. HRQoL was evaluated by the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). We first compared the level of adherence to WCRF/AICR recommendations before and after cancer diagnosis. We then examined whether adherence to these recommendations after diagnosis was associated with HRQoL at 18 months. Results: The mean adherence score significantly increased from baseline (3.2; SD, 1.1) to 18-month follow-up (3.9; SD, 1.1; P<.001). Overall, increasing adherence to the WCRF/AICR guideline was associated with higher scores of global health status/quality of life (QoL; Ptrend=.011), physical (Ptrend<.001) and role functioning (Ptrend=.024), and lower scores for fatigue (Ptrend=.016), nausea and vomiting (Ptrend<.001), pain (Ptrend=.004), dyspnea (Ptrend=.030), loss of appetite (Ptrend=.007), and diarrhea (Ptrend=.020). Patients with cancer who met the BMI recommendation had higher scores for physical functioning (P=.001) and lower scores for fatigue (P=.024), pain (P<.001), and dyspnea (P=.045). Adherence to physical activity recommendation was associated with better scores of global health status/QoL (P<.001), physical functioning (P=.003), fatigue (P=.002), pain (P=.018), and dyspnea (P=.021). Higher adherence to diet recommendation was associated with lower scores of nausea and vomiting (Ptrend=.005), loss of appetite (Ptrend=.026), constipation (Ptrend=.040), and diarrhea (Ptrend=.031). Conclusions: Chinese patients with breast cancer made positive lifestyle changes early after cancer diagnosis. Increased adherence to WCRF/AICR recommendations after cancer diagnosis may improve HRQoL. Our data suggest that Chinese patients with breast cancer should follow the WCRF/AICR guideline to improve overall well-being.

Hypermethylation of NF-κB-Activating Protein-Like (NKAPL) Promoter in Hepatocellular Carcinoma Suppresses Its Expression and Predicts a Poor Prognosis.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is a complicated disease with low survival rate partially due to frequent recurrence and no efficient therapy. Promoter hypermethylation of tumor suppressor genes has been demonstrated as one of the molecular mechanisms contributing to tumorigenesis and progression in HCC. This study aims to investigate regulation of NKAPL expression by promoter methylation and its clinical relevance as a biomarker for HCC. METHODS: We measured mRNA expression of NKAPL in 5 HCC cell lines and a cohort of 62 pairs of primary HCC tumor and their adjacent non-cancer liver tissues. NKAPL protein expression on HCC cell lines and clinical samples was assessed by Western blot and immunohistochemistry, respectively. Association analyses between NKAPL expression and clinicopathologic characteristics in the cohort were conducted. Methylation statuses of NKAPL promoter in 18 pairs of tumor and adjacent non-tumor HCC samples were studied using methylation-specific PCR. Biological functions of NKAPL in HCC were investigated by ectopic expression of NKAPL in HCC cells, and cell viability and cell cycle analyses were performed. RESULTS: Our present study showed suppressed expression and promoter hypermethylation are common events in HCC. Demethylation experiment in HCC cells demonstrated that the NKAPL expression was regulated by promoter methylation. In addition, high methylation level of NKAPL and its low expression predict poor outcome. Furthermore, ectopic expression of NKAPL in the HCC cells inhibited cell growth. CONCLUSIONS: Our findings suggest that methylation of NKAPL is a frequent event and is a potential prognosis biomarker in HCC.