A phase 1 study of pegylated recombinant arginase (PEG-BCT-100) in combination with systemic chemotherapy (capecitabine and oxaliplatin)[PACOX] in advanced hepatocellular carcinoma patients.

INTRODUCTION: We investigated the safety and efficacy of a pegylated arginase (PEG-BCT-100) in combination with chemotherapy (oxaliplatin and capecitabine) [PACOX] in advanced HCC patients. METHODS: This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: intravenous PEG-BCT-100 2.7 mg/kg on days 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m2 twice daily on day 1-14 of each cycle and intravenous oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m2, 100 mg/m2 or 130 mg/m2) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied. RESULTS: Seventeen patients were enrolled at 3 dose levels of oxaliplatin: 85 mg/m2 (8 patients), 100 mg/m2 (3 patients), and 130 mg/m2 (6 patients). The median age was 55 years; all had had locoregional chemotherapy or targeted therapy such as sorafenib, but no systemic chemotherapy. The most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36%; most responses were observed in the 130 mg/m2 cohort with 1 PR and 2 SDs. Median TTP and PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the 130 mg/m2 cohort. CONCLUSION: The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.

Safety and tolerability of subcutaneous trastuzumab and intravenous pertuzumab as adjuvant treatment for HER2 positive breast cancer: a pilot study.

BACKGROUND: Subcutaneous (SC) trastuzumab is similar to intravenous trastuzumab in terms of pharmacokinetics, efficacy and tolerability. The use of dual anti-HER2 agents trastuzumab and pertuzumab has become the new standard for node-positive HER2-positive breast cancers at adjuvant setting, but the safety and tolerability of combining SC trastuzumab and intravenous pertuzumab is not well studied. METHODS: This was a prospective single-arm pilot study with locally advanced HER2-positive breast cancer who received adjuvant SC trastuzumab and intravenous pertuzumab after standard anti-HER2 treatment with chemotherapy. Primary outcomes included adverse events (AEs), severe AEs and cardiac AEs. Secondary outcome was invasive disease-free survival (iDFS). RESULTS: With a median follow-up of 21.7 months, 20 patients were enrolled. One patient (5%) developed asymptomatic drop in left ventricular ejection fraction from 69% to 53%. Two patients (10%) developed grade 1 injection site reaction related to SC trastuzumab. There were no grade 2 or above AEs. All AEs were transient. No new AEs were observed. The 1-year iDFS was 90% (95% CI 0.656 to 0.974). CONCLUSIONS: Combination of SC trastuzumab and intravenous pertuzumab for HER2-positive breast cancer is a safe and well-tolerated option in adjuvant setting.

Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes.

OBJECTIVE: Thyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4). METHODS: We conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes. RESULTS: One hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19-11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17-0.71; P = .004). CONCLUSION: Thyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.

Electroacupuncture trigeminal nerve stimulation plus body acupuncture for chemotherapy-induced cognitive impairment in breast cancer patients: An assessor-participant blinded, randomized controlled trial.

Chemotherapy causes various side effects, including cognitive impairment, known as 'chemobrain'. In this study, we determined whether a novel acupuncture mode called electroacupuncture trigeminal nerve stimulation plus body acupuncture (EA/TNS + BA) could produce better outcomes than minimum acupuncture stimulation (MAS) as controls in treating chemobrain and other symptoms in breast cancer patients. In this assessor- and participant-blinded, randomized controlled trial, 93 breast cancer patients under or post chemotherapy were randomly assigned to EA/TNS + BA (n = 46) and MAS (n = 47) for 2 sessions per week over 8 weeks. The Montreal Cognitive Assessment (MoCA) served as the primary outcome. Digit span test was the secondary outcomes for attentional function and working memory. The quality of life and multiple functional assessments were also evaluated. EA/TNS + BA treated group had much better performance than MAS-treated group on reverse digit span test at Week 2 and Week 8, with medium effect sizes of 0.53 and 0.48, respectively, although no significant differences were observed in MoCA score and prevalence of chemobrain between the two groups. EA/TNS + BA also markedly reduced incidences of diarrhoea, poor appetite, headache, anxiety, and irritation, and improved social/family and emotional wellbeing compared to MAS. These results suggest that EA/TNS + BA may have particular benefits in reducing chemotherapy-induced working memory impairment and the incidence of certain digestive, neurological, and distress-related symptoms. It could serve as an effective intervention for breast cancer patients under and post chemotherapy (trial registration: https://www.clinicaltrials.gov: NCT02457039).

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.

Changing pattern of recurrences in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy in the era of dual anti-HER2 therapy.

BACKGROUND: Over the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to explore the outcome of different neoadjuvant chemotherapy in a tertiary breast cancer centre with early HER2-positive breast cancer as well as factors associated with pathological complete response (pCR) and recurrence-free survival (RFS). The pattern of recurrence was also studied. METHODS: This retrospective study analysed the outcome of neoadjuvant chemotherapy during the period 2005 to 2016 in a tertiary referral centre in Hong Kong. Patients were divided into three groups according to the neoadjuvant chemotherapy they received: chemotherapy only (Chemo), chemotherapy plus trastuzumab (Chemo-H) and chemotherapy plus double anti-HER2 therapy (Chemo-DH). RESULTS: There were 226 cases analysed during the study period. The rate of pCR was 5%, 26% and 60% in Chemo, Chemo-H and Chemo-DH groups, respectively (Chemo vs pooled Chemo-H/DH: p<0.0001; Chemo-H vs Chemo-DH: p<0.0001). This was accompanied by a trend of increased rate of breast conservation therapy in Chemo-DH cohort (p=0.046). Use of double anti-HER2 therapy, older age (>50 years) and hormone receptor negativity were associated with more pCR. pCR was associated with better RFS. Among those with recurrence, the proportion of patients with brain as the only site of recurrence increased remarkably with more efficacious anti-HER2 treatment (0% in Chemo, 8% in Chemo-H, 67% in Chemo-DH). CONCLUSION: pCR remains an important predictive factor for improved RFS. In the era of dual anti-HER2 neoadjuvant therapy, brain-only recurrence poses a challenge to disease surveillance and treatment.

The real-world use of regorafenib for metastatic colorectal cancer: multicentre analysis of treatment pattern and outcomes in Hong Kong.

PURPOSE OF THE STUDY: To evaluate the benefits and tolerability of regorafenib in the real-world setting, we performed a multicentre analysis in Hong Kong. STUDY DESIGN: Individual patient data were retrieved from three leading oncology centres in Hong Kong for analyses. All patients with metastatic colorectal cancer (mCRC) treated with regorafenib after failure of all standard systemic options were included. RESULTS: From July 2013 to December 2015, 45 consecutive patients treated with regorafenib for mCRC were analysed. The median age was 63. Twenty patients were started at 160 mg, while the other 25 patients were started at a lower dose. The median progression-free survival was 15.6 weeks (95% CI 13.1 to 18.1 weeks) and the median overall survival was 30.4 weeks (95% CI 16.6 to 44.3 weeks). Among the 31 evaluable patients, only 1 patient (3.2%) achieved partial response and another 10 patients (32.3%) had stable disease. The commonest grade 3 non-haematological adverse event (AE) was hand-foot skin reaction (26.7%) and the commonest grade 3 or 4 haematological AE was anaemia (8.9%). Notably, patients who were started on a lower dose of regorafenib had significantly lower risk of grade 3 treatment-emergent AEs. Overall, 78.3% of the patients had dose reduction during the first and second cycles. Patients older than 65 years were more likely to experience cycle suspension and require dose reduction. CONCLUSIONS: Our study confirmed the efficacy and tolerability of regorafenib in the real-world setting. It also suggested that individualised dosing of regorafenib in patients with mCRC might result in better clinical outcomes.

Advanced pancreatic cancer: flourishing novel approaches in the era of biological therapy.

The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The mainstream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor ß, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance.

Airway basal cells of healthy smokers express an embryonic stem cell signature relevant to lung cancer.

Activation of the human embryonic stem cell (hESC) signature genes has been observed in various epithelial cancers. In this study, we found that the hESC signature is selectively induced in the airway basal stem/progenitor cell population of healthy smokers (BC-S), with a pattern similar to that activated in all major types of human lung cancer. We further identified a subset of 6 BC-S hESC genes, whose coherent overexpression in lung adenocarcinoma (AdCa) was associated with reduced lung function, poorer differentiation grade, more advanced tumor stage, remarkably shorter survival, and higher frequency of TP53 mutations. BC-S shared with hESC and a considerable subset of lung carcinomas a common TP53 inactivation molecular pattern which strongly correlated with the BC-S hESC gene expression. These data provide transcriptome-based evidence that smoking-induced reprogramming of airway BC toward the hESC-like phenotype might represent a common early molecular event in the development of aggressive lung carcinomas in humans.

Initial experience with the Oncotype DX assay in decision-making for adjuvant therapy of early oestrogen receptor-positive breast cancer in Hong Kong.

OBJECTIVE: To examine the impact of the 21-gene Oncotype DX Breast Cancer Assay on the adjuvant treatment decision-making process for early-stage breast cancer in Hong Kong. DESIGN: Retrospective study. SETTING: Private hospital, Hong Kong. PATIENTS: Study included cases of early-stage breast cancer (T1-2N0-1M0, oestrogen receptor-positive, human epidermal growth factor receptor 2-negative) that were presented at a multidisciplinary breast meeting at a single site. Cases were selected for Oncotype DX testing with the assistance of Adjuvant! Online. The recommendations for adjuvant therapy before and after obtaining the Oncotype DX Recurrence Score results were analysed. RESULTS: A total of 154 cases that met the inclusion criteria were discussed at our multidisciplinary breast meeting. Of these, 64 cases with no clear recommendation by the Meeting Panel were selected for this study and reviewed. The distribution of Recurrence Score results was similar to that reported by others, with a somewhat higher proportion of low Recurrence Scores. Treatment recommendation was changed for 20 (31%) patients after the Oncotype DX result was received. Of the changes in treatment decisions, 16 (80%) were changes to lower-intensity regimens (either equipoise or hormonal therapy). The number of cases receiving an equipoise recommendation decreased by nine (82%), based on the additional information provided by the Oncotype DX test. CONCLUSION: The Oncotype DX Recurrence Score information impacts the decision-making process for adjuvant therapy for early-stage breast cancer in the multidisciplinary care setting in Hong Kong. A larger-scale study is required to gain more experience, evaluate its impact more thoroughly, and assess its cost-effectiveness.

Multimodal Integrative Genomics and Pathology Analyses in Neoadjuvant Nivolumab Treatment for Intermediate and Locally Advanced Hepatocellular Carcinoma.

Introduction: Immunotherapy has resulted in pathologic responses in hepatocellular carcinoma (HCC), but the benefits and molecular mechanisms of neoadjuvant immune checkpoint blockade are largely unknown. Methods: In this study, we evaluated the efficacy and safety of preoperative nivolumab (anti-PD-1) in patients with intermediate and locally advanced HCC and determined the molecular markers for predicting treatment response. Results: Between July 2020 and November 2021, 20 treatment-naive HCC patients with intermediate and locally advanced tumors received preoperative nivolumab at 3 mg/kg for 3 cycles prior to surgical resection. Nineteen patients underwent surgical resection on trial. Seven (36.8%) of the 19 patients had major pathologic tumor necrosis (≥60%) in the post-nivolumab resection specimens, with 3 having almost complete (>90%) tumor necrosis. The tumor necrosis was hemorrhagic and often accompanied by increased or dense immune cell infiltrate at the border of the tumors. None of the patients developed major adverse reactions contradicting hepatectomy. RNA-sequencing analysis on both pre-nivolumab tumor biopsies and post-nivolumab resected specimens showed that, in cases with major pathologic necrosis, the proportion of CD8 T cells in the HCC tissues predominantly increased after treatment. Moreover, to investigate noninvasive biomarker for nivolumab response, we evaluated the copy number variation (CNV) using target-panel sequencing on plasma cell-free DNA of the patients and derived a CNV-based anti-PD-1 score. The score correlated with the extent of tumor necrosis and was validated in a Korean patient cohort with anti-PD-1 treatment. Conclusion: Neoadjuvant nivolumab demonstrated promising clinical activity in intermediate and locally advanced HCC patients. We also identified useful noninvasive biomarker predicting responsiveness.

Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis.

Shwachman-Diamond syndrome (SDS) results from mutations in the SBDS gene, characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. Neutropenia and neutrophil dysfunction are hallmark features of SDS; however, causes for the bone defects are unknown. Dysfunction of bone-resorbing osteoclasts, formed by the fusion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG). Sbds-null murine monocytes formed osteoclasts of reduced number and size because of impaired migration and fusion required for OCG. Phenotypically, Sbds-null mice exhibited low-turnover osteoporosis consistent with findings in SDS patients. Western blotting of Rho GTPases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling downstream of receptor activator of nuclear factor-κB (RANK) and reduced expression of the RANK-ligand-dependent fusion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulating monocyte migration via Rac2 and osteoclast differentiation signaling downstream of RANK. Impaired osteoclast formation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients.

Consensus Statements on Precision Oncology in the China Greater Bay Area.

BACKGROUND: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA. METHODS: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0. RESULTS: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice. CONCLUSION: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits.

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed.

Is there a role for unstimulated thyroglobulin velocity in predicting recurrence in papillary thyroid carcinoma patients with detectable thyroglobulin after radioiodine ablation?

BACKGROUND: In the follow-up of papillary thyroid cancer (PTC) patients treated with curative thyroidectomy and radioiodine ablation, raised thyroglobulin (Tg) predicts recurrence with reasonable sensitivity and specificity. However, a proportion of patients present with raised Tg level but no other clinical evidence of disease. Only limited data on Tg kinetics have been reported to date. Here we aim to evaluate the prognostic and predictive significance of nonstimulated serum Tg velocity (TgV). METHODS: Consecutive PTC patients treated with curative thyroidectomy and radioiodine ablation between 2003 and 2010 were analyzed. Patients with at least one detectable Tg measurement (>0.2 ng/mL) were included. TgV was defined as the annualized rate of Tg change. Logistic regression analyses were performed to evaluate the role of TgV in the prediction of disease recurrence. The optimal TgV cutoff was assigned by receiver-operating characteristic curve analysis. Overall survival of patients above versus below the TgV cutoff were determined by the Kaplan-Meier method and compared. RESULTS: Of a total of 501 patients, 87 had at least one Tg value >0.2 ng/mL; in these latter patients, 29 (33.3%) developed recurrence. TgV was an independent predictor of the recurrence. TgV ≥0.3 ng/mL per year predicted recurrence with a sensitivity of 83.3% and specificity of 94.4%. Patients with TgV below the cutoff had a significantly better overall survival (p = 0.038). CONCLUSIONS: TgV predicts recurrence with high sensitivity and specificity, and is a prognosticator of survival in postthyroidectomy and postablation PTC patients with raised Tg.

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC).

BACKGROUND: With the aging population, hepatocellular carcinoma (HCC) in the elderly represents a significant health burden. We aimed to evaluate and compare the efficacy and tolerability of single-agent sorafenib in treating elderly patients with advanced HCC versus the younger population. METHODS: We retrospectively analyzed a consecutive cohort of advanced HCC patients with Child-Pugh A or B liver function and an Eastern Cooperative Oncology Group performance status score of 0-2 treated with sorafenib. The patients were categorized into older (age ≥70 years) and younger (age <70 years) groups. Treatment outcomes and related adverse events (AEs) were compared. RESULTS: In total, 172 patients, 35 in the older (median age, 73 years) and 137 in the younger (median age, 55 years) group, were analyzed. The median progression-free survival time was similar in the older and younger groups (2.99 months versus 3.09 months; p = .275), as was the overall survival time (5.32 months versus 5.16 months; p = .310). Grade 3 or 4 AEs were observed in 68.6% of older and 62.7% of younger patients (p = .560), with neutropenia (11.4% versus 0.7%; p = .007), malaise (11.4% versus 2.2%; p = .033), and mucositis (5.7% versus 0.0%; p = .041) being more frequently reported in the elderly cohort. CONCLUSIONS: The survival benefits and overall treatment-related AEs of sorafenib are comparable in elderly and younger advanced HCC patients. Nevertheless, more vigilant monitoring in the elderly is warranted because they are more susceptible to develop neutropenia, malaise, and mucositis.

Neoadjuvant Therapy with Concurrent Docetaxel, Epirubicin, and Cyclophosphamide (TEC) in High-Risk HER2-Negative Breast Cancers.

INTRODUCTION: Concurrent anthracycline and taxane is an effective and efficient way to deliver neoadjuvant chemotherapy for HER2-negative breast cancers. Data on efficacy and tolerance to 6 cycles of concurrent docetaxel, epirubicin, and cyclophosphamide (TEC) is limited. METHOD: All patients with HER2-negative breast cancers who received neoadjuvant TEC from January 2013 to December 2019 were reviewed. RESULTS: A total of 71 patients [57 luminal B disease; 14 triple negative breast cancer (TNBC)] received neoadjuvant TEC with prophylactic granulocyte colony-stimulating factor (G-CSF). The pathological complete response (pCR) rate was 26.3% and 28.6% for luminal B and TNBC, respectively. With median follow-up of 48.9 months, 3 years disease-free survival was 85.9%, and 3 years overall survival was 89.6%. Non-hematological toxicities were common but the majority was grade 1 or 2. The most common grade 3 or 4 toxicity were hematological, including neutropenia (26.8%) and anemia (15.5%). There was no cardiotoxicity observed. Half of the patients had at least one dose reduction but all patients completed the planned 6 cycles and had breast surgery done. CONCLUSION: Six cycles of TEC with prophylactic G-CSF is an effective and tolerable neoadjuvant regime for HER2-negative breast cancers. Hematological toxicities were the most common toxicities. Although many patients required dose reduction, all patients completed treatment and there was no observed cardiotoxicity.

The Outcomes of Systemic Treatment in Recurrent Hepatocellular Carcinomas Following Liver Transplants.

BACKGROUND: Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. METHODS: Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. RESULTS: Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months (CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p < 0.001) with a hazard ratio of 0.104 (log-rank test, p < 0.001). A total of 41 patients had received systemic therapies and 79.1% of them were on sorafenib as the first-line treatment. Among these patients treated with sorafenib, median OS from recurrence was 14 months (CI 7.3, 20.7). Hand-foot syndrome (34.7%) was most common among AEs followed by diarrhoea (26.7%). Overall, AEs led to dose interruptions in 8.8% of patients. Notably, 47.1% of patients received subsequent lines of systemic therapies after sorafenib. CONCLUSIONS: Early recurrence within 1 year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.

Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC.

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.