Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer.

OBJECTIVES: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for âˆ¼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. MATERIALS AND METHODS: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. RESULTS: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. CONCLUSION: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

Patterns of care and survival of Chinese glioblastoma patients in the temozolomide era: a Hong Kong population-level analysis over a 14-year period.

Background: The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods: This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results: One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). Conclusions: The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

Genomic Landscape of Non-Small Cell Lung Cancer (NSCLC) in East Asia Using Circulating Tumor DNA (ctDNA) in Clinical Practice.

Plasma-based next-generation sequencing (NGS) has demonstrated the potential to guide the personalized treatment of non-small cell lung cancer (NSCLC). Inherent differences in mutational genomic profiles of NSCLC exist between Asian and Western populations. However, the published mutational genomic data of NSCLC has largely focused on Western populations. We retrospectively analyzed results from comprehensive NGS of plasma (Guardant360®) from patients with advanced non-squamous NSCLC, as seen in clinical practice. Tests were ordered between January 2016 and December 2020 in Hong Kong, Korea, Taiwan, Japan and Southeast Asia. The assay identified single-nucleotide variants (SNV), insertions and deletions, and fusions and amplifications in 74 genes. In total, 1608 plasma samples from patients with advanced non-squamous NSCLC were tested. The median turnaround time for test results was 7 days. Of the samples with detectable ctDNA (85.6%), 68.3% had alterations in at least one NCCN-recommended NSCLC biomarker. EGFR driver mutations were most frequent (48.6%), followed by alterations of KRAS (7.9%), ERBB2 (4.1%) and ALK (2.5%). Co-mutations of EGFR and KRAS occurred in 4.7% of samples. KRAS G12C was identified in 18.6% of all samples with KRAS mutations. Common mutations, such as exon 19 deletions and L858R, accounted for 88.4% of EGFR driver mutations. Among the samples with any EGFR driver mutation, T790M was present in 36.9%, including 7.7% with additional alterations associated with osimertinib resistance (MET amplification, C797X). Comprehensive plasma-based NGS provided the timely and clinically informative mutational genomic profiling of advanced non-squamous NSCLC in East Asian patients.

Repurposing sodium-glucose co-transporter 2 inhibitors (SGLT2i) for cancer treatment - A Review.

Developed as an antidiabetic drug, recent evidence suggests that several sodium-glucose co-transporter 2 inhibitors (SGLT2i), especially canagliflozin and dapagliflozin, may exhibit in vitro and in vivo anticancer activities in selected cancer types, including an inhibition of tumor growth and induction of cell death. When used in combination with chemotherapy or radiotherapy, SGLT2i may offer possible synergistic effects in enhancing their treatment efficacy while alleviating associated side effects. Potential mechanisms include a reduction of glucose uptake into cancer cells, systemic glucose restriction, modulation of multiple signaling pathways, and regulation of different gene and protein expression. Furthermore, preliminary clinical findings have reported potential anticancer properties of canagliflozin and dapagliflozin in patients with liver and colon cancers respectively, with reference to decreases in their tumor marker levels. Given its general tolerability and routine use in diabetes management, SGLT2i may be a good candidate for drug repurposing in cancer treatment and as adjunct to conventional therapies. While current evidence reveals that only certain SGLT2i appear to be effective against selected cancer types, further studies are needed to explore the antitumor abilities of each SGLT2i in various cancers. Moreover, clinical trials are called for to evaluate the safety and feasibility of introducing SGLT2i in the treatment regimen of patients with specific cancers, and to identify the preferred route of drug administration for targeted delivery to selected tumor sites.

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Patient-derived tumor organoid predicts drugs response in glioblastoma: A step forward in personalized cancer therapy?

Despite significant medical advances, glioblastoma multiforme (GBM) remains a formidable therapeutic challenge. Advent of targeted capture sequencing and patients-derived organoid cultures may hold the key to scientifically sound individualized treatment approaches. We report on our initial experience of using the combination of these two technologies to create a tailored approach of systemic therapies for a patient with GBM, which challenges the conventional treatment paradigm, as well as specifically highlighting the complexities of such an approach and the potential for a more favorable treatment outcome.

Predictive biomarkers and tumor microenvironment in female genital melanomas: a multi-institutional study of 55 cases.

Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and KIT and BRAF mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm2. Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored KIT mutations, three of which were hotspots. BRAF V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm2, lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.

Regression of BRAF V600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases.

BACKGROUND: Up to 15% of young adults with glioblastoma have the activating oncogenic BRAF V600E mutation, an actionable target of the MAPK signal transduction pathway governing tumor cell proliferation. Small molecule inhibitors of BRAF and MEK, a downstream protein immediately following BRAF, have been shown to confer a survival advantage for patients with BRAF V600E mutant advanced melanoma. We describe our experience using this combined target therapy for two patients with BRAFV600E mutant glioblastoma (GBM) as primary treatment due to extenuating clinical circumstances that prohibited the prescription of standard treatment. CASE PRESENTATION: The two patients were both 22 years old on presentation. After the initial tumor resection, they both developed rapid deterioration in performance status within a few weeks due to leptomeningeal metastases. In view of the critical condition, BRAF and MEK inhibitors were prescribed as first line treatment. The two patients both achieved dramatic clinical response, which was parallel to the impressive radiological regression of the disease. Unfortunately, the duration of disease control was short as drug resistance developed rapidly. The two patients died 7 and 7.5 month after initial diagnosis of GBM. CONCLUSIONS: Primary treatment with inhibitors of BRAF and MEK can lead to tumor regression for patients with BRAF V600E mutant glioblastoma. We therefore recommend that all young GBM patients should undergo BRAFV600E mutation testing, especially for those with unusual aggressive clinical course.

Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

A feasibility study on using tablet personal computers for self-reported symptom assessment in newly diagnosed lung cancer patients.

AIM: The study aimed to assess the feasibility and acceptability of an innovative tablet-assisted self-reported symptom assessment among newly diagnosed lung cancer patients. BACKGROUND: Routine symptom assessment for lung cancer patients in a fast-paced clinical environment is demanding. Mobile health technology offers a potential platform for symptom assessment and paves the way for tailored self-care intervention. DESIGN: A feasibility study using a mixed method design. METHOD: A convenience sample of 10 newly diagnosed lung cancer patients used tablet personal computers to self-report common symptoms: dyspnoea, fatigue, pain, and anxiety. A nurse reviewed the assessment results and provided tailored educational interventions. Acceptability was evaluated by the Electronic Self-Report Assessment-Cancer. Semi-structured interviews were conducted to explore the patients' perceptions of this symptom assessment method. Data were collected from January to March 2016. RESULTS: An Electronic Self-Report Assessment-Cancer mean score of 23.5 (SD 2.7) showed moderate acceptance of the assessment method. Participants found this approach user-friendly and helpful in identifying their symptoms and they gained awareness and better understanding of them. CONCLUSION: Tablet-assisted symptom assessment is a feasible method that can be further tested in busy clinical settings to assess symptom burden and identify individual needs for tailoring symptom management plans.

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.

Efficacy, Safety, and Pharmacokinetics of Axitinib in Nasopharyngeal Carcinoma: A Preclinical and Phase II Correlative Study.

Purpose: We hypothesized that axitinib is active with an improved safety profile in nasopharyngeal carcinoma (NPC).Experimental Design: We evaluated axitinib in preclinical models of NPC and studied its efficacy in a phase II clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice daily in continuous 4-week cycles. Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria for more than 3 months.Results: We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) receiving ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI, 65.6%-91.2%) at 3 months and 43.2% (30.4%-56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%), and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during the first 3 months of axitinib treatment was significantly associated with improved overall survival (HR, 0.29; 95% CI, 0.13-0.64, P = 0.0012). Patient-reported fatigue symptom was associated with hypothyroidism (P = 0.039). Axitinib PK parameters (Cmax and AUC(0-t)) were significantly correlated with tumor response, toxicity, and serum thyroid-stimulating hormone changes.Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients. Clin Cancer Res; 24(5); 1030-7. ©2018 AACR.

PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy.

We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of non-small cell lung cancer (NSCLC). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates phosphatase and tensin homolog (PTEN) to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using human NSCLC cell models with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was evaluated. PPARγ agonists were found to upregulate PTEN, subsequently inhibiting the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Chemical and genetic inhibition of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARγ agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect by the PPARγ agonists. Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients.

Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer.

The discovery of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has led to unprecedented clinical response in a subset of lung cancer patients carrying the sensitizing EGFR mutations (L858R or exon 19 deletion). However, disease progression invariably occurs within a year after the initial TKI treatment, predominantly due to the development of acquired resistance caused by the secondary EGFR T790 M mutation. Numerous second generation irreversible and third generation EGFR T790 M selective EGFR TKIs have been developed to overcome resistance. Besides developing new EGFR TKIs, combination therapy represents another promising strategy to combat resistance. This approach aims at circumventing drug resistance through a so-called bypass signaling mechanism by targeting horizontal pathways or vertical pathways or both. The logical combinations of different molecular targeted drugs inhibiting various oncogenic signaling have been studied. On the other hand, the repurposing of drugs with indications other than oncology has also emerged as a promising approach. In this review, we focus on the effectiveness of combination therapy of EGFR-TKIs with different agents in advanced lung cancer.

Profiles of lipids, blood pressure and weight changes among premenopausal Chinese breast cancer patients after adjuvant chemotherapy.

BACKGROUND: Adjuvant chemotherapy improves outcome of patients with early breast cancer. However, chemotherapy may be associated with long term toxicities. In this retrospective cohort study, the objectives were to determine body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal Chinese breast cancer patients after adjuvant chemotherapy. Potential factors associated with these parameters were identified. METHODS: Eligibility criteria include premenopausal Chinese patients who were diagnosed to have stage I-III breast cancer within 3-10 years, age < 45 and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Information at initial breast cancer diagnosis were retrieved from patients' medical records and include age at diagnosis, tumor characteristics, anti-cancer treatments, blood pressure and body weight and height. At study entry, all patients had additional background demographics collected, as well as blood pressure, body weight and fasting serum lipid profiles measured. Incidence of chemotherapy-related amenorrhoea (CRA) and menopause were determined. Factors associated with weight gain, hypertension and dyslipidaemias were analyzed. RESULTS: Two hundred and eighty patients were studied. The median age at breast cancer diagnosis was 41 years (range: 24-45). The median time from breast cancer diagnosis to study entry was 5.0 years. The median age at study entry was 46.5 years (range: 28-54). 91.1% developed CRA; 48.9% had become menopausal and 10% were peri-menopausal. Between initial breast cancer diagnosis and the time of study entry, the median weight gain was 1.8 kg; 63.2% gained weight by >2%; 52.1% were overweight/obese; 30.7% had hypertension. Abnormal total-cholesterol and LDL-cholesterol occurred in 34.3% and 56.1% respectively. On multivariate analyses, older age was associated with reduced risk while occurrence of CRA and having received taxane-containing regimens were associated with increased risk of weight gain. Oestrogen-receptor positivity was associated with reduced risk while overweight/obese statuses were associated with increased risk of hypertension. Use of tamoxifen was associated with reduced risk of abnormal LDL-cholesterol. Weight gain, overweight/obese, older age, progression to post/peri-menopausal status at study entry, having received corticosteroid premedication before adjuvant chemotherapy and having received taxane-containing adjuvant chemotherapy were associated with increased risk of dyslipidaemias. CONCLUSION: Among young premenopausal Chinese breast cancer patients who had received adjuvant chemotherapy, the current study has revealed that although there was only a median weight gain of 1.8 kg, there was a nearly 60% increase in abnormal BMI. Further, a significant proportion of patients were detected to have hypertension and dyslipidaemias. Interventional studies with lifestyle modifications are warranted.

Clinical utility of plasma Epstein-Barr virus DNA and ERCC1 single nucleotide polymorphism in nasopharyngeal carcinoma.

BACKGROUND: Single nucleotide polymorphism (SNP) of the excision repair cross-complementing group 1 (ERCC1) gene has been linked with sensitivity to platinum and radiation. The authors hypothesized that the ERCC1 genotype for the SNPs cytosine-to-thymine substitution at codon 118 (C118T) and cytosine-to-adenine substitution at codon 8092 (C8092A) is prognostic in patients with nasopharyngeal carcinoma (NPC) who receive either radiotherapy (RT) or cisplatin plus RT. METHODS: The authors tested their hypothesis using biomarker screening samples from the Hong Kong NPC Study Group 0502 trial, which was a prospective, multicenter clinical trial that used post-RT plasma Epstein-Bar virus (EBV) DNA (pEBV) levels to screen patients with high-risk NPC for adjuvant chemotherapy. RESULTS: ERCC1 SNPs were analyzed in 576 consecutive patients who were screened by pEBV. In the total biomarker population, there was no significant association of ERCC1 C118T or C8092A genotype with relapse-free survival (RFS) or overall survival (OS). There also was no correlation between ERCC1 genotype and ERCC1 protein or messenger RNA expression in a subset of patients who had available paired biopsies. Post-RT pEBV status was the only independent prognosticator for RFS and OS in multivariate analyses. However, there was a significant interaction between ERCC1 C118T genotype and post-RT pEBV status (RFS, P = .0106; OS, P = .0067). The ERCC1 C118T genotype was significantly associated with both RFS (hazard ratio, 1.67; 95% confidence interval, 1.07-2.61; P = .024) and OS (hazard ratio, 2.31; 95% confidence interval, 1.22-4.40; P = .0106) in the post-RT pEBV-negative population, but not in the pEBV-positive population. CONCLUSIONS: The current results prospectively validate pEBV as the most significant prognostic biomarker in NPC that can be used to select high-risk patients for adjuvant therapy. The ERCC1 C118T genotype may help to identify a favorable subgroup (approximately 7%) of pEBV-negative patients with NPC who have an excellent prognosis and can be spared the toxicities of further therapy.

Use of antiviral therapy in surveillance: impact on outcome of hepatitis B-related hepatocellular carcinoma.

BACKGROUND: Antiviral therapy for hepatitis B virus (HBV) infection is frequently prescribed for patients with chronic HBV infection during surveillance for hepatocellular carcinoma (HCC). In patients who subsequently develop HCC, the impact of antiviral therapy on the outcome of HCC remains unclear. AIMS: We aimed to study the impact of antiviral therapy on the survival of patients who developed HCC. METHODS: From two prospective surveillance cohorts, the use of antiviral therapy for patients with HCC was retrospectively reviewed. We compared the overall survival, liver function and tumour characteristics between patients with and without antiviral therapy during surveillance. Multivariate analysis was conducted to determine the independent prognostication of antiviral therapy. RESULTS: During a median follow-up of 10.1 years of 1429 patients, 148 cases of HCC were diagnosed and followed up for a median of 5.7 years. Twenty-nine patients were given antiviral therapy during surveillance and continued treatment after diagnosis of HCC. The median survival of this group of patients was better than the rest of cohorts (hazard ratio: 0.472; 95% CI: 0.25-0.89; P = 0.0191). Use of antiviral therapy remained an independent prognostic factor after adjustment for demographic factors and tumour staging on multivariate analysis. Exploratory analysis revealed that patients who commenced antiviral therapy during surveillance had lower HBV DNA, lower serum alanine transaminase, better hepatic reserves and higher rate of local treatment at diagnosis of HCC. CONCLUSION: This study provides evidence that commencement of antiviral therapy during the surveillance period is associated with improvement in overall survival in HBV-related HCC.