Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Real-world experience of the feasibility and tolerability of the 2:1 dosing schedule with sunitinib in the treatment of patients with advanced renal cell carcinoma in Australia

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Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer

Purpose To report toxicity data from the first 13 consecutive patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), ineligible for cisplatin, treated with concurrent cetuximab and radiotherapy (RT) at our institution. Materials and methods Data were collected prospectively between August 2007 and May 2008. Planned treatment consisted of a cetuximab loading dose (400 mg/m2) via intravenous infusion 1 week prior and then weekly (250 mg/m2) with 70 Gy in 35 daily fractions over 7 weeks. Results Median age was 68 years (range 52–82 years). The predominant primary sites were hypopharyngeal (5) and oropharyngeal (5). Ineligibility for cisplatin consisted of renal impairment (5), hearing impairment (4) and of other major co-morbidities (4). Of the 13 patients, 10 (77%) had grade 3/4 skin reactions and 10 (77%) grade 3/4 mucositis. Six (46%) patients required admission for management of severe skin reactions and/or mucositis with 4 (31%) requiring a treatment break, median 10 days (9-15days). Only 4 (31%) patients managed to complete the planned 8 cycles of cetuximab. Of the 9 patients with 12-week post-therapy data, 7 (78%) achieved a complete response. Conclusions Our early experience with cetuximab/RT has demonstrated a higher rate of toxicity compared with the recently reported randomised trial, resulting in low treatment compliance and delays in completing RT

Intensity-modulated radiotherapy using simultaneous-integrated boost for definitive treatment of locally advanced mucosal head and neck cancer: Outcomes from a single-institution series

Introduction: The study aims to report outcomes for patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous-integrated boost and weekly cisplatin for American Joint Committee on Cancer stage III/IV mucosal head and neck squamous cell carcinomas (HNSCCs). Methods: Records for 67 patients treated definitively with IMRT for HNSCC were reviewed. By including only those treated with weekly cisplatin, 45 patients were eligible for analysis. Treatment outcomes, effect of patient, tumour and treatment characteristics on disease recurrence were analysed. Results: All patients completed IMRT to 7000 cGy in 35 fractions, with concurrent weekly cisplatin 40 mg/m2 (median 6 cycles). Median follow-up was 28 months for living patients. Two-year loco-regional recurrence-free, metastasis-free and overall survival were 85.4, 81.0 and 87.4%, respectively. Local recurrence occurred in three patients, and distant recurrence in eight patients. Conclusions: Our results show efficacy of IMRT and weekly cisplatin in the treatment of stage III/IV HNSCC at our institution with respect to loco-regional control

Cessation of targeted therapy after a complete response in BRAF-mutant advanced melanoma : a case series

Background: It is unknown whether melanoma patients achieving complete response (CR) with targeted therapy can safely discontinue treatment. Methods: All patients treated with BRAF/MEK inhibitors achieving CR and ceasing treatment before progression were identified. Clinical data at treatment initiation, cessation and progression were examined. Results: A total of 12 eligible patients were identified, with median follow-up of 16 months, of whom 6 (50%) recurred at a median of 6.6 months after treatment cessation. One patient lost to follow-up until presentation with symptomatic recurrence was the only relapser to die. At relapse, the remaining five patients had an LDH <1.2 times ULN, four were ECOG 0 and one ECOG 1. Baseline characteristics and time to CR and to discontinuation did not influence the rate of relapse. Conclusions: A large proportion of patients achieving CR with BRAF/MEK inhibitors relapse after treatment cessation. The optimal treatment duration in such patients is unclear, particularly where alternative treatments are available.5 page(s

Residual FDG-PET metabolic activity in metastatic melanoma patients with prolonged response to anti-PD-1 therapy

18-Fluorodeoxyglucose positron emission tomography (FDG-PET) scans were performed on 27 patients with unresectable stage IIIC or IV melanoma after prolonged treatment with anti-PD-1 antibodies to examine the hypothesis that patients with prolonged response to treatment may have metabolically inactive lesions by FDG-PET. Scans were performed at a median of 15.2 months (range 12-29 months) after starting treatment. Overall, 15 of 27 (56%) patients had a positive FDG-PET scan. Eight patients with positive scans underwent biopsy; 5 of 8 (62%) were melanoma and 3 of 8 (38%) were immune cell infiltrates. Of the 12 patients with negative FDG-PET scans, six had residual computerized tomography-visible lesions, five have ceased treatment, and none have recurred with follow-up of 6-10 months. Patients with residual metastases after a prolonged period without progression on anti-PD-1 therapy may have metabolically inactive lesions. Isolated metabolically active lesions in clinically well patients may reveal immune cell infiltrates rather than melanoma.6 page(s

Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

Background: The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. Methods: For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. Results: The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P <.001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. Conclusions: Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.10 page(s