Kiruthikah Thillai

FOLFIRINOX - a new paradigm in the treatment of pancreatic cancer.

Treatment of metastatic and locally advanced pancreatic cancer has made slow progress during the last decade. Single agent gemcitabine or in combination with capecitabine or erlotinib remained the preferred systemic treatment options until 2010 when the ACCORD study demonstrated significantly improved outcomes achieved with FOFIRINOX compared with gemcitabine monotherapy. Since 2010, use of FOLFIRINOX has increased both in metastatic and locally advanced cancer. Despite its gaining popularity among oncologists, unanswered questions remain. Do the often necessary dose modifications affect its efficacy? Are the toxicities manageable and how applicable are the results of the ACCORD study in the general population of patients with newly diagnosed pancreatic cancer? In the present manuscript, we review the published literature regarding the use of FOLFIRINOX, the challenges associated with its use and how it will be optimally incorporated into the management of patients with different stages of pancreatic cancer and ultimately, in a more biomarker-driven pathway algorithm.

PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration.

It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity.

Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?

The development of personalised therapies has ushered in a new and exciting era of cancer treatment for a variety of solid malignancies. Yet pancreatic ductal adenocarcinoma (PDAC) has failed to benefit from this paradigm shift, remaining notoriously refractory to targeted therapies. Chemotherapy is the cornerstone of management but can offer only modest survival benefits of a few months with 5-year survival rates rarely exceeding 3%. Despite these disappointing statistics, significant strides have been made towards understanding the complex biology of pancreatic cancer, with deep genomic sequencing identifying novel genetic aberrations and key signalling pathways. The PI3K-PDK1-AKT pathway has received great attention due to its prominence in carcinogenesis. However, efforts to target several components of this network have resulted in only a handful of drugs demonstrating any survival benefit in solid tumors; despite promising pre-clinical results. p-21 activated kinase 4 (PAK4) is a gene that is recurrently amplified or overexpressed in PDAC and both PAK4 and related family member PAK1, have been linked to aberrant RAS activity, a common feature in pancreatic cancer. As regulators of PI3K, PAKs have been highlighted as a potential prognostic marker and therapeutic target. In this review, we discuss the biology of pancreatic cancer and the close interaction between PAKs and the PI3K pathway. We also suggest proposals for future research that may see the development of effective targeted therapies that could finally improve outcomes for this disease.

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: age is not a problem.

Objective Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but data on its use in the elderly are inconclusive. Methods All consecutive HCC patients who were treated in our institution with sorafenib since its licensing were included in the analysis. Patients were divided into two groups: (A) up to 75 and (B) older than 75 years old. Our endpoints were overall survival (OS) and time to treatment failure (TTF) because of disease progression or toxicity. Safety parameters and the prognostic effect of HCC characteristics were also investigated. Results Data from 190 patients (157 men), median age 66 (26–87) years, were studied (A=151 and B=39). No significant difference in OS and TTF was detected between the two groups [7.1 (5.5–8.7) vs. 10.4 (6.5–14.3) months, P=0.360 and 4.2 (2.3–6.2) vs. 5.6 (3.1–8.1) months, P=0.369, respectively]. Incidence of toxicities at all grades and dose reductions were comparable between groups A and B. In a multivariate setting, patients with Child–Pugh B score at baseline were associated with a higher risk of death (adjusted hazard ratio=2.17, 95% confidence interval:1.24–3.79, P=0.007) and treatment failure (adjusted hazard ratio=4.64, 95% confidence interval: 2.55–8.42, P=0.001) and had shorter OS and TTF compared with patients with a Child–Pugh A (P=0.004 and P<0.001, respectively). Conclusion Elderly patients with advanced HCC, when treated with sorafenib, have an equivalent clinical outcome with similar toxicity rates as their younger counterparts. Age alone should not be a discriminating factor for the management of advanced HCC with sorafenib.

Regorafenib as treatment for patients with advanced hepatocellular cancer

Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwide. Sorafenib was the first and only drug to improve survival for patients with advanced disease, and has been the cornerstone of treatment for nearly a decade. Regorafenib is a multikinase inhibitor that has recently been shown to significantly improve survival in patients who have progressed on first-line sorafenib. In this review, we discuss the pharmacokinetic and pharmacodynamics properties of regorafenib and its efficacy and tolerability in patients with advanced hepatocellular carcinoma.

Abstract P3-17-09: Resolution of DCIS in patients with early breast cancer receiving primary chemotherapy for invasive breast cancer

Background Ductal Carcinoma in Situ (DCIS) plays a pivotal role in surgical planning for patients who are to undertake primary chemotherapy. As DCIS is not thought to be responsive to chemotherapy, many women with large primaries or extensive DCIS on initial diagnosis will be planned for and undergo mastectomy. To investigate the role of chemotherapy in invasive breast cancer with concomitant ductal carcinoma in situ (DCIS), we examined patients who had primary systemic therapy for a primary invasive cancer with either radiologically or histologically proven DCIS to see if there were patients in whom there was no evidence of DCIS at resection. Methods This was a retrospective single centre study. Examining the records of all patients who had received primary chemotherapy between January 2010 and October 2014. Patients were identified through the Guy9s breast cancer database and chemotherapy prescribing system. To fully assess the DCIS status, all patients were cross-referenced with the electronic notes on our electronic noting system (MOSAIQ), radiology on Patient Archiving and Communication System (PACS) and histology on our Electronic Patient Record (EPR). Results 1526 patients were identified, of whom 156 underwent primary chemotherapy. Of these, 46 patients had a pre-chemotherapy biopsy confirming DCIS, of whom 30 also had radiological evidence of DCIS. A further 26 had micro-calcification on their initial imaging which was presumed to be DCIS. Twelve of the 46 patients with biopsy proven DCIS at presentation did not have DCIS at resection. Of these 9 had a mastectomy, with 5 achieving a pathological complete response (pCR), of whom 4 had a complete radiological response (rCR). Of the 26 who had micro-calcification pre-chemotherapy, 15 did not have DCIS in the resection specimen. Of these, 10 had a mastectomy, with 6 having a pCR of whom 3 also had rCR. Conclusion This retrospective study suggests that chemotherapy can influence DCIS, with 12 biopsy proven having a pCR post treatment. This may indicate that some patients may be spared mastectomy. Although there were patients with radiological evidence of DCIS, without a confirmatory biopsy we cannot be sure that these were malignant. This highlights the need to ensure that all suspicious areas distant from the primary tumour should be biopsied before treatment. In conclusion, for patients who have an excellent clinical and radiological response, even in the presence of DCIS at presentation, more intensive evaluation is indicated if conservative surgery is a possibility. Citation Format: Chowdhury MHR, Thillai K, Lucey A, Michalarea V, Mera A, Karapanagiotou E, Sandri I, Mansi J. Resolution of DCIS in patients with early breast cancer receiving primary chemotherapy for invasive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-09.