A.C. Whitley

Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer.

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.

In Regard to Kirchheiner et al

To the Editor: We read with interest the article by Kirchheiner and colleagues (1), as cancer survivorship issues are integral components of cancer care. According to their report, 41% of cervical cancer patients undergoing brachytherapy with 2 fractions given on consecutive days, with epidural anesthesia between fractions, suffer from posttraumatic stress disorder (PTSD) symptoms 3 months after therapy. The most distressing aspect noted was hemibody (epidural) anesthesia between fractions, although 37% of patients declared inadequate pain control, and 2% (1 patient) declared it was placement of the brachytherapy applicator. Although we agree with the authors on the invasiveness of the procedure in an intimate and vulnerable body area, and a cancer diagnosis is a qualifying event, the procedure itself does not meet criterion A as a stressor in the Diagnostic and Statistical Manual of Mental Disorders (DSM), fourth or fifth edition (2, 3), because it is not a lifethreatening stressor. Consent is obtained ostensibly with a “full understanding” by the patient before any procedures/ treatments, although we do not deny the unique nature of this treatment. Similar findings were observed, as noted by the authors, in patients after intensive care unit stays from severe illness (4, 5) and advanced gynecologic cancer patients after surgery (6). This indicates that many, perhaps most, invasive and painful procedures would result in PTSD. We would expect a very high rate of PTSD or PTSD-like symptoms related to medical procedures in the community given the number of people who experience such events. There may be confusion between cause and attribution. Inserting the word “brachytherapy” in the PTSD interview or the Impact of Event Scale-Revision (IES-R) assumes a causal relationship between the stated event and the PTSDlike symptoms. Unless participants actually stated independently prior to the attribution by an interviewer that

Contemporary Guidelines in Whole-Breast Irradiation: an Alternative Perspective

The American Society for Radiation Oncology produced an evidence-based guideline on whole-breast radiation therapy for patients with early-stage invasive breast cancer and ductal carcinoma in situ. This commentary points out areas where we believe the data are too limited to make definitive recommendations and where alternative approaches are supported by evidence.

Novel setup techniques for radiation treatment of severely obese patients with cervical cancer

The prevalence of overweight (body mass index [BMI] N 25 kg/m2) and obesity (BMI N30 kg/m2) in the United States currently exceeds two-thirds of the adult population. Obesity and severe obesity (BMI N 40 kg/m2) may impact the management of early-stage cervical cancer, where surgical resection is often the preferred treatment.1 Due to medical comorbidities and surgical risks, these patients are often not considered surgical candidates, and definitive radiation or chemoradiation may be the only curative option. Although most patients with inoperable cervical cancer are physically able to undergo a computed tomographic (CT) simulation and subsequent radiation treatment, patients with severe obesity and large abdominopelvic girth may present obstacles in simulation, treatment planning and dosimetry, and treatment delivery. Potential clinical problems include weight in excess of simulator or treatment table limits, girth in excess of CT bore or field of view,2 poor image quality secondary to tissue attenuation, creating an accurate body contour, achieving an acceptable dose distribution and heterogeneity index given the confines of beam arrangement and body thickness, gantry clearance issues, issues with patient setup and verification, and reliability of external fiducials. In this study, we report

Abstract 4684: Synthetic lethal interaction between EGFR and PARP inhibition

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Purpose: Dysregulation of the epidermal growth factor receptor (EGFR) family is a hallmark of many cancers. Although targeting of EGFR family has improved outcomes, many patients ultimately fail this therapy. PARP inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing homologous recombination (HR)-deficient tumors while maintaining minimal toxicity in normal tissues. We have previously shown that EGFR inhibition induces synthetic lethality with PARPi in head and neck squamous cell carcinomas (HNSCCs) in vitro by attenuating DNA repair pathways. In this study, we validated these observations in vivo in HNSCCs xenografts. Importantly, we also tested this strategy in other EGFR dysregulated cancers. Methods: Cervical, breast, and head and neck cancer cell lines were used in this study. DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci and/or chromosomally integrated HR and nonhomologous end-joining based GFP reporter assays. Cell viability was determined via colony formation and ATPlite assays. Tumor growth delay was assessed in mice bearing tumor xenografts. Results: Combined EGFR and PARP inhibition resulted in the greatest tumor growth delay versus either agent alone in mice bearing head and neck tumor xenografts (9 week tumor growth delay when compared to PARPi alone, 3 week tumor growth delay when compared to EGFR inhibitor alone). This correlated with persistent γ-H2AX foci indicative of unresolved DNA damage. Interestingly, this combination was also effective in other EGFR dysregulated tumors. Human cervical and breast cancer cells exhibited enhanced cytotoxicity with EGFR and PARP inhibition compared to either agent alone (80-99% cytotoxicity with combination vs 0-20% with either agent alone). Similar to head and neck cancer, susceptibility to PARPi induced by EGFR inhibition was associated with deficient NHEJ- and HR-mediated DNA repair and subsequent persistence of DNA damage. Conclusions: Thus, by generating a DNA repair deficit, EGFR inhibition can induce synthetic lethality with PARP inhibition. This can be an innovative treatment strategy for tumors with dysregulated EGFR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4684. doi:1538-7445.AM2012-4684

Abstract 5496: Cetuximab induces synthetic lethality with the poly (ADP-Ribose) polymerase (PARP) inhibitor ABT-888 in head and neck cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Purpose: Overexpression/amplification of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab, almost half of treated patients fail this therapy. PARP inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing homologous recombination (HR)-deficient tumors while maintaining minimal toxicity in normal tissues. As EGFR inhibition has been reported to alter cellular DNA repair capacity, we investigated whether cetuximab could induce a transient DNA repair deficit and subsequently induce a synthetic lethality with the PARPi ABT-888 in head and neck cancer cells. Methods: The head and neck cancer cell lines UM-SCC1, UM-SCC6, and FaDu were used in this study. Kinetics of DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci at various time points following irradiation (IR). Cell viability was determined via the ATPlite as well as colony formation assays. Apoptosis was evaluated by Annexin V staining as well as cleaved caspase 3 and 9 levels. Cell cycle analysis was performed via flow cytometry. Results: Cetuximab increases γ-H2AX foci, which are well established markers of DNA double strand breaks (DSBs), in head and neck tumor cells. This coincides with reduced DSB-repair as indicated by attenuation of IR-induced Rad51 and DNA-Pk foci, which are well characterized in situ markers of the homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair pathways, respectively. Importantly, cetuximab induces synthetic lethality with the PARPi ABT-888 through a mechanism involving persistent DNA damage and subsequent activation of the intrinsic pathway of apoptosis. The observed effects are not due to cell cycle redistribution. Conclusions: By generating a DSB repair deficiency, cetuximab can render head and neck tumor cells susceptible to PARP inhibition. The combination of cetuximab and the PARPi ABT-888 can thus be an innovative treatment strategy to enhance therapeutic ratio and improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2011-5496