Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

		John Theurer Cancer Center at Hackensack University Medical Center

The preservation of DNA integrity—also called genetic stability&mdash;is essential to our survival. This involves accurate DNA replication with each cell division and the ability to repair any occurring error. Such errors occur for a myriad of reasons including heat, oxidative stress, UV exposure, chemicals, or radiation exposure, among others. It is estimated that up to one million individual lesions occur per cell every day, but only one out of a thousand accidental base change results in a permanent mutation.

Evidently, in the absence of repair, these mutations will either lead to early cells senescence (aging), apoptosis (cell death: thus preventing mutated cells from replicating), or potentially abnormal cells accumulation and/or aberrant cell division (leading to transformation into cancer cells).

	The critical role of the DNA repair complex system is illustrated by rare but well-established syndromes arising from mutations in DNA damage—response genes&mdash;such as ataxia telangiectasia, Bloom syndrome, Fanconi’s anemia, Lifraumeni syndrome (p53 defect), and xeroderma pigmentosum, among others. Such syndromes are characterized by either accelerated aging disease or malformations/degenerative diseases and particularly, by a very high incidence of cancers across all these patients.

	The DNA damage response is a network of cellular pathways that sense, signal and repair DNA lesions. Surveillance proteins that monitor DNA integrity can activate cell cycle checkpoints and DNA repair pathways in response to DNA damage, to prevent the generation of potentially deleterious mutations. In simpler words, the DNA repair system functions like a “gatekeeper,” telling a cell to “stop and repair” or “die if it’s too late.”

	The discovery of the DNA repair system dates back to the late 1980s, with work showing its critical role in both prokaryotes and eukaryotes. The growing importance of this seminal work over the years, led to the recent 2015 Albert Lasker Basic Medical Research Award to Evelyn M. Witkin, 94, of Rutgers University, and Stephen J. Elledge, 59, of Brigham and Women’s Hospital in Boston.

	Witkin’s work started in the 1940s, showing that some bacteria (E Coli) were able to recover from UVinduced DNA damages and that their resistance to UV radiation was heritable and also protected them from x-rays. Elledge’s work in yeast later on established that the DNA damage response in eukaryotes is a signal transduction pathway involving a kinases cascade, with some mammalian homologues of yeast kinases that can prevent cell-cycle progression in response to DNA damage (checkpoints). The DNA can be repaired fairly easily and reliably because it carries two separate copies of all the genetic information in each cell.

	Mammalian cells have evolved highly conserved DNA repair mechanisms with at least eight distinct DNA repair pathways resulting either in simple direct repair after proofreading, excision-repair, cross-link repair, mismatch repair, or recombination. The DNA damage response (DDR) overall however is a highly complex signaling system involving tightly controlled involving regulation at the transcriptional, posttranscriptional, and posttranslational levels.

	The predisposition to cancer conferred by mutations in DNA-repair genes is well documented. Among the most common examples are breast and ovarian cancer from mutations in homologous recombination genes (

) and colon cancer from mutations in mismatch-repair genes, with a number of subentities reported. Impaired DNA repair is a major driver for carcinogenesis (through driver mutations, deletion of tumor suppressors, and/ or chromosomal rearrangements) and could promote aggressive cancer biology.

	Emerging clinical data provide compelling evidence that overexpression of DNA repair factors may have prognostic and predictive significance in patients. Interestingly, in established tumors, DNA repair activity is required to counteract oxidative DNA damage that is often prevalent in the tumor microenvironment. Meanwhile, DNA-damaging agents like most chemotherapy currently used, can potentially induce further damages leading to resistance of cancer cells. On the other hand, recently, DNA repair inhibition has emerged as a promising target for anticancer therapy with a strong rational, for example, for synergistic efficacy of PARP1 inhibitors with chemotherapy in 

	The maintenance of DNA integrity is a very complex and highly regulated, very efficient process (3B bp to check at every division!). This system is by definition constantly challenged from both internal and external factors. The continued progress in understanding and deciphering the critical role of the DNA damage response might help us stratify cancer patients in the future and personalize their therapies. It is a perfect segue to our John Theurer Cancer Center annual survivorship event this past weekend that brings together thousands of patients every year for a Celebration of Life and Liberty!

Articles

The continued progress in understanding and deciphering the critical role of the DNA damage response might help us stratify cancer patients in the future and personalize their therapies.

DNA Damage Response: A Constant Effort to Maintain Cell Integrity Might Help Cancer Patients After All

	Assistant Professor of Pediatrics, Investigator

Adolescents and young adults (AYAs) with cancer diagnosed between the ages of 15 and 39 are a unique group of patients with distinct cancer epidemiology and developmental characteristics. Nearly 70,000 AYAs are diagnosed with cancer each year in the United States and cancer is the leading cause of disease- related death in this group.

AYA cancer patients are often considered to be in “no-man’s-land” for their oncology care as they may not fit a pediatric or adult oncology profile.

When cancer occurs during this time of life, it can interrupt education, work, marriage, and parenthood.

Furthermore, young adults in their 20s are uninsured at higher levels than older adults, meaning that access to timely diagnosis and follow-up care is challenging.

Due to AYAs’ unique characteristics, there is a growing effort to address their oncology needs. In 2005, the Adolescent and Young Adult Oncology Progress Review Group, a partnership between the National Cancer Institute (NCI) and LIVESTRONG Foundation, was developed to evaluate the clinical and research needs of this unique oncology population.

 In 2012, the NCI convened experts in AYA oncology to review the evidence, identify gaps, and provide research priorities on AYA oncology research.

Utah will soon launch the Huntsman Intermountain- Adolescent and Young Adult (HI-AYA) program R. Lor Randall, MD, FACS, and Carolyn Reynolds, MS, APRN, are Co-Directors of HI-AYA, which is a Huntsman-Intermountain Cancer Care Program Best Practices Task Force. Our goal is to develop patient navigation for AYAs with cancer throughout Utah. Funding support includes The L.B. & Olive S. Young Endowed Chair for Cancer Research and a Utah Department of Health grant.

The majority of AYA patients with cancer in Utah are never seen by a pediatric oncologist.

 Because we know AYAs are less likely to be enrolled in a clinical trial, consultation from or treatment at a pediatric or adult cancer center may provide opportunities for this patient group.

Holly Spraker-Perlman, MD, MS, an assistant professor of Pediatrics at the University of Utah, is using Utah Cancer Registry data to ascertain what percentage of AYA patients are seen at a cancer center in Utah and to determine what percentage of these patients go on clinical trials. She will use this information as a platform to assess the need for a specialized AYA program in Utah. Dr Spraker-Perlman is also working to develop a survey to understand how primary care providers refer AYAs with suspected cancer to an oncology specialist.

Yelena Wu, PhD, is an investigator at Huntsman Cancer Institute who does research on healthy lifestyle behaviors (exercise, healthy diet). In the Cancer Survivor Health Study (CASH), she conducted focus groups and interviews with AYA cancer survivors to understand barriers to exercise and a healthy diet. Her research team found that there are several modifiable factors (eg, motivation, mood, knowledge, and skills) that could improve adherence to recommended behaviors for this population.

CASH also included survivors’ supporters (ie, family members, spouses, and friends). Survivors’ supporters were less informed about certain healthy lifestyle behaviors, meaning that supporters should be educated about recommendations for healthy lifestyle behaviors to support AYAs’ adoption of and adherence to exercise and a healthy diet.

Dr Wu also leads a study of the feasibility and acceptability of a smartphone reminder application to promote AYAs’ adherence to oral medications. Oral medications have an expanding role in cancer treatment, which places great responsibility on the patient. Nonadherence to oral medications is prevalent among AYAs and may impact their quality of life in addition to their survival. As such, implementing medication adherence interventions to support this distinct group of patients is crucial.

Through the research programs of Drs Spraker-Perlman and Wu, as well as the development of the HI-AYA initiative, Utah hopes to transform the care and treatment of AYAs with cancer.

			Nass SJ, Beaupin LK, Demark-Wahnefried W, et al. Identifying and addressing the needs of adolescents and young adults with cancer: summary of an Institute of Medicine Workshop (2015). 

			Adolescent and Young Adult Oncology Progress Review Group. Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute, LIVESTRONG Young Adult Alliance; 2006.

			Kirchhoff AC, Spraker-Perlman H, McFadden M, et al. Sociodemographic disparities in quality of life for adolescent and young adult cancer survivors. 

			Parsons HM, Harlan LC, Lynch CF, et al. Impact of cancer on work and education among adolescent and young adult cancer survivors. 

			Albritton KH, Wiggins CH, Nelson HE, Weeks JC. Site of oncologic specialty care for older adolescents in Utah. 

Due to the unique characteristics of adolescents and young adults, there is a growing effort to address their oncology needs.

Supporting Adolescents and Young Adults With Cancer From Diagnosis Through Survivorship

The FDA closed out summer 2015 by taking action on several oncology drug applications, approving new indications and granting several priority reviews.

Rolapitant (Varubi) is now approved for use in combination with other antiemetic agents to prevent delayed CINV from initial and repeat chemotherapy regimens, including highly emetogenic chemotherapy. Also in the area of CINV management, the FDA approved aprepitant capsules (Emend) in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting in patients aged 12 to 17 and for those under the age of 12 who weigh at least 30 kg who are receiving moderately to highly emetogenic chemotherapy.

The antibody-drug conjugate brentuximab vedotin (Adcetris) was also approved by the FDA as a consolidation therapy following autologous stem cell transplantation (ASCT) in patients with Hodgkin lymphoma at risk of relapse or progression. Brentuximab vedotin was granted an accelerated approval in August 2011 as a treatment for patients with Hodgkin lymphoma after failure of ASCT or after failure of at least two prior chemotherapy regimens in patients who were not candidates for ASCT. The new indication moves treatment with the drug forward, as a therapy for patients who are at high risk of relapse following ASCT, and also converts the initial accelerated approval to a full approval.

In its ongoing effort to expedite the availability of novel therapies, the FDA issued several priority review designations, which mandate a shortened review period of ≤6 months. Among these drugs were two monoclonal antibodies for the treatment of multiple myeloma, elotuzumab (Empliciti) and daratumumab. Priority reviews were also granted to nivolumab (Opdivo) in nonsquamous non—small cell lung cancer (NSCLC), frontline pembrolizumab (Keytruda) in melanoma, and the intravesical immunotherapy MCNA for bladder cancer. Additionally, cabozantinib (Cometriq) received a breakthrough therapy designation in renal cell carcinoma and the FDA accepted an application for afatinib in squamous cell NSCLC.

As these drugs progressed through the standard FDA regulatory channel, the end of the summer also marked the dawn of the biosimilar era in the United States. Following a series of lawsuits and court decisions, the first FDA-approved biosimilar, Zarxio (filgrastim-sndz), is now available for patients. The G-CSF analog is approved by the FDA for all five authorized indications for its counterpart, Neupogen (filgrastim) under the newly initiated US biosimilar pathway.

The 300 μg dose of Zarxio will cost $275.66 and the 480 μg dose will cost $438.98. The historic price for Neupogen has been $324.30 and $516.45 for these same dose sizes, respectively, representing a 16.2% difference between the two drugs. As more biosimilars are approved, we will continue to update you on their impact on oncology drug pricing.

With several PDUFA dates for oncology drugs remaining, there remains a flurry of FDA activity yet to come in 2015. We look forward to bringing you the latest on these regulatory developments, as well as keeping you abreast of all the groundbreaking data presented at the year’s major remaining oncology meetings. As always, thank you for reading.

The FDA closed out summer 2015 by taking action on several oncology
drug applications, approving new indications and granting several priority
reviews.

FDA Ends Summer With Surge of Activity

Director, Phase I/Investigational Therapeutics

Director, Melanoma and Soft Tissue Oncology Program

Squamous cell carcinoma of the skin (SCCS) is an increasingly common diagnosis and is the second most common type of skin cancer worldwide.

 The number of cases of SCCS has increased consistently over the past 20 years. This observation may be related to improved detection of skin cancer, increased exposure to UV radiation (including tanning bed exposure), and the aging of the US population, because the incidence of SCCS increases dramatically with age.

With a 10% decrease in stratospheric ozone annually and the continued growth of the aging US population, locally advanced and metastatic squamous cancers arising from a skin primary are likely to continue to increase annually in coming years, particularly in geographic areas with significant sun exposure.

 These cancers also plague patients who are immunosuppressed, such as recipients of solid organ transplants or patients with chronic infections (eg, HIV)—populations that are living longer in recent years and are therefore becoming more likely to develop troublesome SCCS.

	Most often, SCCS and its precursor lesions are localized and amenable to resection. However, larger and more invasive lesions often require multimodality care, with 10-year survival rates dramatically impacted by the development of regional lymph node involvement and distant metastases.

	Relatively little has been done to develop a generalized management plan for these patients.

 Even the development of a widely accepted staging system has been challenging, as the current AJCC system does not easily identify high-risk cancers, with most poor outcomes occurring in stage T2 cases. While alternate staging systems have been proposed to stratify T2 tumors based on poor prognostic factors such as poor differentiation, perineural invasion, tumor diameter ≥2 cm, and invasion beyond subcutaneous fat,

 the lack of validated systems and clear guidelines leads to confusion for practitioners and variability in treatment.

	Questions persist not only about which patients should be defined as high risk, but also what the initial surgical management of high-risk patients should be, particularly the role of sentinel lymph node. There are no high-level data to guide the decision to use this staging tool, although smaller published reports indicate that a select group of patients with high-risk SCCS may benefit from sentinel lymph node biopsy to identify occult nodal metastases, with a suggested cutoff threshold of 10% risk.

 The need to conduct further clinical trials in this area has been identified.

	Not surprisingly, there is also a lack of high-level data on treatment options for SCCS not amenable to resection. Published case reports have demonstrated responses to platinum-based chemotherapy with occasional complete responses.

There are no data from prospective phase III studies available, and only one prospective phase II study examining the use of platinum-based chemotherapy in this population has been reported. Cisplatin, either as a single agent or combined with 5-FU, has occasionally produced meaningful responses, but again, data supporting efficacy is limited. In general, extrapolation of regimens from squamous tumors of the head and neck are employed, despite the fact that these tumors are likely to be biologically distinct. Further investigation is limited by a lack of available trials for SCCS, and by the frequent exclusion of SCCS patients from trials for head and neck cancer patients.

	Because the EGFR is highly expressed in many epithelial tumors, including SCCS,

and EGFR-directed therapy is often a component of treatment for squamous tumors of the head and neck, the use of anti-EGFR therapies for SCCS is increasing. The largest prospective study to date by Maubec et al

 examined the EGFR inhibitor cetuximab. They enrolled 36 poor-prognosis SCCS patients whose tumors expressed EGFR and demonstrated a disease control rate of 69%.

	A smaller, 16-patient study of the EGFR inhibitor panitumumab in patients who received prior local and/or systemic treatment showed antitumor activity with a response rate of 31%, including 3 partial responses and 2 complete responses.

	Furthermore, a trial evaluating the neoadjuvant use of the EGFR tyrosine kinase inhibitor gefinitib enrolled 22 evaluable patients and demonstrated a 18.2% complete and 27.3% partial response rate and did not interfere with subsequent local therapy, indicating antitumor activity worthy of further exploration.

 Due to their availability as FDA-approved agents, and the lack of competing attractive therapeutic options, cetuximab or panitumumab are increasingly employed to treat locally advanced or metastatic SCCS, and EGFR inhibition is now part of NCCN guidelines for treatment of advanced disease. While this may be a useful therapeutic approach, if these patients are not enrolled as part of rigorous randomized studies, practice-changing information cannot be gathered, and many important questions will remain unanswered.

	For example, could preoperative systemic and/ or radiation therapy reduce the morbidity and extent of the subsequent surgical procedure? Does combining chemotherapy with EGFR inhibitors improve clinical outcomes and increase the pathologic complete response rate? In this era of personalized medicine, are there genomic predictors of response and resistance? Finally, is there a role for immunotherapy in this disease? These are questions we routinely ask in other malignancies; the time has come to include SCCS in these investigations.

	In summary, advanced SCCS continues to be a treatment challenge given the aggressive behavior of a subset of cases and the absence of randomized clinical trials to provide guidelines for therapy. Multidisciplinary clinical trials and collaborative efforts are necessary to advance the care of this growing patient population.

				Alam M and Ratner D. Cutaneous squamous-cell carcinoma. 

				Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. 

				Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. 

				Gaffney DC, Soyer HP, Simpson F. The epidermal growth factor receptor in squamous cell carcinoma: an emerging drug target. 

				Schmults CD, Karia PS, Carter JB, et al. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. 

				Navarrete-Dechent C, Veness MJ, Droppelmann N, Uribe P. Highrisk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: literature review.” 

				Lawson JD, Otto K, Chen A, et al. Concurrent platinum-based chemotherapy and simultaneous modulated accelerated radiation therapy for locally advanced squamous cell carcinoma of the tongue base. 

				Nakamura K, Okuyama R, Saida T, Uhara H. Platinum and anthracycline therapy for advanced cutaneous squamous cell carcinoma. 

				DeConti RC. Chemotherapy of squamous cell carcinoma of the skin. 

				Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. 

				Foote MC, McGrath M, Guminski A, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. 

				Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. 

Advanced SCCS continues to be a treatment challenge given the aggressive behavior of a subset of cases and the absence of randomized clinical trials to provide guidelines for therapy.

September 2015 | Oncology & Biotech News

DNA Damage Response: A Constant Effort to Maintain Cell Integrity Might Help Cancer Patients After All

Supporting Adolescents and Young Adults With Cancer From Diagnosis Through Survivorship

FDA Ends Summer With Surge of Activity

Advanced Squamous Carcinoma of the Skin: A Persistent, Growing Challenge