Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study

Kerns, Sarah L.; Fung, Chunkit; Monahan, Patrick O.; Ardeshir-Rouhani-Fard, Shirin; Zaid, Mohammad Issam Abu; Williams, AnnaLynn; Stump, Timothy E.; Sesso, Howard D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Huddart, Robert; Kim, Jeri; Kollmannsberger, Christian; Sahasrabudhe, Deepak M.; Cook, Ryan; Fosså, Sophie D.; Einhorn, Lawrence H.; Travis, Lois B.

doi:10.1200/jco.2017.77.0735

Cited by 101 publications

(116 citation statements)

References 73 publications

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“…Although TGCTs are one of the most curable solid tumors, men diagnosed with metastatic TGCT develop platinum resistant disease and die at an average age of 32 years (49). There have been few new treatments developed in the last two decades, and current therapeutic approaches can, importantly in context of a cancer of young men, result in significant survivorship issues, including sustained morbidities and delayed major sequelae (49,54). There is a need for more effective treatments with fewer side effects, to improve the survival and quality of life of these patients.…”

Section: Discussionmentioning

confidence: 99%

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Zhang

Kitchen-Smith

Xiong

et al. 2019

Preprint

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46Insights into oncogenesis derived from cancer susceptibility loci could facilitate 47 better cancer management and treatment through precision oncology. However, 48 therapeutic applications have thus far been limited by our current lack of 49 understanding regarding both their interactions with somatic cancer driver mutations 50 and their influence on tumorigenesis. Here, by integrating germline datasets relating 51 to cancer susceptibility with tumour data capturing somatically-acquired genetic 52 variation, we provide evidence that single nucleotide polymorphism (SNPs) and 53 somatic mutations in the p53 tumor suppressor pathway can interact to influence 54 cancer development, progression and treatment response. We go on to provide human 55 genetic evidence of a tumor-promoting role for the pro-survival activities of p53, 56 which supports the development of more effective therapy combinations through their 57 inhibition in cancers retaining wild-type p53. 58 59Significance 60 We describe significant interactions between heritable and somatic genetic variants 61 in the p53 pathway that affect cancer susceptibility, progression and treatment 62 response. Our results offer evidence of how cancer susceptibility SNPs can interact 63 with cancer driver genes to affect cancer progression and identify novel therapeutic 64 targets. 65 affect p53's ability to bind to DNA in a sequence-specific manner and regulate 99 transcription of its target genes. Some of these same TP53 mutations when found 100 constitutionally result in Li-Fraumeni Syndrome: a syndrome comprising dramatic 101 increase in cancer risk in many tissues types. Although targeting driver mutations in 102 tumor suppressors has been challenging, the high abundance of p53 mutations in 103 cancer has motivated the development of small molecules that aim to reactivate 104 mutant p53 to increase sensitivities to DNA-damaging therapies or inhibit gain-of 105 function activities (15). 106Somatic driver mutations in other p53 pathway genes are also current drug 107 targets. In a sub-set of p53 wild-type cancers, p53 signaling can be attenuated through 108 somatic driver events that alter key p53 regulators. For example, the MDM2 109 oncogene is amplified in a variety of cancers. Its amplification results in decreased 110 p53-mediated tumor suppression, increased cancer susceptibility, and the reduction of 111 selection pressures for somatic p53 mutations (16). Moreover, cancer cells with 112 amplified MDM2 and wild-type p53 have an attenuated p53-mediated DNA damage 113 response (17). Thus, amplification of MDM2 is a promising target for treatment, in 114 combination with DNA-damaging therapies (15,18). 115Most studies have separately examined the consequences of somatic and 116 germline variation affecting p53 activity to understand their roles in disease risk, 117 progression or response to therapy. Here we hypothesize that cancer-associated 118 germline variants (single nucleotide polymorphisms, SNPs) interact with p53 somatic 119 driver mutations to modify c...

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Section: Discussionmentioning

confidence: 99%

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Zhang

Kitchen-Smith

Xiong

et al. 2019

Preprint

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“…59,65,[69][70][71][72] However, late consequences of cisplatin-based chemotherapy, such as hearing damage and loss, cardiovascular conditions, hypertension, and neuropathy, have been reported during long-term follow-up. [73][74][75][76][77][78][79][80][81] Therefore, 1 cycle of BEP is recommended due to its lower toxicity. Surveillance is also a recommended primary treatment option for patients with stage I nonseminoma with risk factors.…”

Section: Primary Treatment Of Nonseminoma Stage I With Risk Factorsmentioning

confidence: 99%

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Gilligan

Lin

Aggarwal

et al. 2019

Journal of the National Comprehensive Cancer Network

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Testicular cancer is relatively uncommon and accounts for ,1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nervesparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with .50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

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“…Given the fact that the IGCCCG classification is also used to determine the intensity of subsequent chemotherapy (i.e. 3 cycles for good risk and 4 cycles for intermediate and poor risk) incorrect classification may lead to overtreatment, which would result into unnecessary toxicity (Chovanec et al 2017;Kerns et al 2018) without an oncological benefit. Furthermore, incorrect upstaging may also trigger more intense follow-up investigations (e.g.…”

Section: Discussionmentioning

confidence: 99%

Pre-orchiectomy tumor marker levels should not be used for International Germ Cell Consensus Classification (IGCCCG) risk group assignment

Fankhauser

Gerke

Roth

et al. 2019

J Cancer Res Clin Oncol

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PURPOSE To investigate whether the use of pre-orchiectomy instead of pre-chemotherapy tumor marker (TM) levels has an impact on the International Germ Cell Consensus Classification (IGC-CCG) risk group assignment in patients with metastatic germ cell tumors (GCT). METHODS Demographic and clinical information of all patients treated for primary metastatic testicular non-seminomatous GCT in our tertiary care academic center were extracted from medical charts. IGCCCG risk group assignment was correctly performed with pre-chemotherapy marker levels and additionally with pre-orchiectomy marker levels. Agreement between pre-chemotherapy and pre-orchiectomy risk group assignments was assessed using Cohen's kappa. RESULTS Our cohort consisted of 83 patients. The use of pre-orchiectomy TMs resulted in an IGCCCG risk group upstaging in 12 patients (16%, 8 patients from good to intermediate risk and 4 patients from intermediate to poor risk) and a downstaging in 1 patient (1.2%, from intermediate-to good-risk). The agreement between pre-orchiectomy and pre-chemotherapy IGCCCG risk groups resulted in a Cohen's kappa of 0.888 (p < 0.001). CONCLUSIONS Using pre-orchiectomy TMs can result in incorrect IGCCCG risk group assignment, which in turn can impact on the clinical management and follow-up of patients with metastatic GCT. Thus, adherence to the IGCCCG standard using pre-chemotherapy TMs levels is recommended.

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Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study

Cited by 101 publications

References 73 publications

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Pre-orchiectomy tumor marker levels should not be used for International Germ Cell Consensus Classification (IGCCCG) risk group assignment

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