Genomic instability has been an area of active area of research in the last two decades. Based on the initial study for hereditary cancers, DNA repair gene family mutations have been identified. In sporadic (non-hereditary) cancers, several large-scale DNA sequencing studies suggest that mutations in DNA repair genes are less frequent, suggesting the complexity of tumorigenesis of sporadic cancers. So far, several important genes have been identified, by using mostly cell line models and mice studies. These include DNA damage response modifier like ataxia telangiectasia mutated (ATM), conventional tumor suppressor genes like TP53 and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF). Various hypotheses for sporadic tumorigenesis have been developed, and so far, "oncogene-induced DNA replication stress model" has been gaining widespread interests. In this review, we will first describe some of the important concepts of genomic instability. Then, we will outline oncogene-induced genomic instability and discuss the role of the MYC gene during this process, which will be followed by detailed reviews of mutation data. We hope that this review can outline the overall perspectives of genomic instability.

Aim: Few studies have reported that human papillomavirus (HPV) tests using menstrual blood (MB) may be a convenient and effective screening modality for cervical cancer. Therefore, we aimed to investigate the efficacy of detecting high-risk (HR)-HPV from MB in women with high-grade squamous intraepithelial lesions or HR-HPV infections dependent on menstrual days. Materials and Methods: In this prospective exploratory pilot study, a clinical trial was conducted in 19 women. On enrollment into the study, gynecologists collected cervical cells. On the first and second day of menstruation, MB was self-collected by patients using a sanitary pad with a filter. The distribution of HPVs from MB and the accuracy of menstrual HR-HPV tests were evaluated using HPV genotyping. The agreement rate of detecting HR-HPVs using cervical and MB samples was also investigated. Results: The sensitivity, specificity, positive and negative predictive values of the MB HR-HPV test for detecting cervical intraepithelial neoplasia (CIN) 3 or worse were 87.5%, 45.5%, 53.8%, and 83.3%, respectively, during both menstrual cycle day (MCD) 1 and 2 and MCD 1 only; and 62.5%, 27.3%, 38.5%, and 50.0%, respectively, during MCD 2 only. For CIN 3 or worse, the agreement rate between positive cervical and MB HR-HPV test results was 87.5% during MCD 1 and 62.5% during MCD 2. Conclusions: We demonstrated the possibility of using the MB HPV test as a screening modality for cervical cancer.

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e22542 Background: Retroperitoneal lipo-leiomyomata are extremely rare. The usual-type retroperitoneal leiomyoma is itself a rare tumor that is mistaken preoperatively for malignant retroperitoneal tumors or thought of as an exophytic subserosal leiomyoma of the uterus. Lipo-leiomyoma is a variant of leiomyoma with an incidence in uterus ranging between 0.03% - 0.2%, but its presentation as a retroperitoneal mass has not been documented in literature yet. We present a unique case of retroperitoneal lipo-leiomyoma that presented as a diagnostic challenge due to its unique location and unusual histologic appearance. Methods: A 68-year-old female patient with a history of breast cancer diagnosed 4 years ago, currently on antiestrogen therapy (Fulvestrant) and Herceptin, presented to our university hospital with symptomatic left pelvic mass. An abdominal CT showed a heterogeneous low-density pelvic mass with foci of internal calcification and fat with surrounding intermixed intermediate and high density fluid in the expected location of the uterus. Results: A debulking surgery including radical hysterectomy was planned. Intraoperatively, a normal sized uterus was found, the myometrium of which contained multiple variable-sized intramural leiomyomata. In addition, a huge left retroperitoneal mass was found that had no connection to the uterus. Histopathological examination revealed abenign lipoleiomyomatous tumor, composed of an encapsulated proliferation of benign adipocytes and myoid cells intimately admixed. Immunohistochemistry confirmed myoid differentiation, with negative reactions for HMB45 and CKIT, and . MDM2 gene amplification by fluorescence in situ hybridization (FISH) was negative. Conclusions: Some unusually located extra-uterine leiomyomata have been reported; retroperitoneal leiomyoma being among them. Such a tumor with the added feature of lipomatous differentiation presents a differential diagnosis that includes leiomyosarcoma, liposarcoma, angiomyolipoma, and gastrointestinal stromal tumor. The association of an uncommonly located leiomyoma with subsequent lipomatous change withantiestrogen therapy is an unexplored issue that merits further investigation.

5080 Background: CA-125 progression criterion for OC by Vergote et al (JNCI 2000; 92:1534) has been widely adopted, with 35 U/ml as the most commonly used normal limit. Based on recent findings (ASCO Proceedings 2005, #5013), primary therapy cCR OC pts with nadir CA-125 ≤10 versus >10–20 versus >20–35 have different prognosis. We propose to modify the CA-125 progression criterion in this setting as follows: for pts with nadir ≤10, value ≥20 that is confirmed equals progression; for pts with nadir >10, value ≥ 2×nadir that is confirmed equals progression. This new criterion essentially treats 10 U/ml as the normal limit. Methods: The proposed criterion combined with RECIST was tested on SWOG 9701/GOG 178 pts (n = 287) and compared to the existing criterion. All pts achieved cCR from primary therapy and entered the above maintenance trial with CA125 ≤35. Results: Of 91 pts last known to be progression-free by existing criterion, 10 (11%) new progressions were called. Available CA-125 values continued to rise in all except 1 case (1%). For 196 pts with known progressive disease, the progression date was unchanged by the new criterion in 42%, and was earlier by ≤60 days in 31%, 61–180 days in 16% and >180 days in 11% (overall median days early = 56). Conclusions: In a series of 39 primary therapy cCR pts with CA-125 ≤35, Santillan et al found a progressive low-level increase in CA-125 to be strongly predictive of disease recurrence (JCO 2005; 23:9338). Similarly, initial testing of the proposed CA-125 criterion demonstrated a low false positive rate and early detection of disease progression >2 months in approximately 30% of the same first line complete responders with progressive disease during or after maintenance treatment. Such pts can potentially benefit from starting alternative treatments early. The proposed criterion should be further investigated. No significant financial relationships to disclose.

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Severe hypoxia causes resistance to conventional chemotherapy and has been reported to synergize with PARP inhibitors (PARPi) through suppression of homologous recombination (HR). While this synergistic killing is true at oxygen levels less than 0.5%, our study shows that less severe hypoxia (e.g. 2% oxygen) is instead associated with resistance to PARPi in HR proficient cells. Interestingly, we demonstrate that HR deficient hypoxic tumors are significantly less responsive to PARPi, due to limited ROS-induced intrinsic DNA damage. To determine the contribution of hypoxic cells to PARPi, we used the hypoxic cytotoxin Tirapazamine to target hypoxic tumor cells. We found that the elimination of hypoxic tumor cells by Tirapazamine led to a substantial antitumor response with PARPi compared to PARPi treated tumors alone, without enhancing normal tissue toxicity. These studies indicate that tumor hypoxia reduces the efficacy of PARPi to tumor cells and that eliminating hypoxic tumor cells will enhance the efficacy of PARPi therapy. Citation Format: Manal Mehibel, Jimmy Xu, Grace Li, Jung Moon, Kaushik Thakkar, Anh Diep, Ryan Kim, Joshua Bloomstein, Siren Xiao, Julien Bacal, Joshua Saldivar, Quynh Le, Karlene Cimprich, Erinn Rankin, Amato Giaccia. Oxygen dependent resistance to PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-003.

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