DNA repair targeted therapy: The past or future of cancer treatment?

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

The risk of subsequent malignancies in women with uterine papillary serous or clear cell endometrial cancers.

OBJECTIVE: Type II endometrial cancers include uterine papillary serous carcinoma (UPSC) and clear cell endometrial cancer (CC). Given their relative rarity, aggressive nature, and poor prognosis, little is known about the risk of subsequent malignancies at other sites. Our objective was to determine if women with UPSC or CC are at increased risk of subsequent malignancies.Type II endometrial cancers include uterine papillary serous carcinoma (UPSC) and clear cell endometrial cancer (CC). Given their relative rarity, aggressive nature, and poor prognosis, little is known about the risk of subsequent malignancies at other sites. Our objective was to determine if women with UPSC or CC are at increased risk of subsequent malignancies. METHODS: Women diagnosed with UPSC or CC were identified from the SEER (Surveillance Epidemiology and End Results) Program from 1973 to 2005. Cases with a second gynecologic malignancy were excluded. Using SEER*Stat software, standardized incidence ratios (SIRs) of subsequent malignancies were calculated. RESULTS: A total of 8045 and 1740 patients were diagnosed with UPSC and CC, respectively. Four hundred sixty-one (5.7%) of the UPSC cases were diagnosed with at least 1 additional nongynecologic malignancy. Significant associations were found with the following malignancies: the renal pelvis, soft-tissue sarcomas, acute myeloid leukemia, the bladder, and colon. Seventy-eight CC cases (4.5%) were diagnosed with at least 1 additional malignancy. In comparison with the baseline population risk, there was no statistically significant increased risk of any subsequent malignancy with a primary diagnosis of CC. CONCLUSIONS: This is the first large population-based analysis of second primary malignancies after type II endometrial cancers. Uterine papillary serous carcinoma is associated with increased risks of certain subsequent malignancies, and providers should be aware of these when following up patients with this diagnosis, especially those with stage I disease. In contrast, no such associations were found with CC in this cohort.

Malignant transformation of a mature cystic ovarian teratoma into thyroid carcinoma, mucinous adenocarcinoma, and strumal carcinoid: a case report and literature review.

Malignant transformation of a mature cystic teratoma (MCT) is an infrequent, often asymptomatic event. We report the first example of a struma ovarii with a focus of follicular variant of papillary thyroid carcinoma (a), mucinous adenocarcinoma (b), and strumal carcinoid tumor (c)-all three arising in one mature cystic teratoma of the ovary. From our reviews, we found limited data to guide management when these malignant foci occur within an MCT. Consideration should be given to thyroidectomy followed by total-body scanning and serum studies for foci of thyroid carcinoma and adjuvant therapy with thyroidectomy and radioablation if residual disease is identified (a). Additionally, extrapolating from data for mucinous adenocarcinomas, consideration could be given to adjuvant chemotherapy after appropriate staging (b). Strumal carcinoid tumors should be treated as tumors of low malignant potential. Observation is appropriate if after complete staging, no invasive implants are noted (c).