Pathologic complete response to cisplatin with dose-dense paclitaxel as neoadjuvant chemotherapy for locally advanced cervical cancer: Preliminary results of a multicenter phase II study with additional mutation analysis of adeno/adenosquamous carcinoma.

5528 Background: We report efficacy and safety of neoadjuvant cisplatin plus dose-dense paclitaxel (ddTP) within a phase II trial (UMIN-CTR ID: UMIN000006440), designed to investigate recurrence-free survival of neoadjuvant ddTP plus radical hysterectomy followed by adjuvant ddTP without radiotherapy for patients (pts) with stage IB2, IIA2, and IIB cervical cancer, whose driver mutations have been poorly understood. Methods: All enrolled pts received 3 cycles of cisplatin 75 mg/mq on day1 with paclitaxel 80 mg/mq on days 1, 8, and 15 every 21 days. Pathologic complete response (pCR) was defined as no evidence of malignancy in all surgical specimens observed. Using a selected panel of 535 oncogenes (Otogenetics, Norcross, GA), mutations of pretreatment biopsy tissues were analyzed in 6 non-pCR pts with adeno/adenosquamous carcinoma (AC/ASC). Results: Among 51 enrolled pts, 50 were evaluable (40 with squamous cell carcinoma [SCC], 9 with AC/ASC, and 1 with small cell carcinoma). Median age was 52 years (range 30-70), the FIGO stage was IB2 in 14 pts, IIA2 in 3, and IIB in 34. Eighteen pts achieved complete response and 29 pts achieved partial response, with response rate of 94% (47/50). A total of 14 pts (28%; 13 with SCC, 1 with AC) achieved pCR. Grade 3/4 adverse events were neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). The analysis of oncogenes revealed that all 6 pts had mutations in the mixed-lineage leukemia (MLL3) gene, a histone methyltransferase, whose mutations have recently been reported in breast, pancreas, and colorectal cancers. Specifically, in MLL3 gene, identical frameshift mutation was found in 2 pts and 2 common non-synonymous point mutations were found in 4 pts, despite no relevance to the ddTP response. No mutations were detected in TP53 and PIK3CA genes. Conclusions: The pCR rate with neoadjuvant ddTP for locally advanced cervical cancer was one of the highest reported in a prospective trial setting. Novel mutations of the MLL3 gene were identified in non-pCR pts with AC/ASC. Clinical trial information: UMIN000006440.