Erlotinib added to carboplatin and paclitaxel as first-line treatment of ovarian cancer: A phase II study based on surgical reassessment

Abstract

Background The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC). Methods Patients with stage III-IV OFPC initiated treatment within 12 weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks for up to 6 cycles, plus oral erlotinib 150 mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (< 1 cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1 cm residual disease) using a two-stage design (alpha = 0.10, beta =0.10). Results The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum. Conclusions Among unselected patients, erlotinib plus carboplatin-paclitaxel is not more effective than historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC.

BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin

“…39,40,42,54 Adding support to that is the increased expression of several survival pathways, including survivin, Bcl-2, Bcl-xL and c-IAP-2 in BRCA1-IRIS-overexpressing cells. 55 Moreover, enhancement of ErbB2 and its ligand, NRG1 (when in complex with ErbB3), by BRCA1-IRIS overexpression further suggest that cancer cells that moved out from the ovary to the peritoneal cavity have also acquired metastatic ability, 7,24,31,36,56 in part through activating PI3′K/AKT pathway, which also is activated by BDNF/TrkB signaling loop in addition to NRG1/ErbB2-ErbB3. PI′3K/AKT signaling drives numerous other cellular functions associated with metastasis, such as lamellipodia formation (key aspect of tissue invasion) and angiogenesis within tumors when oxygen level is low.…”

“…[19][20][21][22][23][24] BRCA1-IRIS overexpression in HOSE cells upregulated the expression of ErbB2 but not EGFR or ErbB3 (Figure 2b, left panels), and BRCA1-IRIS silencing in SKOV3 and OVCAR3 cells downregulated ErbB2 expression only (Figure 2b, left panels). Notably, compared with ErbB2 and ErbB3, EGFR is expressed at the lowest level in ovarian cancer cell lines ( Figure 2b).…”

“…The role of ErbB family members in ovarian cancer (as well as other cancers) is well established. [20][21][22][23][24][25][26][27] On the other hand, the role of TrkB in ovarian cancer development and progression is not yet well defined.…”

Comprehensive Profiling of EGFR/HER Receptors for Personalized Treatment of Gynecologic Cancers

“…Erlotinib has been the target of some optimism in the treatment of ovarian cancer based on a phase II study of daily erlotinib in combination with paclitaxel and carboplatin [93]. However, this trial was not randomized, and the results should thus be interpreted with caution since most ovarian cancers are initially responsive to chemotherapy.…”

Targeted molecular therapies for ovarian cancer: An update and future perspectives (Review)

“…Some preliminary data showed that the effect of the advances on clinical outcomes has been disappointing; few patients had sustained responses or stable disease; and treatment with imatinib did not prolong the PFS (39). (40). Utilizing erlotinib in combination with standard therapy did not improve pCR rates.…”