To investigate the relationship between molecular subtype, intraperitoneal (IP) disease dissemination patterns, resectability, and overall survival (OS) in advanced high-grade serous ovarian cancer ...(HGSOC).
Patients undergoing primary surgery for stage III-IV HGSOC at Mayo Clinic from 1994 to 2011 were categorized into three IP disease dissemination patterns: upper abdominal or miliary; lower abdominal; and pelvic. Residual disease was defined as 0 (RD0), 0.1–0.5, 0.6–1.0, or >1 cm. Molecular subtypes were derived from Agilent 4x44k tumor mRNA expression profiles and categorized as mesenchymal (MES) or non-mesenchymal (non-MES).
Operative and molecular data was available for 334 patients. Median OS was shorter in patients with MES compared to non-MES subtypes (34.2 vs 44.6 months; P = 0.009). Patients with MES subtype were more likely to have upper abdominal/miliary disease compared to non-MES subtype (90% vs. 72%, P < 0.001). For patients with upper abdominal/miliary disease, complete resection (RD0) was less common in MES compared to non-MES subtypes (11% vs. 27%, P = 0.004). On multivariable analysis, RD was the only factor associated with OS (P < 0.001). In patients with upper abdominal/miliary disease, though less commonly achieved, RD0 improved survival irrespective of molecular subtype (median OS of 69.2 and 57.9 months for MES and non-MES subtype).
Our results support a paradigm in which molecular subtype is an important driver of dissemination pattern; this in turn impacts resectability and ultimately survival. Consequently mesenchymal subtype is associated with much lower rates of complete resection, though RD0 remains the most important independent predictor of survival.
•Median OS is shortest in patients with upper abdominal/miliary disease and mesenchymal subtype•Median OS is shortest in patients with RD >1 cm•RD is the only predictor of OS in multivariable analysis•Among patients with upper abdominal/miliary disease, there is a survival benefit of achieving RD0, irrespective of tumor biology•Among patients with upper abdominal/miliary disease, there is a survival benefit of achieving RD0, irrespective of subtype.
On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability.
In this ...phase I dose-escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparib/temozolomide or talazoparib/irinotecan. Talazoparib was dose-escalated from 500 mcg to 1 mg daily before dose escalation of temozolomide/irinotecan. The starting dose of temozolomide was 25 mg/m2/day orally on days 1 to 5 and irinotecan was 25 mg/m2/day intravenously on days 1 and 15. The primary objectives of this trial were safety and tolerability, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD).
Of 40 patients enrolled, 18 (mean: 7 prior therapies) were enrolled in talazoparib + temozolomide and 22 in talazoparib + irinotecan. DLTs were hematologic in both arms, but all hematologic adverse events resolved with either treatment interruption and/or dose reductions of talazoparib. The MTDs were talazoparib 1 mg + temozolomide 37.5 mg/m2 and talazoparib 1 mg + irinotecan 37.5 mg/m2. There were four partial responses in the talazoparib + temozolomide arm and five in the talazoparib + irinotecan arm for a response rate of 23% (9/40). The pharmacokinetic profiles of talazoparib + temozolomide/irinotecan were similar to that of talazoparib monotherapy. Responses were seen independent of homologous recombination (HR) status and HR deficiency score.
These results show that talazoparib with low-dose temozolomide or irinotecan is reasonably well tolerated and demonstrates clinical activity in a wide range of cancers. Randomized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer.
AbstractObjectivesTo assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four ...Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. MethodsArchival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. ResultsUsing POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for ‘copy-number’ status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3–69 months). ConclusionsCGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.
Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth ...inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.
To review the recently published trials to help us refine and optimize the use of approved HER2-targeted agents (trastuzumab and lapatinib) and highlight future combination strategies for the ...treatment of HER2-positive breast cancer.
Pertuzumab, which prevents the dimerization of HER2/HER3, and trastuzumab emtansine (T-DM1), a novel antibody drug conjugate (trastuzumab joined via a stable linker to a derivative of the potent cytotoxic agent maytansine), have both demonstrated promising clinical activity in HER2-positive breast cancer. Dual anti-HER2 regimens combining trastuzumab with lapatinib or pertuzumab show remarkable synergy and improved outcomes in patients previously thought to have refractory disease. In the neoadjuvant setting, dual anti-HER2 blockade and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. A better understanding of the mechanisms of resistance has led to the development of rational combination therapies cotargeting the PI3K and vascular endothelial growth factor signaling pathways.
New therapeutic options such as pertuzumab or T-DM1 will yield clinically meaningful improvements for patients with HER2-positive breast cancer. Given the high prevalence of intrinsic and acquired resistance to single-agent regimens, the treatment paradigm is shifting toward a dual anti-HER2 therapeutic approach.
•Patients with upper abdominal and miliary disease have similar RD0 rates.•IP disease dissemination patterns are associated with molecular subtypes.•>90% of patients with MES tumors have either upper ...abdominal or miliary disease.•Patients with MES tumor subtype were significantly less likely to achieve RD0.
To investigate the association between intraperitoneal (IP) disease dissemination patterns, residual disease (RD), surgical complexity, and molecular subtypes in advanced high-grade serous ovarian cancer (HGSOC).
741 patients with operable stage III-IV HGSOC undergoing primary debulking surgery at Mayo Clinic from 1994 to 2011 were categorized into four mutually exclusive IP disease dissemination patterns: upper abdominal (60%), miliary (16%), lower abdominal (15%), and pelvic (9%). Surgical complexity was classified as high, intermediate, or low; RD status was defined as 0, 0.1–0.5, 0.6–1.0, or >1cm; molecular subtype assignments were derived from expression profiling of tumors from 334 patients.
Patients with either miliary or upper abdominal dissemination patterns were less likely to achieve RD0 compared to patients with pelvic and lower abdominal dissemination patterns (25% vs. 9% and 62%, each P<0.001) despite higher surgical complexity (39% vs. 6% and 20%, each P<0.001). Among the subset with molecular subtype data, patients with mesenchymal subtype of tumors were more likely to have upper abdominal or miliary dissemination patterns compared to patients with differentiated, proliferative, or immunoreactive subtypes (90% vs. 77%, 70%, 69%, respectively, P<0.05).
IP disease dissemination patterns are associated with RD, surgical complexity, and tumor molecular subtypes. Patients with upper abdominal or miliary dissemination patterns are more likely to have mesenchymal HGSOC and in turn achieve lower rates of complete resection. This provides a plausible model for how the biologic behavior of molecular subtypes is manifest in disease and oncologic outcomes.
Invasive lobular carcinomas (ILC) show better clinical behaviour compared with other histological types, but significantly lower pathological complete response (pCR) rates after neoadjuvant ...chemotherapy (NACT). We investigated whether factors influencing pCR rate in ILC after NACT can be identified and whether clinical outcome is different. 9,020 breast cancer patients from nine German neoadjuvant trials with known histological type were pooled. 11.7 % of tumours were ILC. Endpoints were: pCR rate, surgery type and survival. ILC was associated with older age, larger tumour size, lymph node negativity, lower grade and positive hormone-receptor-status (HR). Patients with ILC achieved a significantly lower pCR rate compared with non-ILC patients (6.2 vs. 17.4 %,
P
< 0.001). The pCR rate was 4.2 % in ILC/HR+/G1-2, 7.0 % in ILC with either HR− or G3, and 17.8 % in ILC/HR−/G3. Mastectomy rate was higher in ILC compared with non-ILC patients irrespective of response to NACT (pCR: 27.4 vs. 16.6 %,
P
= 0.037 and non-pCR: 41.8 % vs. 31.5 %,
P
< 0.0001). Age and HR independently predicted pCR in ILC. In ILC patients, pCR did not predict distant disease free (DDFS) and loco-regional disease free survival (LRFS), but overall survival (OS). Non-pCR patients with ILC had significantly better DDFS (
P
= 0.018), LRFS (
P
< 0.0001) and OS (
P
= 0.044) compared with non-ILC patients. Patients with ILC had a low chance of obtaining a pCR and this is not well correlated with further outcome. The mastectomy rate was considerably high in ILC patients even after obtaining a pCR. We, therefore, suggest to offer NACT mainly to ILC patients with HR-negative tumours.
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