A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04)

Fizazi, Karim; Maillard, Aline; Penel, Nicolas; Baciarello, Giulia; Allouache, Djelila; Daugaard, Gedske; Wouw, A. van de; Soler, G.; Vauléon, Élodie; Chaigneau, L.; Janssen, Raj; Gaspà, Fernando Losa; Barrera, Rafael; Balañá, C.; Tosi, Diego; Chauffert, Bruno; Schnabel, Claudia; Martineau, Geraldine; Culine, S.; Borget, Isabelle

doi:10.1093/annonc/mdz394

Cited by 191 publications

(133 citation statements)

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“…In principle, there are two strategies to improve outcome in unfavorable CUP based on molecular profiling of cancer tissue. One strategy aims to predict the putative primary based on gene expression or methylation profiling and to tailor treatment accordingly . However, this putative primary based treatment approach did not prove superior over empiric standard chemotherapy in both randomized clinical trials conducted so far .…”

Section: Discussionmentioning

confidence: 99%

“…One strategy aims to predict the putative primary based on gene expression or methylation profiling and to tailor treatment accordingly . However, this putative primary based treatment approach did not prove superior over empiric standard chemotherapy in both randomized clinical trials conducted so far . The other strategy to improve prognosis based on molecular profiling aims to identify clinically actionable mutations for targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

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Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Bochtler

Reiling

Endris

et al. 2020

Intl Journal of Cancer

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Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Here, we address prognostic and therapeutic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Targeted panel sequencing was performed in 252 CUP patients. 71.8% of patients had unfavorable CUP according to ESMO guidelines. 74.7% were adeno‐ and 13.7% squamous cell carcinomas. DNA was extracted from microdissected formalin‐fixed, paraffin‐embedded tissues. For library preparation, mostly multiplex PCR‐based Ion Torrent AmpliSeq™ technology with Oncomine comprehensive assays was used. Most frequent genetic alterations were mutations/deletions of TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01), PIK3CA activation in squamous cell carcinomas (p = 0.03). Male sex, high ECOG score, unfavorable CUP, higher number of involved organs and RAS activation predicted decreased event‐free and overall survival in multivariate analysis. Deletions of CDKN2A were prognostically adverse regarding overall survival. TP53 mutations did not significantly influence prognosis in the overall cohort, but worsened prognosis in otherwise favorable CUP subtypes. Although not standard in CUP, for 17/198 (8.6%) patients molecularly targeted treatment was recommended and 10 patients (5.1%) were treated accordingly. In conclusion, besides the identification of drug targets, panel sequencing in CUP is prognostically relevant, with RAS activation and CDKN2A deletion emerging as novel independent risk factors in a comprehensive assessment with clinicopathological data.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Bochtler

Reiling

Endris

et al. 2020

Intl Journal of Cancer

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“…In an interim analysis presented at ESMO congress last year, olaparib treatment resulted in significantly prolonged radiographic progression-free survival in cohort A (HR 0.34) and the overall population (cohort A+B, HR 0.49) as well as a trend for prolonged overall survival not reaching the previously determined levels of statistical significance for cohort A. Most likely, heavy cross-over between treatment arms hindered the observation of a statistically significant difference in OS for cohort A in the interim analysis (HR 0.64, n. s.), but could be met in the final analysis [13].…”

Section: Introductionmentioning

confidence: 88%

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

Marhold

Topakian

2020

memo

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SummaryHomologous repair deficiency is a clinically relevant molecular aberration in prostate cancer. The goal of this short review is to summarize the study landscape of treatments targeting these aberrations through discussion of the most relevant clinical trials. Due to its shortness, this review does not claim to be exhaustive and a major focus is being laid on PARP inhibitors in clinical development for prostate cancer.

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“…17 The KEYNOTE-119 (NVT02555657) study is a Phase 3 randomized trial evaluating pembrolizumab monotherapy compared to single-agent chemotherapy of the physician's choice in the second-or third-line treatment of patients with metastatic TNBC. 18 Outcomes were stratified by PD-L1 tumor status as measured by combined positive score (CPS). The primary endpoint was OS.…”

Section: Introductionmentioning

confidence: 99%

“…Among these patients, the hazard ratio for 12-months OS was 0.58 (95% CI 0.38-0.88). 18 Conclusively, the Phase III KEYNOTE-119 study detected a failure in outcomes with the use of pembrolizumab versus chemotherapy for recurrent metastatic TNBC. Nevertheless, these patients with the highest tumor and immune cell level of PD-L1 may benefit from pembrolizumab.…”

Section: Introductionmentioning

confidence: 99%

<p>Combination Strategies of Checkpoint Immunotherapy in Metastatic Breast Cancer</p>

Liu¹,

Zhang²,

Ji³

et al. 2020

OTT

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Checkpoint immunotherapy is emerging as a new therapeutic approach for metastatic breast cancer. Monotherapy of immunoagents against PD1/PD-L1 or CTLA-4 has shown little efficacy in these patients. Recently, to determine the optimal use of immunotherapy, there has been a rapid expansion in the number of clinical trials developing immunotherapy combinations. These combination therapeutic approaches can enhance various aspects of cancer immunity, such as tumor antigenicity or intratumor T cell infiltration, which provides a theoretical basis for combining them with checkpoint immunotherapy to achieve synergistic effects. Here, we review the available data and ongoing efforts to establish the safety and efficacy of immunoagents in combination with chemotherapy, radiotherapy, HER2-targeted therapy, CDK4/6 inhibitors, PARP inhibitors, and another checkpoint immunoagents.

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A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04)

Cited by 191 publications

References 0 publications

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

<p>Combination Strategies of Checkpoint Immunotherapy in Metastatic Breast Cancer</p>

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