815MO The impact of chemosensitivity assessed by modeled CA-125 KELIM on the likelihood of long progression-free survivorship (PS) after 1st line treatment in ovarian cancer: An analysis of 4,450 patients

You, Benoît; Tod, Michel; Sonke, Gabe S.; Kruitwagen, Roy F.P.M.; Bois, Andreas du; Selle, Frédèric; Perren, Timothy J.; Pfisterer, Jacobus; Joly, Florence; Cook, Adrian; Kaminsky-Forrett, M-C.; Wollschlaeger, K.; Lortholary, Alain; Tomé, Oliver; Léary, Alexandra; Aa, M. van der; Colomban, Olivier

doi:10.1016/j.annonc.2020.08.954

Cited by 7 publications

(7 citation statements)

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“…Of note, KELIM was shown to be more accurate than the CA-125 Gynecology Cancer In-terGroup response criterion for characterizing chemotherapy efficacy in the first-line setting. 15,17,[19][20][21] Veliparib is an oral PARPi that inhibits poly (adenosine diphosphate-ribose) polymerase (PARP) activity without substantial trapping of PARP onto DNA damage repair intermediates, 22,23 thereby making veliparib more suitable for administration in combination with platinum-based chemotherapy. 24 The efficacy of veliparib was assessed in combination with standard frontline platinum-based chemotherapy (concomitant-veliparib arm; dose reduced during combination therapy) or in the same regimen followed by veliparib continued as a monotherapy in the maintenance phase (veliparib-throughout arm) in the VELIA phase III trial.…”

Section: Introductionmentioning

confidence: 99%

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study

You

Sehgal

Hosmane

et al. 2023

JCO

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PURPOSE In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib. PATIENTS AND METHODS Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status ( BRCA mutation, HR deficiency [HRD], or HR proficiency [HRP]). RESULTS The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and BRCA mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or BRCA wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a BRCA mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect. CONCLUSION In addition to HRD/ BRCA status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.

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Section: Introductionmentioning

confidence: 99%

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study

You

Sehgal

Hosmane

et al. 2023

JCO

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“…These analyses also showed that their respective impacts were different according to the chemosensitivity. Indeed, the benefit offered by complete IDS relative to the risk of subsequent platinum-resistant relapse, and survival, was maximum in patients with poorly chemosensitive diseases, in contrast to patients with highly chemosensitive diseases, whose prognostic was mainly driven by the chemosensitivity [54,58,59]. For example, Fig.…”

Section: Respective Roles Of the Surgery And Of The Tumor Primary Chemosensitivitymentioning

confidence: 99%

“…These studies have confirmed the capacity of KELIM to reproducibly predict: (1) the likelihood of complete resection at IDS in the neoadjuvant setting [54,55,57], (2) the probability of subsequent platinum-resistant relapse [54,58], (3) the patient PFS and OS (Fig. 1 showing hazard-ratios for PFS and OS in patients having favorable or unfavorable KELIM)) [51,[53][54][55]57], and 4) the probability of complete remission >5 years after first-line treatment (OR, 4.24, 95 %CI 2.36-7.69) [59]. These data confirmed that the longitudinal kinetics of CA-125 during the first 3 cycles of chemotherapy, captured by KELIM, is the reflection of an intrinsic property of the tumor cells related to the sensitivity to chemotherapy independently on the received regimen.…”

Section: Indicators Of Tumor Primary Chemosensitivitymentioning

confidence: 99%

The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas

You

González-Martín

Lheureux

et al. 2021

Cancer Treatment Reviews

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In patients with advanced ovarian carcinomas, the first-line treatment has historically relied on debulking surgery and platinum-based chemotherapy. If the major therapeutic/prognostic role of the surgery part is well understood, and integrated in disease-management algorithms, the impact of chemotherapy efficacy has been insufficiently addressed.This review describes the main indicators of the chemosensitivity reported in the literature (pathological response score & biomarkers; genomic alterations; DNA scars; imaging; and circulating tumor markers), and investigates the respective roles of the debulking surgery and tumor primary chemosensitivity relative to the success of the comprehensive medical-surgical treatment. The tumor primary chemosensitivity exhibits a major independent prognostic impact on the feasibility of complete interval debulking surgery after neoadjuvant chemotherapy, risk of subsequent platinum-resistant relapse, efficacy of subsequent maintenance therapies with bevacizumab or PARP inhibitors, progression-free survival, overall and long-term survival. While both the completeness of the surgery and the tumor primary chemosensitivity are undoubtedly major prognostic factors, the impact of the surgery may differ according to the primary chemosensitivity. This assumption raises a potential new concept: in patients with advanced ovarian carcinomas, the maximum tumor debulking should ideally be both biological (induced by systemic treatments) and physical (induced by surgery) for maximizing patient survival. Besides BRCA and HRD biomarkers, future trials and algorithms may integrate indicator(s) of the tumor primary chemosensitivity for guiding more subtly the surgical and medical management in first-line setting. Moreover, such a parameter would help in the development of novel approaches meant to reverse the resistance to chemotherapy and PARP inhibitors.

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“…In a pooled analysis of datasets presented above, the prognostic value of KELIM regarding the probability of long-term complete remission (LCR) was assessed after first-line treatment [ 3 ]. LCR was defined as complete remission >5 years after initial treatment.…”

Section: Kelim: An Early Marker Of the Tumor Primary Chemosensitivity In Ovarian Cancer In First-line Settingmentioning

confidence: 99%

“…Due to an initially asymptomatic disease, approximately 75% of patients at the time of diagnosis present with advanced tumors (FIGO stages III to IV) known to have a poor prognosis [ 2 ]. Despite standard treatment associating debulking surgery and platinum-based chemotherapy, recurrent disease develops in more than 95% of patients within 5 years [ 3 ]. Relapse is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.…”

Section: Introductionmentioning

confidence: 99%

The Increasing Prognostic and Predictive Roles of the Tumor Primary Chemosensitivity Assessed by CA-125 Elimination Rate Constant K (KELIM) in Ovarian Cancer: A Narrative Review

Lauby

Colomban

Corbaux

et al. 2021

Cancers

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Ovarian cancer is the gynecological cancer with the worst prognosis and the highest mortality rate because 75% of patients are diagnosed with advanced stage III–IV disease. About 50% of patients are now treated with neoadjuvant chemotherapy followed by interval debulking surgery (IDS). In that context, there is a need for accurate predictors of tumor primary chemosensitivity, as it may impact the feasibility of subsequent IDS. Across seven studies with more than 12,000 patients, including six large randomized clinical trials and a national cancer registry, along with a mega-analysis database with 5842 patients, the modeled CA-125 ELIMination rate constant K (KELIM), the calculation of which is based on the longitudinal kinetics during the first three cycles of platinum-based chemotherapy, was shown to be a reproducible indicator of tumor intrinsic chemosensitivity. Indeed, KELIM is strongly associated with the likelihood of complete IDS, subsequent platinum-free interval, progression-free survival, and overall survival, along with the efficacy of maintenance treatment with bevacizumab or veliparib. As a consequence, KELIM might be used to guide more subtly the medical and surgical treatments in a first-line setting. Moreover, it could be used to identify the patients with poorly chemosensitive disease, who will be the best candidates for innovative treatments meant to reverse the chemoresistance, such as cell cycle inhibitors or immunotherapy.

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815MO The impact of chemosensitivity assessed by modeled CA-125 KELIM on the likelihood of long progression-free survivorship (PS) after 1st line treatment in ovarian cancer: An analysis of 4,450 patients

Cited by 7 publications

References 0 publications

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study

The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas

The Increasing Prognostic and Predictive Roles of the Tumor Primary Chemosensitivity Assessed by CA-125 Elimination Rate Constant K (KELIM) in Ovarian Cancer: A Narrative Review

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