Edited by: Haifeng Qiu, Zhengzhou University, China
Reviewed by: Syed S. Islam, King Faisal Specialist Hospital & Research Centre, Saudi Arabia; Franco Muggia, New York University, United States
*Correspondence: Kazuho Nakanishi,
This article was submitted to Gynecological Oncology, a section of the journal Frontiers in Oncology
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The purpose of this study was to investigate the predictors of the effect of olaparib on platinum-sensitive recurrent ovarian cancer with unknown germline BRCA mutations. We retrospectively examined 20 patients with platinum-sensitive ovarian cancer who were treated at the Nippon Medical School Chiba Hokusoh Hospital, Japan, from 2018 to 2020. We found that the median progression-free survival was 11.4 months (95% Confidence interval (CI): 3.8–Not Available (NA)) in the group with NLPN score [recurrent neutrophil-lymphocyte ratio (rNLR) × number of previous regimens] >7.51, and median progression-free survival was not reached in the group with NLPN score <7.51 (95% CI: 21.8–NA) (p = 0.0185). There was a clear correlation between the degree of dose reduction of olaparib and recurrence (p = 0.00249). Our results show that NLPN scores lower than 7.51 are associated with a favorable outcome of olaparib treatment for platinum-sensitive recurrent ovarian cancer. In cases with a high rNLR, it may be necessary to start olaparib treatment as early as possible to obtain low NLPN scores. Our results imply that the effectiveness of olaparib can be determined after recurrence and before platinum treatment begins. As newer drugs for ovarian cancer are developed, the measurement of biomarker levels at the start of treatment for recurrent ovarian cancer, as shown in our study, may provide strong support for cancer treatment protocols.
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related deaths in women (
Several prognostic factors have been proposed to reliably predict EOC outcomes, including histology, tumor stage, residual lesions after surgery, weight loss, response to chemotherapy, and BRCA1/2 mutation status (
In contrast to the strong immune response with respect to the presence of TILs and a better prognosis in some patients, tumor immune escape (a mechanism by which antitumor immunity is effectively neutralized) is considered one of the main reasons for disease progression and treatment failure in others. The coordination of many mediators, including cytokines (interleukin (IL)-10, tumor growth factor (TGF)-β, and prostaglandin E2), membrane-bound ligands (B7-H1), and programmed cell death-1 (PD-1), is required to suppress tumor cells and immunosuppressive T-regulatory cells (Tregs) such as FOXP3+CD4+ cells. In addition, tumor-associated macrophages (TAMs) are involved in inhibiting the activity of immune-effector cells such as CD4+ T cells, CD8+ T cells, and natural killer cells in tumor microenvironments (
The poly ADP-ribose polymerase inhibitor (PARPi), olaparib, was recently approved by the United States Food and Drug Administration (
Recently, in addition to BRCA, homologous recombination deficiency, platinum sensitivity, excision repair cross complementation group 1 (ERCC1), and ADP-ribosylation (ADPRylation) levels have been reported as factors that predict the therapeutic effect of PARPi; however, there are no reports on predictive biomarkers that can be easily measured (
The purpose of this study was to explore the predictors of the effects of olaparib on platinum-sensitive recurrent ovarian cancer by analyzing data, such as NLR, systemic inflammation index (SII), blood inflammatory response, cancer antigen-125 (CA125) levels, and the number of chemotherapy rounds that the patients have undergone.
Written informed consent was obtained from all patients. In addition, approval was obtained from the Ethics Committee of the Nippon Medical School Chiba Hokusoh Hospital (approval number: 874).
Between January 2018 and December 2020, 28 patients were diagnosed with ovarian cancer recurrence at our hospital. Of these patients, 22 were diagnosed with platinum-sensitive recurrence when the recurrence occurred more than 6 months after the last use of platinum-based anticancer drugs. Of these 22 patients, 20 had chosen olaparib as maintenance therapy after treatment with platinum-based anticancer drugs, none chose maintenance treatment with bevacizumab, one did not wish for maintenance therapy after platinum-based anticancer drugs, and one chose best supportive care as her performance status was poor. The remaining six patients developed platinum-resistant recurrences. Platinum-based drug treatment in the 20 patients selected for this study included Paclitaxel (PTX) (175 mg/m2 day 1) + Carboplatin (CBDCA) (area under the concentration-time curve (AUC) 5 day 1) every 21 days, PTX (80 mg/m2 day 1, 8, 15) + CBDCA (AUC 6 day 1) every 21 days, Gemcitabine (1000 mg/m2 day 1, 8) + CBDCA (AUC 4 day 1) every 21 days, and Irinotecan (60 mg/m2 day 1, 8, 15) + Cisplatin (60 mg/m2 day 1) every 21 days; these previous treatments lasted from 2 to 4, 4, 4, and 4 months, respectively.
The 20 patients subjected to olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer were eligible for our study. Doses ranged from 400-600 mg/day and treatment time had a mean of 12.9 months (range 4-30 months). Of these 20 patients, 9 had recurrence after the start of olaparib administration: median time to recurrence 9.9 months (range 4-22 months). No dropouts due to side effects were observed in any case. Olaparib dose reduction was performed in 11 patients. Among them, one patient received a one-step dose reduction for anemia and 10 patients received a two-step dose reduction [eight for renal dysfunction (creatinine clearance <50) and two for persistent fatigue]. The basic dose was 600 mg/day, with a one-step dose reduction to 500 mg/day and a two-step dose reduction to 400 mg/day.
Here, we retrospectively examined 20 patients with platinum-sensitive ovarian cancer who were treated at the Nippon Medical School Chiba Hokusoh Hospital from 2018 to 2020. The patients were placed into two groups: those who relapsed after starting olaparib treatment and those who did not. The age, histology, and number of treatment regimens before recurrence for all patients are shown in
Patient characteristics (n = 20).
Recurrent- | Recurrent+ | P | |
---|---|---|---|
Number of patients (n) | 11 | 9 | |
Age; average (years) | 61.36 ± 11.79 | 62.33 ± 9.97 | 0.847 |
HGSOC (n) | 5 | 5 | 1 |
NPR; average (n) | 2.63 (range 2-6) | 4 (range 2-7) | 0.0527† |
Therapeutic effect by platinum-based therapy | |||
CR (n) | 9 | 4 | 0.172* |
PR (n) | 2 | 5 | |
No dose reduction of olaparib (n) | 8 | 1 | 0.00249**† |
One-step dose reduction (n) | 1 | 0 | |
Two-step dose reduction (n) | 2 | 8 |
HGSOC, high-grade serous ovarian cancer; NPR, number of previous regimens; CR, complete response; PR, partial response; †p < 0.1. *calculated by Log-rank test; **calculated using the Cochran-Armitage test; the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) were used to judge the therapeutic effect [complete response (CR) or partial response (PR)].
Blood samples were obtained from the patients: (i) immediately after detection of recurrence and before the start of platinum-based treatment, and (ii) immediately after completion of platinum-based treatment and before the start of olaparib treatment. These blood samples were used to determine the white blood cell, neutrophil, and lymphocyte counts using a multi-item automatic blood cell analyzer (XE-2100, Sysmex, Kobe, Japan). A chemistry autoanalyzer (Hitachi 7700, Hitachi, Ibaraki, Japan) was used to measure the serum lactate dehydrogenase (LDH) levels that were analyzed using a lactate dehydrogenase kit (L-type LD J, FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan) and the c-reactive protein (CRP) levels that were analyzed using an N-assay LA CRP-S D-type assay (Nittobo Medical, Tokyo, Japan) according to the manufacturer’s protocols. The CA125 levels were determined using the ARCHITECT i2000SR immunoassay analyzer (Abbott, Chicago, IL, USA). The NLR, which has already been reported as a prognostic factor in EOC, was calculated using the neutrophil/lymphocyte count, and the SII was calculated as platelet count × neutrophil/lymphocyte count (
Surgical tissue specimens obtained during debulking surgery were stained with hematoxylin and eosin to determine the different histological cancer types of the patients. Specimens positive for serous carcinoma were analyzed for p53 overexpression by immunostaining with anti-p53 [DO-7] antibody (GeneTex, Inc. Irvine, CA, USA) to identify those positive for HGSOC. We also analyzed the number of regimens used thus far, and used the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) to judge the therapeutic effect [complete response (CR) or partial response (PR)] in patients after platinum-based treatment.
The age, histology, number of treatment regimens before recurrence (
Laboratory findings from blood samples obtained from epithelial ovarian cancer patients (n = 20).
Recurrent- | Recurrent+ | P | |
---|---|---|---|
At recurrence | |||
NLR | 2.12 ± 0.85 | 3.00 ± 1.26 | 0.080† |
SII | 537.64 ± 308.63 | 684.11 ± 376.95 | 0.352 |
LDH (U/L) | 195.18 ± 37.39 | 205.20 ± 72.40 | 0.693 |
CRP (mg/L) | 0.36 ± 0.57 | 1.33 ± 2.45 | 0.217 |
CA125 (U/mL) | 143.92 ± 154.55 | 591.73 ± 850.50 | 0.102 |
Before Olaparib | |||
NLR | 1.86 ± 0.86 | 2.34 ± 0.95 | 0.254 |
SII | 407.95 ± 249.70 | 400.09 ± 237.71 | 0.944 |
LDH (U/L) | 186.10 ± 40.86 | 203.33 ± 43.87 | 0.388 |
CRP (mg/L) | 1.07 ± 2.77 | 0.18 ± 0.23 | 0.382 |
CA125 (U/mL) | 56.11 ± 79.02 | 92.21 ± 174.72 | 0.546 |
Data a presented as medians and standard deviation. NLR, neutrophil-lymphocyte ratio; SII, Systemic inflammatory index; LDH, lactate dehydrogenase; CRP, c-reactive protein; CA125, cancer antigen-125; †means p < 0.1.
Eleven patients did not relapse and nine relapsed. The average age of these patients was 61.36 and 62.33 years, respectively, with the most common histology of each being HGSOC, as shown in
The average progression-free survival (PFS) during the observation period was 12.9 months. The application of the revised RECIST guidelines (version 1.1) after platinum-based treatment showed 13 cases of CR and 7 cases of PR (
Regarding bloodwork and olaparib effectiveness (
When combining rNLR and NPR data, we obtained NLPN scores. The AUC of the ROC curve for PFS was 0.828 (95% CI 0.611–1), and the threshold NLPN score value NPR at which the sum of sensitivity and specificity is maximized on the ROC curve was 7.51 (sensitivity = 0.909, specificity = 0.778) (
Receiver operating characteristic (ROC) curve for progression-free survival (PFS) based on the NLPN score (neutrophil-lymphocyte ratio at recurrence × number of previous regimens followed).
Patients were then grouped according to high (>7.51) and low (<7.51) NLPN scores. The median PFS was 11.4 months in the high-NLPN score group (95% CI 3.8–NA). The median PFS was not reached in the low-NLPN score group (95% CI 21.8–NA, p = 0.0185) (
Progression-free survival (PFS) in patients grouped according to high (>7.51) and low (<7.51) NLPN scores (neutrophil-lymphocyte ratio at recurrence × number of previous regimens followed).
There was a clear correlation between the degree of olaparib dose reduction and recurrence (p=0.00249) (
Relationship between olaparib dose reduction and NLPN (neutrophil-lymphocyte ratio at recurrence × previous number of regimens) score.
NLPN score >7.51 | NLPN score <7.51 | |
---|---|---|
No dose reduction (600 mg/day) | 2 | 7 |
One-step reduction (500 mg/day) | 0 | 1 |
Two-step reduction (400 mg/day) | 5 | 5 |
Cochran-Armitage test p = 0.202.
We identified two important clinical issues in this study.
We investigated the inflammation index as a predictor of olaparib susceptibility in patients with platinum-sensitive recurrent EOC and the potential value of the number of treatment regimens they have received. We found that a low NLPN score was an independent predictor of platinum sensitivity when adjusted for age, histology, and platinum-treatment response (CR or PR).
The NLR just before starting olaparib after the end of platinum treatment also predicted the therapeutic effect of olaparib. However, there was a correlation between the rNLR and the NLR just before starting olaparib administration. This implies that the effectiveness of olaparib is determined and measurable after recurrence and before platinum treatment begins.
The role of neutrophils in promoting ovarian cancer has been previously described (
There was no correlation between the NLPN score and the dose of olaparib (Cochran-Armitage test, p = 0.202). To date, no reports have been associated with olaparib and platinum-sensitive recurrent ovarian cancer. In a previous clinical trial that showed the effect of maintenance treatment with olaparib on platinum-sensitive recurrent ovarian cancer, the initial dose was 400 mg; therefore, the two-step dose reduction of 400 mg in our study was not too small, as the therapeutic effect of the 400 mg dose was insufficient (
The dose setting for olaparib in Study 19 is based on the Phase 1 study presented at ASCO 2007 (
Currently, the only PARPi effectiveness biomarkers are BRCA, homologous recombination status, and platinum sensitivity (
Another limitation of our study was the small patient sample size that can cause bias in interpreting the relationship between NLPN scores and clinical responses. Additionally, this post-hoc study of 20 patients was for exploratory purposes, and the sample size of the study was insufficient to effectively address this relationship in detail. Therefore, the NLPN score may not be able to predict clinical response. As this was a retrospective study, the association between high and low NLPN scores and gBRCA1/2 status was unknown.
In conclusion, our results suggest that the NLPN score is an independent predictor of olaparib susceptibility in platinum-sensitive ovarian cancer. A high NLPN score is a poor prognostic factor for olaparib treatment in platinum-sensitive ovarian cancer, regardless of age, histology, or degree of response to platinum treatment (CR or PR). There was a significant correlation between the degree of olaparib dose reduction and recurrence. Since this result supports the conclusions of Study 24, the experience must be carried on to the more relevant early settings. The exploratory nature of our research requires that these findings be investigated in a positive and powerful setting before drawing decisive conclusions. A low NLPN score is associated with a favorable outcome of olaparib treatment for platinum-sensitive recurrent ovarian cancer. In cases with a high rNLR, it may be necessary to start olaparib as early as possible to achieve a low NLPN score.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by the Ethics Committee of the Nippon Medical School Chiba Hokusoh Hospital. The patients/participants provided their written informed consent to participate in this study.
TY and GI contributed to conception and design of the study. KN organized the database, performed experiments, and wrote the manuscript. SS approved the final draft of the article. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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We would like to thank Editage (