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BRCA status and platinum sensitivity in advanced ovarian cancer according to Chemotherapy Response Score
  1. Raffaella Ergasti1,2,
  2. Claudia Marchetti1,2,
  3. Riccardo Tudisco1,2,
  4. Adelaide Iervolino2,
  5. Angelica Naldini1,
  6. Riccardo Oliva1,2,
  7. Frediano Inzani1,
  8. Giovanni Scambia1,2 and
  9. Anna Fagotti1,2
  1. 1 Department of Woman, Child and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
  2. 2 Catholic University of the Sacred Heart Faculty of Medicine and Surgery, Rome, Italy
  1. Correspondence to Professor Giovanni Scambia, Department of Woman, Child and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Lazio, Italy; giovanni.scambia{at}policlinicogemelli.it

Abstract

Objective To evaluate a relation between BRCA1/2 status and the Chemotherapy Response Score in patients with epithelial ovarian cancer undergoing neoadjuvant chemotherapy and interval debulking surgery.

Methods Data were retrospectively collected on patients with unresectable disease undergoing three or four cycles of neoadjuvant chemotherapy and interval debulking surgery at the Gynecologic Oncology Unit of the Catholic University of the Sacred Heart from January 2016 to December 2020. All patients were assessed for BRCA1/2 somatic mutation at diagnosis. The omental specimens obtained at the interval surgery were evaluated according to Bohm’s Chemotherapy Response Score System.

Results A total of 172 patients were included in the analysis, 69 (40%) patients were BRCA1/2 mutation carriers and 103 (60%) patients were wild type. In the wild-type group (BRCAwt), 73 (70.9%) patients had a Chemotherapy Response Score of 1 or 2 and 30 (29.1%) patients had a score of 3. In the BRCA1/2 carriers group (BRCAmut), 39 (56.5%) patients had a score of 1 or 2 and 30 (43.5%) patients had a score of 3. Among the BRCAwt group, those with a Chemotherapy Response Score of 3 had a prolonged median progression-free survival (22 vs 15 months, p=0.003). Among the BRCAmut carriers group, no differences were found (30 vs 27 months, p=0.55). No difference in overall survival was observed in either the BRCAmut carriers population (p=0.23) or the BRCAwt population (60 vs 44 months, p=0.06).

Conclusions Patients with BRCA1/2mut seem to achieve a score of 1, 2 or 3 with the same frequency. In contrast, patients with BRCAwt seem to have a score of 1 or 2 more frequently than a score of 3. In patients with BRCA1/2mut, this score may not be an indicator of chemosensitivity.

  • ovarian cancer
  • BRCA1 protein
  • BRCA2 protein

Data availability statement

Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplementary information.

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HIGHLIGHTS

  • There was a higher rate of Chemotherapy Response Score of 1 or 2 in women with wild-type BRCA (BRCAwt).

  • Chemotherapy Response Score may not be the best response marker in patients with BRCA1/2 mutation undergoing neoadjuvant chemotherapy.

  • Chemotherapy Response Score may have a prognostic role in patients with BRCAwt only.

Introduction

Ovarian cancer remains the most lethal gynecological malignancy in developed countries, with nearly 75% of women presenting with advanced disease (stage III or IV).1

Primary debulking surgery followed by adjuvant chemotherapy (possibly with the addition of maintenance therapy) remains the standard treatment for advanced-stage epithelial ovarian cancer. Upfront optimal cytoreduction cannot be achieved in all patients due to patients’ frailty or to unresectable disease because of high tumor burden.2 3 Thus, neoadjuvant chemotherapy followed by interval debulking surgery has been proposed as a valid alternative in patients at high surgical risk4 5 and has been increasingly performed.

In these patients, residual tumor at the time of interval debulking surgery still maintains its prognostic value, but response to neoadjuvant chemotherapy, defined either as clinical or pathological, is also a strong predictor of survival. Recently, the Chemotherapy Response Score, a three-tier approach, has been suggested as a reproducible, prognostically significant, and validated system for assessing the response of ovarian cancer to neoadjuvant chemotherapy. It is based on the histopathological evaluation of the omentum resected during interval cytoreduction. This score, which was internally validated, seems to correlate with patient survival: the higher the score, the longer the progression-free survival and the overall survival. Interestingly, in the work of Bohm and colleagues,6 patients with higher score had higher rates of complete cytoreduction, suggesting that the increased survival could be related to more favorable tumor biology; subsequently other authors have externally confirmed these data.7 8

BRCA mutational status has been recently proven to be a positive prognostic factor,9 but also a possible biomarker of response to platinum-based chemotherapy10 11 and, more recently, to PARP inhibitors therapy.12 13 Therefore, it could be expected that patients with BRCA mutations might achieve a greater pathological response to neoadjuvant chemotherapy, which could eventually be expressed as a higher Chemotherapy Response Score. Nonetheless, the association with BRCA mutational status and the Bohm’s scoring system (also known as Chemotherapy Response Score) has rarely been explored.14

This retrospective study aimed to evaluate whether there is a correlation between BRCA1/2 mutational status and pathological complete response expressed as Chemotherapy Response Score in a large ovarian cancer population undergoing neoadjuvant chemotherapy followed by interval debulking surgery.

Methods

Patients

We retrospectively collected data on 172 patients with advanced ovarian cancer who underwent neoadjuvant chemotherapy and subsequent interval debulking surgery who were admitted to the Gynecologic Oncology Unit of the Catholic University of the Sacred Heart from January 2016 to December 2020 (Online Supplemental File 1). The institutional review board approved the study (CICOG-01-07-19/33) and patients gave informed consent for the collection and use of their data for a scientific purpose. Inclusion criteria were: epithelial advanced ovarian cancer (mostly high-grade serous ovarian cancer), International Federation of Gynecology and Obstetrics (FIGO) stage IIIC/IV, platinum-based neoadjuvant chemotherapy, interval debulking surgery after three or four cycles of neoadjuvant chemotherapy, and knowledge of BRCA mutational status.

Supplemental material

According to our institutional model, patients initially underwent clinical evaluation, thorax and abdominal computed tomography (CT scan) and staging laparoscopy to be triaged towards primary debulking surgery versus neoadjuvant chemotherapy and subsequent interval debulking surgery. Possible options for neoadjuvant chemotherapy were as follows: 3-weekly carboplatin AUC-5 or 6/paclitaxel 175 mg/m2; weekly carboplatin AUC-2/paclitaxel 60–80 mg/m2.

Interval debulking surgery was performed either by laparotomy or minimally invasive surgery according to preoperative evaluation and surgeon preference. Surgical procedures were recorded and graded according to the surgical complexity score by Aletti.15 Patients then completed an additional two or three cycles of adjuvant chemotherapy. Bevacizumab 15 mg/kg or PARP inhibitors (olaparib/niraparib) were given as maintenance, when appropriate, according to international and national guidelines.16

After completion of primary treatment, all women were triaged to clinical routine follow-up procedures according to our internal protocol, based on European Society of gynaecological oncology (ESGO) guidelines.17 We routinely stratify patients as follows: patients on maintenance therapy with PARP inhibitors or bevacizumab and patients not on maintenance therapy. For patients on maintenance therapy, we perform a monthly serum CA125 marker and re-evaluation every 3 months (alternating CT scan with abdominal and pelvic ultrasound), based on the symptoms reported. In patients who do not undergo maintenance therapy, a CT scan is performed every 3 months for the first year, then every 6 months for the following 2 years, and then annually. In these patients, CA125 is evaluated monthly for the first year, then every 3 months for the following 2 years and finally every 6–12 months up to clinical evaluation of the patient. The type of follow-up is not dependent on the presence or absence of the mutation.

All included patients were screened for somatic mutation for BRCA1/2 genes by biopsy taken at the time of diagnostic laparoscopy, after specific preoperative counseling and signing informed consent before surgery.18 All patients with tissue BRCA1/2 mutation (pathogenic variant) or variants of uncertain significance received a blood test to determine the presence of a germline mutation. Patients with germline BRCA1/2 mutation were then referred for genetic counseling.

All patients considered to be carriers of a BRCA1/2 mutation in the present study are pathogenic mutation carriers.

The resected specimens from interval debulking surgery were formalin fixed and paraffin embedded according to standard procedures and stained with hematoxylin and eosin (H&E) in our Pathology Department .

Until April 2017, a single gynecological pathologist reviewed all the slides and subsequently histological specimens were analyzed by a group of pathologists dedicated to the Gynecologic Oncology Unit, independently of any data in the original histopathology reports. The pathologist assigned a Chemotherapy Response Score based on omental assessment, according to Bohm and colleagues.6 Chemotherapy Response Score 1 corresponds to no or minimal tumor response (no or minimal regression-associated fibro-inflammatory changes limited to a few foci), cases in which it is difficult to decide between regression and tumor-associated desmoplasia or inflammatory cell infiltration; Chemotherapy Response Score 2 means appreciable tumor response with viable tumor readily identifiable, ranging from multifocal or diffuse regression-associated fibro-inflammatory changes with a viable tumor in sheets, streaks, or nodules to extensive regression-associated fibro-inflammatory changes with multifocal residual tumor; Chemotherapy Response Score 3 corresponds to complete absence of tumor cells or individual cells, cell groups, or nodules with a maximum size of 2 mm. Moreover, the presence of residual disease was evaluated in the ovaries as well as in all other available sites. According to the literature,6 patients belonging to the Chemotherapy Response Score 1 and Chemotherapy Response Score 2 groups have been compiled into a single group. The pathological response was also expressed as absence of disease, according to Petrillo and colleagues.19

Statistical Analysis

Descriptive data are reported as median (range) or frequency (percentage). Categorical variables were compared with the χ2 test or continuous variables with the Student’s t-test or Mann-Whitney U test for parametric/non-parametric variables, respectively. Progression-free survival was defined as the time from diagnosis to the time when disease progression/recurrence or death was documented. The overall survival was defined as the time from diagnosis to death or the last follow-up. Survival analysis was performed using the Kaplan-Meier method with a log-rank test. For all analyses, the significance level was set at 0.05. All statistical calculations were performed using statistical analysis, IBM SPSS 28.0 for Mac (SPSS, Chicago, Illinois, USA).

Results

The median age at diagnosis was 61 years (range 27–83). A total of 103 (60%) patients were BRCA wild type and 69 (40%) patients had a BRCA1/2 pathogenetic variants. Of the total mutation carriers, 62 patients (90%) had the same mutation confirmed on germline testing. No patient with a somatic variant of uncertain significance was subsequently classified as a germline carrier. Characteristics of patients are described in Table 1. In terms of Chemotherapy Response Score, 60 (35%) patients achieved a Chemotherapy Response Score of 3, while 44 (25.5%) patients and 68 (39.5%) achieved a Chemotherapy Response Score of 2 or 1, respectively. A total of 14 (8.1%) patients had a complete pathological response, all among those achieving a Chemotherapy Response Score of 3 (as expected), including 6 (43%) patients with BRCAmut and 8 (57%) BRCAwt patients (p=0.52).

Table 1

Patient characteristics

Concerning the BRCA status and Chemotherapy Response Score, patients with BRCAwt were found to have a Chemotherapy Response Score of 1 or 2 in 70.9% of cases (n=73) compared with 29.1% of patients (n=30) with a Chemotherapy Response Score of 3. In BRCAmut carriers no difference was found between patients with a score of 3 (43.5%) and a score of 1 or 2 (56.5%).

Overall, BRCA1/2 carriers were more represented in the score 3 than in the score 1 and 2 group (50% vs 34.8%, p=0.04) (Table 1).

As shown in Table 1, disease stage (p=0.08), histotype (p=0.53), and peritoneal spread of disease (p=0.25) were not correlated with Chemotherapy Response Score at the time of interval debulking surgery. As expected, residual tumor correlated with the fibro-inflammatory response found on the omental specimen at the time of interval surgery: patients with residual tumor >0 (n=31, 18%) more frequently had a Chemotherapy Response Score of 1 or 2 (n=26) than a Chemotherapy Response Score of 3 (n=5) (p=0.01).

All women received six cycles of chemotherapy. After standard chemotherapy, 49 (28.5%) patients received maintenance treatment with bevacizumab (11 had BRCA1/2 mutation and 38 were BRCAwt, 22% vs 78%, p<0.003) and 66 (38.4%) patients received a PARP inhibitor as maintenance treatment (45 had BRCA1/2 mutation and 21 were BRCAwt, 68% vs 32%, p<0.001). At the time of interval debulking surgery, 52 patients received hyperthermic intraperitoneal chemotherapy (HIPEC) (30.2% of the overall population).

The median follow-up was 24 months (range 1–68). At the time of final analysis, 93 (54%) patients had recurring disease, with no differences among groups (p=0.74). Similarly, 148 (86%) patients were still alive, with similar death rates (p=0.81). In the overall population, the median progression-free survival was 22 months; those within the Chemotherapy Response Score 3 group showed a significant 6 months increase in median progression-free survival compared with patients in the Chemotherapy Response Score 1 or 2 group (23 months vs 17 months, p=0.005, Figure 1A). With regards to the BRCA status, in the overall population, patients with BRCAmut had a longer progression-free survival (27 months) compared with patients with BRCAwt (17 months, p<0.001). Median overall survival was not reached in the entire population. The 3-year overall survival in the Chemotherapy Response Score 3 group was 88% compared with 71% in the Chemotherapy Response Score 1 or 2 group (p=0.015, Figure 1B).

Figure 1

(A) Progression-free survival (PFS) according to Chemotherapy Response Score, overall population. (B) Overall survival (OS) according to Chemotherapy Response Score, overall population.

When correlating BRCA status with response assessment, among patients with BRCAwt, those with a Chemotherapy Response Score of 3 had a significantly prolonged median progression-free survival compared with those with a score of 1 or 2 (22 months vs 15 months, p=0.003, Figure 2A). Conversely, among BRCAmut carriers, no differences in progression-free survival were found (30 months vs 27 months, p=0.44, Figure 2B). At multivariate analysis for progression-free survival, independent factors of prolonged progression-free survival were BRCA mutational status (HR 0.45, CI 95% 0.28–0.71) and having a Chemotherapy Response Score of 3 (HR 0.54, 95% CI 0.35 to 0.84) (Table 2). Regarding overall survival, in the BRCAwt cohort, the Chemotherapy Response Score 3 group achieved a median overall survival of 60 months compared with 44 months in the score 1 or 2 group (p=0.06). In the BRCAmut carriers population, no difference in terms of overall survival was found between the two groups (not reached vs not reached, p=0.23). In the multivariate analysis, the strongest predictors of longer overall survival were BRCA mutational status (HR 0.31, 95% CI 0.11 to 0.86) and Chemotherapy Response Score of 3 (HR 0.31, 95% CI 0.12 to 0.83) (Table 3).

Figure 2

(A) Progression-free survival (PFS) according to Chemotherapy Response Score, BRCAwt population. (B) Progression-free survival according to Chemotherapy Response Score, BRCAmut population.

Table 2

Cox proportional hazard model for progression-free survival (univariate and multivariate analysis)

Table 3

Cox proportional hazard model for overall survival (univariate and multivariate analysis)

Discussion

Summary of Main Results

In this study, we found a statistically significantly higher rate of patients with BRCAmut than those with BRCAwt achieving a Chemotherapy Response Score of 3 (43.5% vs 29.0%, p=0.04). This result confirms that patients with BRCAwt are less responsive to platinum-based chemotherapy than those with BRCAmut.

Additionally, our study shows that Chemotherapy Response Score keeps its prognostic role in patients with BRCAwt only, while it does not correlate with progression-free survival in BRCAmut carriers. Indeed, median progression-free survival was consistently longer in patients with BRCAmut than in those with BRCAwt, regardless of their Chemotherapy Response Score. Accordingly, in the multivariate analysis, both BRCA status and Chemotherapy Response Score were independent prognostic factors of survival, further underlying the importance of tumor biology and treatment response.

Our data suggest that Chemotherapy Response Score may not represent the best marker of response in patients with BRCA1/2 mutation undergoing neoadjuvant chemotherapy. A possible explanation could be the different extent of disease of those with BRCA1/2 mutation, who frequently present with nodal spread and grossly appearing ovaries20; therefore, assessment of response in this subgroup of patients could be inadequate if limited to the omentum and a more tailored score could be hypothesized.

Results in the Context of Published Literature

A possible association between Chemotherapy Response Score and BRCA mutational status of patients with advanced epithelial ovarian cancer has been previously investigated. Overall, the proportion of patients with Chemotherapy Response Score 3 reported in the literature21–23 is mainly close to 30% of the population, similar to the 35% described in our series. Only Barrington and colleagues recorded a 14% rate of Chemotherapy Response Score 3, although describing 42% of patients with a BRCA mutation. However, this was a retrospective single institution cohort study with a small sample size (50 patients), and they failed to show any correlation between Chemotherapy Response Score and survival.24

Conversely, all other series21–23 confirmed the prognostic significance of the scoring system, but no evidence of an association between BRCA status and Chemotherapy Response Score was found.14 21–23 Except for Lee and colleagues,14 none of the other mentioned studies had investigated this correlation as a primary endpoint, but merely as a surrogate finding. Furthermore, BRCA status was unknown in a range between 16% and 55%, limiting data robustness and interpretation. In particular, Lee and colleagues did not find any difference in terms of Chemotherapy Response Score rates between patients with BRCAwt and those with BRCAmut. However, in line with our results, they showed that Chemotherapy Response Score can predict survival in patients with BRCAwt only, whereas it was not effective in women with BRCA1/2mut.14

Moreover, while we always assessed BRCA status on tissue (and confirmed on peripheral blood if positive), other authors performed germline testing only14 22 or did not clearly describe the method used.23 Finally, in these studies, only antiangiogenic treatment is mentioned as maintenance therapy, while data about possible PARP inhibitor therapy are missing.14 21–23

Strengths and Weaknesses

Our study highlights the possible different impact of BRCA status on Chemotherapy Response Score. Moreover, our population shows 40% of patients had BRCAmut, which is higher than 30% reported in the literature.25 The high rate of patients carrying the mutation in Italy26 and the retrospective nature of this study may also create a selection bias and explain different results with respect to reported data.25

We must underline the different distribution of maintenance therapies. Roughly, 38.4% of patients in our cohort had received a PARP inhibitor (Table 1); however, patients with BRCA1/2 mutations received this treatment more frequently, with 65.2% of BRCAmut carriers receiving PARP inhibitors. Conversely, patients with BRCAwt more frequently received bevacizumab. This unbalanced administration of treatment may have an impact on both progression-free and overall survival. A longer follow-up is certainly necessary, as well as a subsequent stratification of the results based on the type of treatment provided to patients and their BRCA mutational status.

Implications for Practice and Future Research

The role of Chemotherapy Response Score as a possible biomarker of PARP response has not been explored and should be investigated in future research. Indeed, assuming that PARP inhibitors are best used in patients who are platinum sensitive, the Chemotherapy Response Score could potentially predict response to PARP. Because almost all patients with advanced epithelial ovarian carcinoma now receive first-line maintenance treatment, neoadjuvant platinum-based chemotherapy with Chemotherapy Response Score assessed at interval debulking surgery could help in discriminating who benefits most from PARP inhibitors compared with bevacizumab, particularly in the BRCAwt population.

Conclusions

Chemotherapy Response Score is a predictive and prognostic marker for platinum response and longer progression-free survival in patients with BRCA wild type only. Its prognostic and predictive role drops in patients with BRCAmut, and therefore other predictive scores of neoadjuvant chemotherapy response are needed in this population. Further studies may clarify if the assessment of Chemotherapy Response Score has a role in predicting PARP inhibitor response.

Data availability statement

Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by the Institutional Review Board (CICOG-01-07-19/33). Participants gave informed consent to participate in the study before taking part.

References

Footnotes

  • Contributors RE (guarantor), CM, RT, RO: as gynecological oncologists, they were mainly involved in data collection, evaluating individual patients and the possibility of enrolling them in the study. AI: a medical student who was mainly involved in data transcription. AN: mainly involved in tumor samples collection in the operating room. FI: a gynecology dedicated pathologist, mainly involved in CRS evaluation on the omental specimens. GS, AF: mainly involved in planning the retrospective study and surveying all the staff working around it. They also participated in sample collection during surgery.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.