Abstract
Background
High-grade serous ovarian cancer (HGSOC) can be treated with platinum-based neoadjuvant chemotherapy (NACT) and delayed primary surgery (DPS). Histopathological response to NACT can be assessed using Böhm’s chemotherapy response score (CRS). We investigated whether germline BRCA1/2 (gBRCA1/2) genotype associated with omental CRS phenotype.
Methods
A retrospective study of patients with newly diagnosed FIGO stage IIIC/IV HGSOC prescribed NACT and tested for gBRCA1/2 pathogenic variants (PVs) between September 2017 and December 2022 at The Christie Hospital. The Cox proportional hazards model evaluated the association between survival and key clinical factors. The chi-square test assessed the association between CRS3 (no/minimal residual tumour) and gBRCA1/2 status.
Results
Of 586 eligible patients, 393 underwent DPS and had a CRS reported. Independent prognostic factors by multivariable analysis were gBRCA1/2 status (PV versus wild type [WT]), CRS (3 versus 1 + 2), surgical outcome (complete versus optimal/suboptimal) and first-line poly (ADP-ribose) polymerase-1/2 inhibitor maintenance therapy (yes versus no) (all P < 0.05). There was a non-significant trend for tumours with a gBRCA2 PV having CRS3 versus WT (odds ratio [OR] = 2.13, 95% confidence intervals [CI] 0.95–4.91; P = 0.0647). By contrast, tumours with a gBRCA1 PV were significantly less likely to have CRS3 than WT (OR = 0.35, 95%CI 0.14–0.91; P = 0.0291).
Conclusions
Germline BRCA1/2 genotype was not clearly associated with superior omental CRS. Further research is required to understand how HGSOC biology defines CRS.
Subject terms: Prognostic markers, Oncology
Background
Ovarian cancer is the second commonest cause of gynaecological cancer-related death worldwide, with more than 200,000 deaths attributed to the disease each year [1]. The most common histological subtype is high-grade serous ovarian cancer (HGSOC), which accounts for approximately 70% of all malignant tumours of the ovary [2]. The predilection of HGSOC to metastasise early to the peritoneal surfaces means most women are diagnosed with advanced-stage disease and cure is unlikely. Advanced HGSOC can be treated with neoadjuvant chemotherapy (NACT) followed by delayed primary surgery (DPS) [3–6]. A NACT plus DPS approach provides an opportunity to assess a tumour’s histopathological response to systemic anticancer therapy. However, there is no universally accepted scoring system to define the pathological response of HGSOC to NACT [7–14]. Moreover, the biology that defines histopathological responses to NACT in HGSOC is unknown. Consequently, all women treated with NACT plus DPS are offered the same platinum-containing chemotherapy in the immediate postoperative setting, potentially missing an opportunity to personalise therapy [15].
The genomic hallmarks of HGSOC are near-ubiquitous somatic TP53 mutations, germline and somatic BRCA1/2 mutations, homologous recombination deficiency (HRD) and genomic instability [16–20]. Germline BRCA1/2 mutations occur in 10–20% of HGSOCs and are now routinely tested for in all newly diagnosed women [21]. Epithelial ovarian cancers harbouring a germline BRCA1/2 mutation are highly sensitive to platinum-containing chemotherapy [22–25]. The putative mechanism for this platinum sensitivity is somatic loss (genetic or epigenetic) of the remaining BRCA1/2 wild type allele, leading to a biallelic loss-of-function, a deficiency in homologous recombination, and an inability to repair lethal DNA double-strand breaks caused by platinum chemotherapy [26]. We hypothesised that because epithelial ovarian cancers containing a germline BRCA1/2 mutation often have a better radiological response to platinum-containing chemotherapy compared to tumours with germline BRCA1/2 wild type, they would also have a better histopathological response to NACT. To investigate this, we used the Böhm scoring system, which defines histopathological responses of HGSOC to NACT by examining omental tissue resected during DPS [12]. Tumours with a complete/near-complete response to NACT (i.e., no/minimal residual omental tumour) have a chemotherapy response score (CRS) of 3, while tumours with no/minimal response to NACT (i.e., viable residual omental tumour) have a CRS of 1 [12]. We hypothesised that HGSOCs harbouring a germline BRCA1/2 mutation were more likely to have CRS3 than those with germline BRCA1/2 wild type.
Methods
Patient cohort
A retrospective study in which eligible patients included those with newly diagnosed FIGO (International Federation of Gynaecology and Obstetrics) stage IIIC or IV [27] ovarian, fallopian tube or primary peritoneal cancer that were prescribed NACT at The Christie NHS Foundation Trust (Manchester, United Kingdom). All patients had histologically confirmed HGSOC and had been tested for germline BRCA1/2 variants by the North West Genomic Laboratory Hub between 1st September 2017 and 31st December 2022. The decision to proceed to DPS after NACT was made by local multidisciplinary teams. All patients who received at least one dose of NACT were included in the overall population. All patients who underwent DPS were included in the DPS group.
BRCA1/2 testing
All patients provided informed consent for germline BRCA1/2 testing. The next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assays used in the North West Genomic Laboratory Hub have been reported previously [28]. Germline testing was performed on DNA extracted from peripheral blood lymphocytes. The NGS assay tested the coding regions of BRCA1 and BRCA2 plus 15 base pairs either side of each exon-intron boundary. Target coverage was at least 90% at a read depth of 100X. Small sequencing variants (<40 base pairs) were reported with a variant allele fraction ≥5%. Copy number variants including whole gene/exon deletions/duplications were detected using MLPA. Only pathogenic (class 5) and likely pathogenic (class 4) variants were reported (hereafter described as ‘pathogenic variants’ or ‘PVs’) [29].
Efficacy outcomes
Chemotherapy response scores were determined by gynaecological Histopathologists by examining omental tissue removed at DPS using the Böhm scoring system [12]. Reporting Histopathologists were based at two tertiary referral centres, The Christie NHS Foundation Trust and Manchester University NHS Foundation Trust (Manchester, United Kingdom). The outcome of cytoreductive surgery was categorised as complete (no macroscopically visible tumour), optimal (1–10 mm of residual disease) or suboptimal (>10 mm of residual disease) [30]. Efficacy outcomes included progression-free survival (PFS), time to first subsequent therapy (TFST) and overall survival (OS). Progression-free survival was defined as the time interval from cycle 1 day 1 of NACT to the date of clinical or radiological progression or death, whichever occurred first. Time to first subsequent therapy was defined as the time interval from cycle 1 day 1 of NACT to the start of the subsequent therapy or death, whichever occurred first. Overall survival was defined as the time interval from cycle 1 day 1 of NACT to the date of death. The final date of data cut-off was 8th January 2024 to allow a minimum of 12 months follow-up from cycle 1 day 1 of NACT in all patients. The GCIG CA 125 criteria was used to define response to NACT but not progression [31]. The GCIG CA 125 response was determined by comparing the pre-treatment serum CA 125 value with the pre-surgical serum CA 125 value. Only patients with a pre-treatment serum CA 125 value twice the upper limit of normal (range 0–30 U/mL) were eligible for GCIG CA 125 response assessment. The CA 125 ELIMination Rate Constant K (KELIM) was also used to define response to NACT [32]. It was calculated using the same model as implemented on the online calculator (https://www.biomarker-kinetics.org/) [33]. Only those patients with at least three CA 125 values measured within the first 100 days (or less) after starting NACT were eligible for KELIM.
Statistical analysis
The chi-square test was used to determine whether there was an association between omental CRS3 (no/minimal residual tumour) and germline BRCA1/2 status. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) and P values were calculated. Kaplan–Meier statistics were used to estimate median survival times and corresponding 95% CI. Univariable and multivariable Cox proportional hazards regression was applied to evaluate the association between survival outcomes and key clinical factors in the overall population and DPS group. Hazard ratios (HRs) together with their corresponding 95% CI and P values were calculated. All reported P values were two-sided. Statistical analyses were performed with R version 4.3.1.
The study was approved by the Quality Improvement & Clinical Audit Committee at The Christie NHS Foundation Trust. The study was performed in line with the principles of the Declaration of Helsinki.
Results
Overall population
In total, 586 eligible women were identified (Fig. 1). Of these, 581 patients received at least one dose of NACT and were included in the overall population (Supplementary Table S1). There were 77 (13%) germline BRCA1/2 PVs detected (40 BRCA1, 37 BRCA2) in 77 women (Supplementary Data). The median PFS, TFST and OS for the overall population were 14.3 (95% CI 13.5–15.3; 474 events), 16.1 (95%CI 15.4–17.1; 462 events) and 35.7 months (95% CI 33.4–40.1; 337 events), respectively (Supplementary Fig. S1). The median follow-up for patients alive at the date of data cut-off was 30.1 months (interquartile range 19.8–34.9).
Fig. 1. CONSORT diagram.
Key: C1 cycle 1, CT computed tomography, CRS chemotherapy response score, DPS delayed primary surgery, NACT neoadjuvant chemotherapy.
Univariable and multivariable analyses showed that ECOG performance status (0–1 versus 2–4), germline BRCA1/2 status (PV versus wild type), cytoreductive surgery (yes versus no) and use of first-line poly (ADP-ribose) polymerase-1/2 inhibitor (PARPi) maintenance therapy (yes versus no) were prognostic factors in the overall population (Supplementary Tables S2 and S3). The median PFS was significantly longer in patients who received first-line maintenance therapy versus those who underwent surveillance (Supplementary Table S4). Taken together, these observations validated our overall population dataset and supported the next stage of evaluating omental CRS as a prognostic factor in women undergoing DPS.
Delayed primary surgery group
Of the 581 patients who received at least one dose of NACT, 402 (69%) underwent DPS and 393 (98%) had an omental CRS reported (Supplementary Table S5). The 9 patients without a documented CRS had no evidence of neoplasia or chemotherapy-related regression changes in the omentum (n = 6) or no CRS reported (n = 3). Of the 179 patients who did not undergo DPS, the commonest reason for not undergoing debulking surgery was the extent of residual disease seen radiologically following NACT (n = 99 [55%]) (Fig. 1). Of these 99 patients, 57 (58%) had FIGO stage IV disease.
Of the 393 patients in the DPS group with a CRS reported, 336 (85%) received 3–4 cycles of NACT and 246 (63%) had complete debulking (Table 1). The proportion of patients who received 3–4 cycles of NACT in the CRS3 versus CRS1 + 2 group did not differ significantly (114/131 [87%] versus 222/262 [85%], respectively; P = 0.60) (Table 1). Fifty-nine women received pre-operative bevacizumab (Table 1). There was no significant difference between the proportion of patients who received bevacizumab prior to DPS in the CRS3 versus CRS1 + 2 group (19/131 [15%] versus 40/262 [15%], respectively; P = 0.84) (Table 1). However, patients with CRS3 were more likely to achieve complete debulking than those with CRS1 + 2 (108/131 [82%] versus 138/262 [53%], respectively; P < 0.0001) (Table 1). Moreover, patients with CRS3 were more likely to have a GCIG CA 125 response (120/121 [99%] versus 229/246 [93%], respectively; P = 0.0085) or KELIM CA 125 favourable score (78/109 [72%] versus 112/218 [51%], respectively; P = 0.0005) than those with CRS1 + 2 (Table 2 and Supplementary Table S6). The median PFS, TFST and OS were significantly longer in the CRS3 group compared to the CRS1 + 2 group (Table 2, Fig. 2 and Supplementary Table S7).
Table 1.
Demographic data for delayed primary surgery group.
| CRS1 + 2 | CRS3 | |
|---|---|---|
| 262 patients | 131 patients | |
| Age at diagnosis/years | ||
| Median (range) | 63 (37–83) | 67 (36–86) |
| ECOG performance status | ||
| 0–1 | 218 (83%) | 109 (83%) |
| 2–4 | 44 (17%) | 22 (17%) |
| FIGO stage | ||
| IIIC | 180 (69%) | 96 (73%) |
| IVA | 30 (11%) | 9 (7%) |
| IVB | 52 (20%) | 26 (20%) |
| Germline BRCA1/2 status | ||
| Pathogenic variant | 40 (15%) | 18 (14%) |
| Wild type | 222 (85%) | 113 (86%) |
| Neoadjuvant chemotherapy | ||
| Carboplatin-Paclitaxel | 256 | 126 |
| 3-weekly | 202 (77%) | 96 (73%) |
| Weekly | 54 (21%) | 30 (23%) |
| Carboplatin-Caelyx | 4 (2%) | 0 |
| Carboplatin | 2 (<1%) | 5 (4%) |
| Cycles of neoadjuvant chemotherapy | ||
| <3 | 1 (<1%) | 0 |
| 3-4 | 222 (85%) | 114 (87%) |
| >4 | 39 (15%) | 17 (13%) |
| Median (range) | 4 (2–6) | 4 (3–6) |
| Pre-operative bevacizumab | ||
| Yes | 40 (15%) | 19 (15%) |
| Median (range) | 3 (1–6) | 3 (2–4) |
| Hyperthermic Intraperitoneal Chemotherapy | ||
| Yes | 15 (6%) | 6 (2%) |
| Surgical outcome | ||
| Complete | 138 (53%) | 108 (82%) |
| Optimal | 102 (39%) | 20 (15%) |
| Suboptimal | 22 (8%) | 3 (2%) |
| Total cycles of first-line chemotherapy | ||
| <6 | 17 (6%) | 5 (4%) |
| ≥6 | 245 (94%) | 126 (96%) |
| Median (range) | 6 (2–8) | 6 (3–8) |
| First-line maintenance therapy | ||
| None | 73 (28%) | 45 (34%) |
| Bevacizumab | 90 (34%) | 40 (31%) |
| Olaparib | 15 (6%) | 13 (10%) |
| Niraparib | 52 (20%) | 23 (18%) |
| Bevacizumab and olaparib | 32 (12%) | 10 (8%) |
DPS delayed primary surgery, ECOG Eastern Cooperative Oncology Group, FIGO International Federation of Gynaecology and Obstetrics.
Table 2.
Efficacy outcomes in delayed primary surgery group.
| CRS1 + 2 | CRS3 | Hazard ratio (95% CI) | P value | |
|---|---|---|---|---|
| 262 patients | 131 patients | |||
| GCIG CA 125 response – number (%) | ||||
| Eligible | 247 (94%) | 121 (92%) | – | – |
| CA 125 Response | 229 (93%) | 120 (99%) | – | 0.0085 |
| No CA 125 response | 18 (7%) | 1 (<1%) | – | |
| CA 125 KELIM – number (%) | ||||
| Eligible | 218 (83%) | 109 (83%) | – | – |
| Favourable score (≥1.0) | 112 (51%) | 78 (72%) | – | 0.0005 |
| Unfavourable score (<1.0) | 106 (49%) | 31 (28%) | – | |
| Progression-free survival | ||||
| Events – number (%) | 218 (83%) | 80 (61%) | - | – |
| Median (95% CI) – months | 14.8 (13.9–15.9) | 24.4 (21.9–31.9) | 2.45 (1.9–3.2) | <0.0001 |
| Time to first subsequent therapy | ||||
| Events – number (%) | 210 (80%) | 80 (61%) | – | – |
| Median (95% CI) – months | 16.4 (15.7–17.8) | 26.81 (23.2–34.4) | 2.42 (1.9–3.2) | <0.0001 |
| Overall survival | ||||
| Events – number (%) | 148 (56%) | 47 (36%) | – | – |
| Median (95% CI) – months | 38.0 (33.1–42.7) | 58.8 (50.1–NR) | 2.28 (1.6–3.2) | <0.0001 |
95% CI 95% confidence interval, CRS chemotherapy response score, DPS delayed primary surgery, GCIG Gynecologic Cancer Intergroup, KELIM ELIMination Rate Constant K.
Fig. 2. Kaplan–Meier curves for progression-free survival (PFS) and overall survival (OS) in CRS groups.
a, c show Kaplan–Meier curves for PFS (a) and OS (c) for CRS1 versus CRS2 versus CRS3; b, d show Kaplan–Meier curves for PFS (b) and OS (d) for CRS1+2 versus CRS3.
Univariable and multivariable analyses showed that germline BRCA1/2 status (PV versus wild type), surgical outcome (complete versus optimal/suboptimal debulking), CRS (3 versus 1 + 2) and use of first-line PARPi maintenance therapy (yes versus no) were prognostic factors in the DPS group (Table 3 and Supplementary Table S8). These observations validated our DPS group dataset and supported the next stage of evaluating the association between omental CRS3 and germline BRCA1/2 status.
Table 3.
Multivariable analysis of delayed primary surgery group.
| Progression-free survival | Time to first subsequent therapy | Overall survival | |||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | HR | 95% CI | P value | |
| Age at diagnosis | 1.00 | 0.98–1.01 | 0.6925 | 1.00 | 0.98–1.01 | 0.6069 | 1.00 | 0.99–1.02 | 0.7802 |
| ECOG performance status | |||||||||
| 0–1 (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| 2–4 | 1.25 | 0.92–1.69 | 0.1603 | 1.22 | 0.89–1.67 | 0.2083 | 1.40 | 0.95–2.05 | 0.0858 |
| FIGO stage | |||||||||
| IIIC (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| IV | 1.27 | 0.99–1.63 | 0.0572 | 1.27 | 0.99–1.64 | 0.0614 | 1.22 | 0.89–1.66 | 0.2161 |
| Germline BRCA1/2 status | |||||||||
| Pathogenic variant (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| Wild type | 1.44 | 1.01–2.07 | 0.0447 | 1.47 | 1.02–2.13 | 0.0398 | 1.70 | 1.08–2.68 | 0.0223 |
| Number of cycles of NACT | |||||||||
| 3–4 (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| >4 | 0.84 | 0.60–1.18 | 0.3109 | 0.92 | 0.65–1.30 | 0.6351 | 0.91 | 0.60–1.38 | 0.6499 |
| Surgical outcome | |||||||||
| Complete (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| Optimal/suboptimal | 1.74 | 1.35–2.23 | <0.0001 | 1.79 | 1.39–2.31 | <0.0001 | 1.60 | 1.18–2.17 | 0.0026 |
| Chemotherapy response score | |||||||||
| 3 (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| 1 + 2 | 2.34 | 1.77–3.09 | <0.0001 | 2.27 | 1.71–3.01 | <0.0001 | 2.08 | 1.45–2.97 | 0.0001 |
| First–line PARPi therapy | |||||||||
| Yes (Ref) | 1.00 | – | – | 1.00 | – | – | 1.00 | – | – |
| No | 2.35 | 1.79–3.09 | <0.0001 | 2.37 | 1.79–3.14 | <0.0001 | 1.64 | 1.07–2.51 | 0.0231 |
95% CI 95% confidence interval, DPS delayed primary surgery, ECOG Eastern Cooperative Oncology Group, HR hazard ratio, NACT neoadjuvant chemotherapy, PARPi poly (ADP-ribose) polymerase-1/2 inhibitor.
Germline BRCA1/2 status and chemotherapy response score
In the 393 patients in the DPS group with an omental CRS reported, there was no significant difference between the proportion of tumours with CRS3 in the germline BRCA1/2 PV group versus the germline BRCA1/2 wild type group (OR 0.88, 95% CI 0.49–1.63; P = 0.6875) (Table 4). When the subgroups of women with a germline BRCA1 and BRCA2 PV were analysed separately, there was a trend towards a significantly greater proportion of tumours with CRS3 in the germline BRCA2 PV subgroup compared to the germline BRCA1/2 wild type group (OR 2.13, 95% CI 0.95–4.91; P = 0.0647) (Table 4 and Fig. 3). In contrast, there was a significantly smaller proportion of tumours with CRS3 in the germline BRCA1 PV subgroup compared to the germline BRCA1/2 wild type group (OR 0.35, 95% CI 0.14–0.91; P = 0.0291) (Table 4 and Fig. 3).
Table 4.
Association between chemotherapy response score and germline BRCA1/2 (gBRCA1/2) status.
| Group | CRS1 + 2 | CRS3 | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| Wild type | 222 (66%) | 113 (34%) | – | – |
| gBRCA1 | 28 (85%) | 5 (15%) | 0.35 (0.14–0.91) | 0.0291 |
| gBRCA2 | 12 (48%) | 13 (52%) | 2.13 (0.95–4.91) | 0.0647 |
| gBRCA1/2 | 40 (69%) | 18 (31%) | 0.88 (0.49–1.63) | 0.6875 |
95% CI 95% confidence interval, CRS chemotherapy response score.
Fig. 3.
Chemotherapy response score reported for patients with a germline BRCA1/2 pathogenic variant.
Discussion
A key question in HGSOC research is what is the biology that drives histopathological responses to NACT. Improving our understanding of the biology that underpins responses to NACT may help optimise the use of postoperative therapies. At present, the standard approach for women with newly diagnosed, advanced-stage HGSOC, who are treated with NACT and DPS, is to offer the same platinum-based chemotherapy postoperatively that was used preoperatively, regardless of how well the tumour had responded histopathologically [15]. This treatment strategy misses a potential opportunity to develop personalised postoperative therapies through improved understanding of the biology that underpins a tumour’s histopathological response to NACT.
Epithelial ovarian cancers that harbour a germline BRCA1/2 PV respond better radiologically to platinum-based chemotherapy compared to those with germline BRCA1/2 wild type [23]. Moreover, women with a germline BRCA1/2 PV have longer survival outcomes than those with germline BRCA1/2 wild type, largely due to enhanced primary platinum sensitivity and retained platinum sensitivity in the relapsed setting [22, 24, 25]. In their original study, Böhm and colleagues reported that omental CRS3 had a negative predictive value of 94.6% for primary platinum resistance, implying that HGSOCs with CRS3 were highly unlikely to develop primary platinum-resistant disease [12]. Taken together, these observations suggest that one factor underpinning histopathological responses to NACT in HGSOC could be germline BRCA1/2 status. Thus, we hypothesised that tumours with CRS3 were more likely to have a germline BRCA1/2 PV compared to tumours with germline BRCA1/2 wild type.
To evaluate an association between omental CRS phenotype and germline BRCA1/2 genotype, we firstly confirmed that key clinical factors in our overall population and DPS group were prognostically reproducible. Here, we showed that undergoing cytoreductive surgery and achieving complete debulking were prognostic in our overall population and DPS group. Moreover, we showed that having CRS3 or a germline BRCA1/2 PV were independent prognostic factors in our DPS group, regardless of the use of first-line PARPi maintenance therapy. These observations provided us with confidence that data from our cohort aligned with data reported in prospective ovarian cancer cohorts [30, 34–39]. Following this validation exercise, we were able to show a trend towards omental CRS3 in tumours harbouring a germline BRCA2 PV compared to tumours with germline BRCA1/2 wild type. In contrast, and surprisingly, we found that tumours with CRS3 were less likely to have a germline BRCA1 PV than those with germline BRCA1/2 wild type.
It is unclear why we found no clear association between germline BRCA1/2 genotype and CRS phenotype. It is notable that in their original study, Böhm and colleagues did not use BRCA1/2 status to develop the CRS, because germline BRCA1/2 status was not known in most women included in their discovery or validation cohorts [12]. Thus, it is plausible that the histopathological changes seen in the omentum that define CRS, including the fibro-inflammatory response and extent of residual disease, are not biologically related to the presence of a germline BRCA1/2 PV. A multicentre, individual patient data meta-analysis performed by The HGSC CRS Collaborative Network did report a positive associated between tumours with CRS3 and a germline BRCA1/2 PV (P = 0.027) [40]. However, in this meta-analysis only 306 patients (35%) out of 807 included had known germline BRCA1/2 status. Moreover, 80/306 (26%) had a germline BRCA1/2 PV and 33/80 (41%) had CRS3. The prevalence of germline BRCA1/2 PVs in this meta-analysis was higher than expected in an unselected population of women with ovarian cancer [41]. Thus, by unavoidably including a disproportionally high number of germline BRCA1/2 heterozygotes, the meta-analysis may have overestimated the association between CRS3 and germline BRCA1/2 status [40]. Nonetheless, the lack of a clear association between CRS3 and germline BRCA1/2 status in our study, and other smaller observational studies [42–50], implies that CRS biology cannot be explained using the current dogma linking BRCA1/2 status and platinum sensitivity in HGSOC. To deconvolute the complexity of CRS biology, detailed analysis of tumour-intrinsic factors and the tumour immune microenvironment is required, using spatial multiomic platforms and next-generation high-dimensional tissue imaging. Indeed, detailed understanding of the biology of the residual omental tumour and/or the tumour immune microenvironment in patients with CRS1 + 2 may lead to optimisation of post-operative treatments through personalised medicine.
What is evident from our study is that a large number of tumours with CRS3 have germline BRCA1/2 wild type. These tumours may have a BRCA1/2 wild type/HRD-positive genotype, although this remains unknown as routine genomic instability score (GIS) testing was not available during most of the study period [51]. Indeed, tumour HRD/GIS testing was only performed on 215/586 (37%) patients in the overall population (151/402 [38%] patients in the DPS group) because it only became available as a standard test in the North West of England in April 2021. Thus, further research is required to determine if omental CRS3 associates with tumour HRD/GIS status [52, 53]. Nevertheless, our study does validate CRS3 as an independent prognostic factor for primary platinum efficacy. It is well established that HRD-positive tumours are highly sensitive to PARPi, and that PARPi efficacy is linked to primary platinum response [34–39]. All women with newly diagnosed, advanced-stage HGSOC now undergo routine tumour HRD testing to access first-line olaparib-bevacizumab maintenance therapy [37]. Tumours with better histopathological responses to NACT are more likely to fail HRD testing due to the paucity of residual viable tumour cells available for testing in the DPS specimen [52]. In this scenario, when tumour HRD testing fails, omental CRS3 may offer a surrogate biomarker of PARPi efficacy. Thus, we advocate prospectively investigating omental CRS3 as a surrogate biomarker of PARPi efficacy; the main advantage of CRS being that it is cost-free [12].
Our retrospective study has some limitations based on the study design, which may have led to unavoidable selection bias. Firstly, germline BRCA1/2 testing occurred over a five-year period, in which standard eligibility criteria for testing changed from relapsed, platinum-sensitive HGSOC to any patient diagnosed with HGSOC. As a result, not all women with newly diagnosed HGSOC that were treated at The Christie Hospital will have undergone germline BRCA1/2 testing between 2017 and 2022. Indeed, patients who did not undergo germline BRCA1/2 testing were not included in our study. Secondly, only those patients that underwent DPS could be included in our analysis of omental CRS phenotype versus germline BRCA1/2 genotype, meaning the conclusions drawn about HGSOC biology cannot be applied to patients who did not receive NACT or undergo DPS. Thirdly, the decision to proceed with DPS was made by two multidisciplinary teams working in isolation, thus there may have been subtle differences between patients chosen for upfront primary surgery versus DPS. Fourthly, histology reporting occurred across two gynaecology pathology laboratories, so there may have been interobserver variation in CRS amongst reporting histopathologists, although this was not assessed in the study. One way to mitigate against interobserver variability would be to include a centralised review panel of expert gynaecology pathologists and/or use a digital pathology tool. Finally, we have not included patients with somatic BRCA1/2 PVs in the analysis, largely because local testing showed that many of these mutations do not have variant allele frequencies consistent with biallelic loss-of-function [54]. Overall, however we were reassured by the fact that the Böhm scoring system was prognostic in our study, consistent with data reported by other observational studies [43, 45, 46, 48, 49, 55–64]. Moreover, median survival data in our overall population aligned with prospective trial data for patients with epithelial ovarian cancer treated with NACT [65].
To our knowledge, we report the largest observational study assessing the association between omental CRS and germline BRCA1/2 status in newly diagnosed, advanced-stage HGSOC. Unexpectedly, we found no evidence to show a clear association between established pathology (omental CRS) and genetic (germline BRCA1/2 status) biomarkers of platinum sensitivity in HGSOC. We also add to the growing evidence that the modified two-tier Böhm scoring system (CRS1 + 2 versus CRS3) is an independent prognostic biomarker in FIGO stage IIIC/IV HGSOC. Finally, we demonstrate that patients with CRS1 + 2 are less likely to have a GCIG CA 125 or KELIM CA 125 response to platinum-based NACT or achieve complete debulking surgery compared to those with CRS3.
Supplementary information
Acknowledgements
The data was presented at the European Society for Medical Oncology 2023 Congress (Annals of Oncology 2023;34 (Suppl 2): S527-S528).
Author contributions
Conceptualization: RDM; Methodology: RDM, XW; Formal Analysis: RDM, XW, AC; Data Curation: RDM, XW, BMB, LS, AC; Supervision: BY, DGRE, GCJ, SST; Writing - Original Draft: RDM, XW, AC, GCJ, SST; Writing - Review & Editing: RDM, XW, BMB, LS, AC, DN, JH, CM, ZS, SD, JS, BW-R, HS, GJB, ARC, RJE, BY, DGRE, GCJ, SST.
Funding
This work was funded by a generous gift to Ovarian Cancer Research Team at The Christie NHS Foundation Trust, Manchester, by the family of Mrs Margaret Evans from North Ferriby, East Yorkshire. Robert Morgan is supported by a National Institute for Health Research (NIHR) Clinical Lectureship (CL-2022-06-002). Bethany Barnes and Stephen Taylor are funded by a Cancer Research UK Programme Grant awarded to Stephen Taylor (C1422/A19842 and C1422/A31334); and the Medical Research Council (MR/X008088/1); with co-funding from the NIHR Manchester Biomedical Research Centre (NIHR203308); and the Cancer Research UK Manchester Centre (C147/A25254). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Data availability
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
The study was approved by the Quality Improvement & Clinical Audit Committee at The Christie NHS Foundation Trust. The Genetic Variants in Gynaecological Cancer database has been approved by The Christie NHS Foundation Trust. The study was performed in line with the principles of the Declaration of Helsinki. Informed consent was obtained from all subjects involved in the study.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41416-024-02874-6.
References
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Data Availability Statement
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