
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01454-6
10.1016/j.esmoop.2024.103685
103685
Original Research
Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms
Valenza C. 12†
Mongillo M. 3†
Gigli F. 4
Trapani D. 12
Katrini J. 12
Nicolò E. 12
Boldrini L. 12
Boscolo Bielo L. 12
Castellano G. 12
Guidi L. 12
Pellizzari G. 12
Derio S. 3
Lapresa M. 3
Parma G. 3
Derenzini E. 4
Curigliano G. 12
Colombo N. nicoletta.colombo@ieo.it
35∗
1 Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan
2 Department of Oncology and Hemato-Oncology, University of Milan, Milan
3 Division of Gynecologic Oncology, European Institute of Oncology, IRCCS, Milan
4 Division of Haematology Oncology, European Institute of Oncology, IRCCS, Milan
5 Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
∗ Correspondence to: Prof. Nicoletta Colombo, Division of Gynecologic Oncology, European Institute of Oncology, IRCCS, Via Ripamonti 435, Milan 20141, Italy. Tel: +390257489543 nicoletta.colombo@ieo.it
† Equally contributed as cofirst authors.

29 8 2024
9 2024
29 8 2024
9 9 103685© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status.

Patients and methods

We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers.

Results

A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers.

Conclusions

The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.

Highlights

• Germline BRCA mutations are present commonly in heterozygosity in noncancer tissues, including hematopoietic stem cells.

• A higher prevalence of MDSs was observed among patients with ovarian carcinoma and a gBRCA mutation.

• The contribution of PARPi in MDS-pCT onset seems to be diluted by other cytotoxic regimens among highly pretreated patients.

Key words

advanced high-grade ovarian carcinoma
germline BRCA pathogenic variant
myelodysplastic neoplasms
PARP inhibitors
==== Body
pmcIntroduction

Myeloid neoplasms postcytotoxic therapy (MN-pCT) are clonal hematopoietic stem cell disorders that are diagnosed after exposure to cytotoxic therapies, including DNA damage repair (DDR) targeting agents, such as poly (ADP-ribose) polymerase inhibitors (PARPis).1,2 MN-pCTs account for 10%-20% of all myeloid neoplasms and include myelodysplastic neoplasms (MDSs-pCT), myelodysplastic-myeloproliferative neoplasms, and acute myeloid leukemia (AML-pCT). In terms of prognosis, MN-pCTs are life-threatening diseases, characterized by a median life expectancy of 8 months, that is inferior to the same diseases occurring sporadically.3

PARPi have been included in the pharmacopeia of advanced high-grade ovarian carcinoma (aHGOC), which is the leading cause of death from gynecologic cancers.4 PARPi magnitude of clinical benefit in patients with aHGOC depends on cancer cells’ homologous recombination (HR) system status: the therapeutic benefit is higher in patients with a pathogenic variant of BRCA1 or BRCA2 genes (BRCA-PVs; 20% of patients), less consistent in those with a deficient HR system but without BRCA-PVs [homologous recombination deficiency (HRD)-positive/BRCA-wild type; 20%], and smaller in those with an HRD-negative tumor (60%).

Post-PARPi myeloid neoplasms are observed in 1.2%-8% of patients with aHGOC, according to PARPi exposure duration and receipt of previous chemotherapy with cytotoxic agents.1 Their incidence is increasing due to the improved overall survival (OS) of patients with aHGOC and the raised awareness of the PARPi toxicity profile. Unlike postchemotherapy MN-pCTs, post-PARPi MN-pCTs are characterized by a shorter time to onset after treatment exposure (0.5-2 versus 5-10 years).

To better identify the risk-to-benefit ratio when prescribing PARPi for patients with aHGOC, a better characterization of post-PARPi MN-pCTs’ biology as well as their risk factors is warranted. In this regard, the presence of a germline BRCA-PV (gBRCA-PV) may increase the risk of MN-pCTs, because germline alterations are expressed in heterozygosity even in hematopoietic stem cells, which are therefore more susceptible to DDR targeting agents and have a higher a priori risk of acquiring sporadic mutations, eventually leading to MN-pCTs.5,6 However, despite this strong biological rationale, the contribution of gBRCA status in the pathogenesis of MN-pCTs has never been reported and remains to be defined.

This study aims to investigate the occurrence of MN-pCTs in patients with gBRCA-PV treated with PARPi for aHGOC.

Patients and methods

Study population

We conducted a single-center, retrospective, observational study at the European Institute of Oncology (IEO), Milan, Italy.

We collected data from all consecutive women aged ≥18 years old, with a histologically confirmed diagnosis of high-grade serous or endometrioid ovarian cancer and a known gBRCA mutational status, who received at least 8 weeks of PARPi maintenance in any line of treatment, from February 2017 to December 2022 in our center.

Patients were categorized according to gBRCA status into carriers of a gBRCA-PV and non-carriers. The latter group included carriers of gBRCA variants of uncertain significance and patients with tumors characterized by any HRD status or a somatic BRCA-PV.

As per clinical practice, all patients treated at our institution with PARPi underwent complete blood count tests weekly for the first 2 months of treatment and then every month. Patients were referred to the hematologist in case of (i) unexplained acute and/or severe cytopenia (including those cases occurring early under PARPi); (ii) blood parameters remain clinically abnormal 4 weeks after dose interruption; (iii) recurrent cytopenia despite dose modifications; and (iv) single or multilineage cytopenia after the first 3 months of PARPi and especially after 7 months from PARPi exposure. The onset of MN-pCTs was tracked also beyond the end of treatment with PARPi (possible later occurrence), up to the last follow-up.

All information was obtained through access to medical records. The study was approved by the IEO institutional review board (project code: UID 4135) and was conducted in accordance with the principles stated in the Declaration of Helsinki and with the principles of good clinical practice.

Clinicopathological parameters

The following baseline clinicopathological parameters were evaluated by gBRCA-PV status: age at aHGOC diagnosis; histotype; International Federation of Gynecology and Obstetrics (FIGO) stage; receipt of chemotherapy for other cancers and aHGOC, including the number of cycles, both before and after PARPi therapy; line of PARPi receipt and type of PARPi; number of cycles of PARPi; median follow-up and OS; occurrence of an MN-pCT, considering MDS-pCT and AML-pCT, and its characteristics (karyotype, molecular alteration, and time of onset). MN-pCTs were collected during and after treatment with PARPi, to encompass possible later occurrence, up to the last follow-up.

Statistical analyses

To compare patient clinicopathologic characteristics, continuous variables were presented as a median with interquartile range (IQR) or a mean with standard deviation, and categorical variables were presented as numbers and percentages. Mann–Whitney U test or Student’s t-test was used to compare continuous variables, and Fisher exact or χ2 test was used to compare categorical variables, as appropriate.

The study endpoints were the proportion of patients who experienced MDS-pCT and AML-pCT during and after treatment with PARPi and OS. We compared MDS-pCT and AML-pCT occurrence according to gBRCA-PV status. The OS was calculated by the Kaplan–Meyer method, expressed as months and 95% confidence interval (CI), and compared with the log-rank test. The median follow-up was calculated by the reverse Kaplan–Meyer method on OS curves. Analyses were conducted using R statistical software version 4.0.3 (R Project for Statistical Computing; R Foundation, Vienna, Austria), and two-sided P values <0.05 were considered statistically significant.

Results

A total of 166 patients were included: 71 (43%) without gBRCA-PV and 95 (57%) with gBRCA-PV, including 73 with gBRCA1 (77%), 21 gBRCA2 (23%), and 1 patient harboring mutations in both gBRCA1 and gBRCA2. Furthermore, 20/71 (28%) of tumors from the gBRCA-PV-wild type subgroup had a somatic BRCA-PV.

Patient characteristics are reported in Table 1. As far as differences in baseline characteristics are concerned, gBRCA-PV carriers were younger (age in years ± standard deviation: 56.6 ± 8.9 versus 60.1 ± 9.9; P < 0.001) and received more commonly olaparib, which is consistent with registration studies and current clinical practice. There was no difference among gBRCA-PV carriers and non-carriers in the median (IQR) number of previous lines of chemotherapy for aHGOC [2 (1-3) versus 2 (1-3); P = 0.79], of cycles of chemotherapy for aHGOC [12 (7-17) versus 12 (6-20); P = 0.61], of cycles of chemotherapy with alkylating agents (i.e. platinum salts or pegylated liposomal doxorubicin) for aHGOC [12 (7-14) versus 12 (6-18); P = 0.18], and in the number of patients who received chemotherapies for other cancers [10 (10%) versus 6 (9%); P = 0.79]. Similarly, the median (IQR) number of PARPi treatment cycles received was comparable among the two groups [11 (8-24) versus 13 (6-22); P = 0.34]. Overall, 72% of patients (120/166) received PARPi for recurrent aHGOC, therefore until progression or unacceptable toxicity.Table 1 Patient characteristics

Characteristic	All patients (N = 166)	gBRCA-PV carriers (n = 95, 57%)	gBRCA-PV non-carriers (n = 71, 43%)	P-value	
Age at baseline, mean (SD)	57.6 (9.5)	56.6 (8.9)	60.1 (9.9)	0.01	
Histotype				0.12	
 High-grade serous, n (%)	152 (92)	89 (94)	63 (89)		
 High-grade endometrioid, n (%)	8 (5)	5 (5)	3 (4)		
 Other (mixed), n (%)	6 (3)	1 (1)	5 (7)		
Stage FIGO at diagnosis				0.32	
 Early stage (I-II), n (%)	14 (8)	5 (5)	9 (13)		
 III (IIIA-IIIB-IIIC), n (%)	108 (65)	66 (69)	42 (59)		
 IV (IVA-IVB), n (%)	44 (27)	24 (25)	20 (28)		
Previous chemotherapy for other cancers, n (%)	16 (10)	10 (10)	6 (9)	0.79	
Number of cycles of previous CT for aHGOC, median (IQR)	12 (6-18)	12 (7-17)	12 (6-20)	0.61	
 With alkylating agents, median (IQR)	12 (6-17)	12 (7-14)	12 (6-18)	0.18	
Line of PARPi, median (IQR)	2 (1-3)	2 (1-3)	2 (1-3)	0.79	
 PARPi after first-line chemotherapy, n (%)	46 (28)	25 (26)	21 (30)	0.27	
Type of PARPi				<0.001	
 Olaparib, n (%)	91 (55)	64 (67)	27 (38)		
 Niraparib, n (%)	63 (38)	22 (23)	41 (58)		
 Rucaparib, n (%)	12 (7)	9 (10)	3 (4)		
Number of cycles of PARPi, median (IQR)	12 (7-23)	11 (8-24)	13 (6-22)	0.34	
Median (95% CI) follow-up, months	40.0 (35.7-44.3)	40.0 (32.0-48.0)	37.0 (29.8-44.2)	0.06	
Median (95% CI) overall survival, months	41.0 (35.5.-46.5)	40.0 (34.7-45.2)	NR (NR-NR)	0.45	
Receipt of CT post-PARPi for aHGOC, n (%)	79 (48)	47 (50)	32 (45)	0.57	
Number of cycles of post-PARPi CT for aHGOC, median (IQR)	2 (0-8)	2 (0-10)	3 (0-8)	0.96	
 With alkylating agents, median (IQR)	0 (0-6)	0 (0-6)	0 (0-5)	0.41	
Statistically significant differences are in bold.

aHGOC, advanced high-grade ovarian carcinoma; CI, confidence interval; CT, chemotherapy; FIGO, International Federation of Gynecology and Obstetrics; gBRCA-PV, germline pathogenic variants in BRCA1 or BRCA2 genes; IQR, interquartile range; NR, not reached; PARPi, PARP inhibitor; SD, standard deviation.

After a median follow-up of 40.0 months (95% CI 35.7-44.3 months), which was comparable between gBRCA-PV carriers and non-carriers (40.0 months, 95% CI 32.0-48.0 months versus 37.0 months, 95% CI 29.8-44.2 months; P = 0.06), 14 (8.4%) patients received a diagnosis of MN-pCT (Table 2; Figure 1). In particular, 10 patients were diagnosed with an MDS-pCT and 4 with an AML-pCT. Furthermore, 6 of 10 MDS-pCTs and 4 of 4 AML-pCTs occurred during the treatment with PARPi, while 4 of 10 MDS-pCTs occurred after PARPi discontinuation.Table 2 Clinical and molecular features of 14 patients developing a myeloid neoplasm postcytotoxic therapy

Number	gBRCA status	Age at PARPi initiation	PARPi exposure (months)	Type of PARPi	Line of PARPi	Onset; time from PARPi initiation to MN-pCT (months)	Type of MN-pCT	% of bone marrow blasts	Karyotype	Molecular alterations (VAF %)	mOS after MN-pCT (mo)	CT for other cancers	CT-L prior MN-pCT	
1	Mutated	43	13.9	N	2	Post-PARPi; 19	MDS-pCT	3	45-43,XX,del(5)(q22;q35),−7,+15[13]/39-44,XX,del(5)(q22;q35),−7,+mar[3]/46,XX[4]	Mut. TP53 p.(Gly244Ser) (74%)	2.9	Yes	3	
2	Mutated	39	33.0	O	2	On PARPi; 43	MDS-pCT	8	44,XX,−7,del(5),t(5;18)(q11;?);del5(q11),−18[11]/46XX	ND	0.5	No	2	
3	Mutated	64	9.0	R	4	Post-PARPi; 31	MDS-pCT	10	40-46,XX+2mar[cp8]/46,XX[2]	Mut. TP53 p.(Lys321Argfster25) (39%); TP53 p.(Ser183ter) (39%)	3.9	No	6	
4	WT	65	8.9	N	4	On PARPi; 10	AML-pCT	40	79-98,XXXX,+3-4mar[cp11]	Mut. WT1 p.Thr382ArgfsTer73 (30%); Mut. TP53 p.His193Leu (91%)	2.3	No	4	
5	WT	55	23.8	R	4	On PARPi; 25	AML-pCT	20	46,XX,del(13)(q12q14)[2]/46,XX[20].nus ish (MECOMx2)[200],(EGR1,D5S23,D5S721)x2[200],(D7S486x1,D7Z1x2)[15/200],(D8Z1)x2[200],(RARA,PML)x2[200],(TP53x2)[200], (D20S108x2)[200]	Mut. TP53 (8%)	76.0	No	4	
6	Mutated	43	41.6	O	2	On PARPi; 43	MDS-pCT	15	46,XX,del(5)(q12q33),+13,−16,del(17)(p12pter)[cp12]/46,XX[6]	Mut. TP53 (53%)	13.1	No	2	
7	Mutated	63	21.4	N	2	On PARPi; 22	AML-pCT	30	47,XX,+6,t(16;21)(q24;q22)[6]/46,XX[15]	Mut. SH2B3 p.(Thr355Asnfs∗30) (17%) RUNX1-cbfa2T3.R3c4 (90%)	6.0	No	2	
8	Mutated	52	29.9	N	2	On PARPi; 31	MDS-pCT	10	46,XX,del(5)(q22q35)[3]/45,XX,del(5)(q22q35),−7,+8,+mar[2]/45,XX,del(5)(q22q35),−7[1]/45,XX,del(5)(q22q35),−7,+8,−17[1]/46,XX[3]	Mut. TP53 p.(Arg175His) (20%)	8.3	No	2	
9	Mutated	69	20.0	O	2	On PARPi; 32	MDS-pCT	8	46,XX,del(5)(q22q35),−7,+8,+8,−17[10]/46,XX,del(5)(q22q35),−17[3]/46,XX[2]	Mut. TP53 c.746G>C (53%)	3.8	Yes	2	
10	Mutated	44	12.8	O	3	Post-PARPi; 60	MDS-pCT	5	43-45,XX,−6,del(6)(p12),−9,−13,+4mar[cp2]/45,XX,−5,−6,−15,+2mar[2]/46,XX[11]	Mut. TP53 p.Arg175His (12%)	9.6	No	6	
11	Mutated	57	23.0	O	4	On PARPi; 24	AML-pCT	80	46,XX[15]	Mut. TP53 (13%)	6.1	No	4	
12	Mutated	58	26.3	O	2	On PARPi; 34	MDS-pCT	8	45,XX,del(5)(q22q35),der(6)del(6)(p?22.3p?)t(6;14)(p22;p11.2),+8,−17[8]/46,XX[7]	Mut. TP53 p.(Cys176Ser), (19%)	7.0	No	2	
13	Mutated	63	25.2	R	5	On PARPi; 26	MDS-pCT	3	46,XX,del(5)(q12q33)[2]/45XX,del(5)(q12q33),−7[8]/46,XX,del(5)(q12q33),del(7)(q22qter)[4]	Mut. TET2 p.(Pro288Leufs∗4) (27%); Mut. TP53 p.(Ser99Glufs∗48) (24%)	14.96	No	4	
14	WT	75	16.6	O	4	Post-PARPi; 37	MDS-pCT	9	41,XX,dup(1)(q31q32),−5,−6,−9,−13,add(13)(p11.1),der(14)t(14;16)(p11.1;p11.1),add(15) (p11.1),ad17(p13),−18,add(20)(q13.3),add(21)(p11.1),+mar[30]/46,XX[1]	ND	4	No	4	
AML-pCT, acute myeloid leukemia; CT, chemotherapy; CT-L, chemotherapy lines; gBRCA, germline BRCA; MDS-pCT, myelodysplastic syndrome; MN-pCT, myeloid neoplasm postcytotoxic therapy; mOS, median overall survival; Mut, mutation; N, niraparib; ND, not done; O, olaparib; PARPi, PARP inhibitor; R, rucaparib; VAF, variant allele frequency; WT, wild type.

Figure 1 Swimmer plot describing the treatment history of patients diagnosed with an MN-pCT. 1L, first line CT; 2L, second line CT; 3L, third line CT; 4L; fourth line CT; CT POST-PARPi-1, first-line CT post-PARPi; CT POST-PARPi-2, second-line CT post-PARPi; CT POST-PARPi-3, third-line CT post-PARPi; F-UP, follow-up for ovarian cancer after pCT-MN; MN-pCT, myeloid neoplasm postcytotoxic therapy; PARPi, treatment with PARPi; PARPi-2, retreatment with PARPi; pCT-MN, postcytotoxic therapy myeloid neoplasm; preCT, previous CT for other cancer; time onset-MN, interval before onset of myeloid neoplasm; †, death.

Considering these 14 patients, the median age at diagnosis of MN-pCT was 60.8 (range 43-78) years. All patients received PARPi for recurrent aHGOC. The median line of cancer therapy was 2.5 (IQR 2-4) and 50% received maintenance PARPi after second-line chemotherapy. Only 2/14 (14%) patients had received chemotherapy for other tumors and 79% (11/14) carried a gBRCA-PV. The median PARPi exposure was 21.4 months (95% CI, 15.9-26.9 months) and the median time to MN-pCT onset was 30.6 months (95% CI 21.6-39.6 months).

Overall, 10% (11/95) of gBRCA-PV carriers received the diagnosis of an MN-pCT compared with 2% (3/71) of non-carriers; however, the +8% difference did not reach the statistical significance (P = 0.16). Instead, when dissecting MDS-pCTs and AML-pCTs, the presence of a gBRCA-PV was associated with a higher proportion of MDS-pCTs [9/95 (9%) versus 1/71 (1%); P = 0.04], but not of AML-pCTs [2/95 (2%) versus 2/71 (2%); P = 0.77].

The median OS was comparable between gBRCA-PV carriers and non-carriers [40.0 months (34.7-45.2) versus not reached (NR) (NR-NR); P = 0.45], as well as the number of patients who received chemotherapy after PARPi [47 (50%) versus 32 (45%); P = 0.57], the median number of cycles of any post-PARPi chemotherapy [2 (0-10) versus 3 (0-8); P = 0.96] and of post-PARPi chemotherapy with alkylating agents [0 (0-6) versus 0 (0-5); P = 0.41].

Discussion

In this study, we reported a unique dataset of patients with aHGOC undergoing PARPi treatments, demonstrating a statistically significant higher proportion of MDS-pCTs in patients with a gBRCA-PV, compared with non-carriers (9% versus 1%). The occurrence of MN-pCT was higher among gBRCA-PV carriers (10% versus 2%), despite not being statistically significant, due to the small number of events. The overall MN-pCT proportion of 8% was consistent with findings from trials evaluating PARPi in recurrent aHGOC (3.5%-8%)1; indeed, 72% of patients included in our study received PARPi for recurrent disease, therefore until progression or unacceptable toxicity, and were exposed at least to two lines of platinum-based chemotherapy.

In our population, known risk factors for MN-pCT, namely, the number of previous treatment lines and the receipt of previous chemotherapies for other tumors, were well balanced between gBRCA-PV carriers and non-carriers.1,3 Furthermore, median follow-up, median OS, and post-PARPi treatments were comparable among the two groups.

Therefore, the receipt of PARPi and the presence of a gBRCA-PV remain the two most significant risk factor to analyze, although the interaction between gBRCA-PV, PARPi, and MN-pCT onset is difficult to dissect.

Two more arms of patients with aHGOC non-exposed to PARPi would be needed to clearly address this issue: one of gBRCA-PV carriers and one of non-carriers. However, this population is not easily identifiable, even retrospectively, because testing for gBRCA-PVs became widespread with the advent of PARPis.4 Consequently, only indirect comparisons can be carried out to understand these interactions, amidst the widespread use of PARPi in all patients with gBRCA-PV across multiple cancer types.

As far as the relationship between PARPi and MN-pCT is concerned, a meta-analysis of 18 randomized clinical trials (RCTs) evaluating PARPis in 7307 patients with solid tumors showed that PARPi significantly increased the risk of MN-pCT compared with placebo treatment [Peto odds ratio (OR) 2.63; P = 0.026], both in studies restricted and in those unrestricted for BRCA-PVs.7 However, the Peto OR methodology cannot include trials without events in the analysis and is dependent on the group size ratio.

To overcome these methodological limitations, Nitecki et al.8 addressed the same question in a meta-analysis of 14 RCTs on 5739 patients with solid tumors who received PARPi, using the Poisson model. In this analysis, the risk of MN-pCT was similar among patients who had received PARPi versus control (incidence rate ratio 1.32; P = 0.29). Interestingly, the association between PARPi exposure and MN-pCT occurrence emerged only in subgroups of patients with lower rates of MN-pCTs (front-line setting, less than two lines of chemotherapy, and unrestricted for BRCA-PV), which partially overlap. On the contrary, among patients with higher rates of MN-pCT (with a BRCA-PV, recurrent disease, or who received two or more lines of chemotherapy), PARPi exposure did not affect the risk of MN-pCT occurrence. According to these data, BRCA-PV carriers seem to be intrinsically at higher risk of MN-pCT, regardless of PARPi receipt, and it is unclear how PARPi can modify such a risk.

However, the interpretation of RCTs and, consequently, of meta-analyses is burdened by many concerns, including differences in crossover rates and treatment exposure. For example, in the NOVA trial (maintenance niraparib or placebo for patients with platinum-sensitive recurrent aHGOC), after a median follow-up of 66 months, gBRCA-PV status was associated with a higher occurrence of MN-pCTs among patients from the niraparib arm [gBRCA-PV versus non-gBRCA-PV: 9/138 (7%) versus 4/234 (2%); Fisher’s exact test: P = 0.019], consistent with our study.9 Instead, in the ARIEL3 trial (maintenance rucaparib or placebo for patients with recurrent platinum-sensitive aHGOC), no difference in MN-pCTs among patients from the rucaparib arm emerged according to gBRCA-PV status [gBRCA-PV versus non-gBRCA-PV: 4/82 (5%) versus 10/285 (4%); Fisher’s exact test: P = 0.524], probably due to a longer rucaparib exposure among non-carriers.10

Another methodological limitation of RTCs is represented by the differences in median follow-up among RCTs and among trial arms. Indeed, when the median follow-up is shorter than those reported in the NOVA or ARIEL3 trials (66-77 months), MN-pCT events may be less and the association with gBRCA-PVs status is nonstatistically significant. For example, after a median follow-up of 22 months in the ORZORA trial (maintenance olaparib for patients with platinum-sensitive recurrent aHGOC), MN-pCT events were higher in the gBRCA-PV arm than in the somatic BRCA-PV or HRD-positive arm, although the statistical significance was NR [2/87 (2%) versus 0/87 (0%); Fisher’s exact test: P = 0.49).11 By contrast, however, longer follow-ups can reveal more chemotherapy-related MN-pCTs, which are characterized by a longer time to onset than post-PARPi myeloid neoplasms (5-10 versus 0.5-2 years).1

Furthermore, in the recurrent aHGOC setting, PARPi was demonstrated to improve OS among gBRCA-PV carriers (SOLO-2) but not in the unselected or BRCA-wild type population (ARIEL3 and NOVA).9,12,13 Therefore MN-pCTs can be overrepresented among gBRCA-PV carriers due to the PARPi-related OS benefit (wider time window) and, consequently, also due to the exposure to more lines of subsequent cytotoxic chemotherapies. In other terms, there may be a potential competitive bias between death, MN-pCT occurrence, and receipt of cytotoxic chemotherapies. For example, in the SOLO-2 trial (maintenance olaparib or placebo for patients with platinum-sensitive recurrent aHGOC and a gBRCA-PV), after a median follow-up of 66 months, the crossover rate of 38% and the gain in mOS of 13 months (52 versus 39 months) translated into an increase in MN-pCTs of 4% (8% versus 4%).12 Nevertheless, in our study, the median follow-up, the median OS, and the median number of cycles after PARPi chemotherapy were comparable between gBRCA-PV carriers and non-carriers.

As far as the relationship between gBRCA-PV and MN-pCTs is concerned, Churpek et al.14 showed that 10/47 (21%) patients with breast cancer who developed a therapy-related AML-pCT harbored a germline pathogenic variant in BRCA1, BRCA2, TP53 (tumor protein p53), CHEK2 (checkpoint kinase 2), or PALB2 (partner and localizer of BRCA2).

Similarly, after PARPi, MN-pCTs are enriched by alterations in genes involved in the HR system. Indeed, the prevalence of gBRCA-PVs in patients who developed an MN-pCT during/after PARPi was 75% (15/20) and 67% (6/9) in two case series from Gustave Roussy Institute in France and Mayo Clinic in the United States, respectively, which is consistent with the prevalence reported in our study (79%).15,16

Furthermore, gBRCA-PVs and alterations in other genes involved in the HR system were demonstrated to be significantly over-represented also in patients with spontaneous MN-pCTs, compared with the general population (8% versus 0.1%; P < 0.001).17

All these observations suggest that gBRCA-PVs have a role in the leukemogenesis of MN-pCT, which is consistent with our results, in which all potential confounding factors were well balanced among gBRCA-PV carriers and non-carriers. In this context, PARPi and chemotherapy exert selective pressure, resulting in the expansion of DDR-altered clonal hematopoiesis, which eventually increases the risk of MN-pCT.1 However, when considering a heavily pretreated population, as patients with recurrent aHGOC, the specific role of PARPis seems to be less evident and diluted by other cytotoxic regimens.

The use of PARPi in the first-line setting and the limited treatment duration of 2-3 years resulted in a drop in post-PARPi MN-pCT occurrence in RCTs.1 However, close monitoring for any MN-pCT is required in the recurrent setting, especially for patients with gBRCA-PVs and in case of PARPi rechallenge in clinical trials.

To the best of our knowledge, this is the first study assessing the role of germline (versus non-germline) BRCA-PVs in post-PARPi MN-pCTs. Indeed, other analyses did not clearly address this issue because they combined germline and somatic BRCA-PVs. The limitations of our analysis are the retrospective observational design of the study that, however, included all consecutive patients; the limited number of MN-pCT events, which affects the statistical significance of tests; the lack of data on germinal HRD status, which is usually determined in the tumor, to guide therapeutic decisions rather than to determine patients’ germline status; and the lack of information about preexisting TP53-mutated clonal hematopoiesis, which was reported to be a risk factor for MN-pCT in patients with aHGOC treated with PARPi.18

In conclusion, this study supports that the presence of a gBRCA-PV is associated with a higher risk of MDS-PCTs and possibly of MN-pCT in patients with aHGOC who received PARPi. In the recurrent setting and heavily pretreated patients, its impact seems to be even higher than PARPi exposure itself. Because of this higher risk of MN-pCT, patients with a gBRCA-PV receiving PARPi need close monitoring of blood parameters.

Funding

None declared.

Disclosure

NC reports institutional research funding from Clovis Oncology; serving in a consulting or advisory role for Clovis Oncology, AstraZeneca, BIOCAD, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana, Novartis, Nuvation Bio, OncXerna, Pfizer, PharmaMar, Roche, and Tesaro; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis; and support for attending meetings and/or travel from AstraZeneca. GC reports financial interests with AstraZeneca, Celcuity, Daiichi Sankyo, Exact Sciences, Lilly, Merck, Novartis, Pfizer, Roche, Veracyte, Ellipsis, Astellas, Blueprint Medicine, BMS, Kymab, Merck, Novartis, Philogen, Relay Therapeutics, Sanofi; and nonfinancial interests with the Italian National Health Council as Advisor for Ministry of Health ESMO, ESMO as Clinical Practice Guidelines Chair, Europa Donna as Member of the Scientific Council, EUSOMA as member of the Advisory Council, Fondazione Beretta, Lega Italiana Lotta ai Tumori as member of Board of Directors. All the competing interests were outside the submitted work. All other authors have declared no conflicts of interest.
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References

1 Caruso G. Gigli F. Parma G. Myeloid neoplasms post PARP inhibitors for ovarian cancer Int J Gynecol Cancer 33 4 2023 598 606 36707087
2 Khoury J.D. Solary E. Abla O. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms Leukemia 36 7 2022 1703 1719 35732831
3 Kuendgen A. Nomdedeu M. Tuechler H. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification—an approach to classification of patients with t-MDS Leukemia 35 3 2021 835 849 32595214
4 Lheureux S. Gourley C. Vergote I. Oza A.M. Epithelial ovarian cancer Lancet 393 10177 2019 1240 1253 30910306
5 Yang H. Jeffrey P.D. Miller J. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure Science 297 5588 2002 1837 1848 12228710
6 Vasanthakumar A. Arnovitz S. Marquez R. Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice Blood 127 3 2016 310 313 26644450
7 Morice P.-M. Leary A. Dolladille C. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database Lancet Haematol 8 2 2021 e122 e134 33347814
8 Nitecki R. Melamed A. Gockley A.A. Incidence of myelodysplastic syndrome and acute myeloid leukemia in patients receiving poly-ADP ribose polymerase inhibitors for the treatment of solid tumors: a meta-analysis of randomized trials Gynecol Oncol 161 3 2021 653 659 33736856
9 Matulonis U. Herrstedt J. Oza A. Long-term safety and secondary efficacy endpoints in the ENGOT-OV16/NOVA phase III trial of niraparib in recurrent ovarian cancer Gynecol Oncol 162 2021 S24 S25
10 O’Malley D.M. Ledermann J.A. Coleman R.L. Response to letter to the editor “AML and MDS associated with PARP inhibitor treatment of ovarian cancer.” Gynecol Oncol 171 2023 164 165 36774327
11 Pignata S. Oza A. Hall G. Maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer: outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status in the ORZORA trial Gynecol Oncol 172 2023 121 129 37030280
12 Poveda A. Floquet A. Ledermann J.A. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial Lancet Oncol 22 5 2021 620 631 33743851
13 Coleman R.L. Oza A.M. Lorusso D. 2022-RA-249-ESGO Overall survival results from ariel3: a phase 3 randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma Int J Gynecol Cancer 32 suppl 2 2022 A226.1 A22226
14 Churpek J.E. Marquez R. Neistadt B. Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia Cancer 122 2 2016 304 311 26641009
15 Martin J.E. Khalife-Hachem S. Grinda T. Therapy-related myeloid neoplasms following treatment with PARP inhibitors: new molecular insights Ann Oncol 32 8 2021 1046 1048 34107346
16 Oliveira J.L. Greipp P.T. Rangan A. Jatoi A. Nguyen P.L. Myeloid malignancies in cancer patients treated with poly(ADP-ribose) polymerase (PARP) inhibitors: a case series Blood Cancer J 12 1 2022 11 35078980
17 Williams L. Kuzmanovic T. Hirsch C.M. BRCA1 & BRCA2 germline variants are enriched in MDS/AML and portend higher average mutational burden Blood 132 suppl 1 2018 4352
18 Kwan T.T. Oza A.M. Tinker A.V. Preexisting TP53-variant clonal hematopoiesis and risk of secondary myeloid neoplasms in patients with high-grade ovarian cancer treated with rucaparib JAMA Oncol 7 12 2021 1772 34647981
