Heterozygote Germline Mutations in Homologous Recombination Core Genes Can Predict for Pathologic Complete Response in Early Triple Negative Breast Cancer

Article Information

C Fontaine1,2*, S De Brakeleer3, ETeugels3, V Renard2,4, H Van den Bulck2, P Vuylsteke2,5,6, P. Glorieux2, C Dopchie2, S Joris1,2, L Decoster1,2, A Awada2,7, K Punie2,8, H Wildiers2,8, J De Grève1,2,3,9, on behalf of the BSMO Breast cancer working group

1Department of Medical Oncology, Oncologisch Centrum UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium

2Belgian Society of Medical Oncology (BSMO), Corneel Heymanslaan 10, 9000 Gent, Belgium

3Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussels, Belgium

4Department of Medical Oncology, AZ St. Lucas, Gent, Belgium

5Department of Medical Oncology, CHU Namur, Site Ste-Elisabeth, UCL Louvain, Belgium

6Department of Medical Oncology, University of Botswana, Gaborone, Botswana

7Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

8Department of Medical Oncology, UZ Leuven, Leuven, Belgium

9Department of Medical Genetics, UZ Brussel, Brussels, Belgium

*Corresponding author: Christel Fontaine, Department of Medical Oncology, Oncologisch Centrum UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.

Received: 05 September 2023; Accepted: 12 September 2023; Published: 17 October 2023

Citation: C Fontaine, S De Brakeleer, ETeugels, V Renard, H Van den Bulck, P Vuylsteke, P. Glorieux, C Dopchie, S Joris, L Decoster, A Awada, K Punie, H Wildiers, J De Grève, on behalf of the BSMO Breast cancer working group. Heterozygote Germline Mutations in Homologous Recombination Core Genes can Predict for Pathologic Complete Response in Early Triple Negative Breast Cancer. Journal of Biotechnology and Biomedicine. 6 (2023): 476-490.

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Abstract

Background: BSMO 2014-01 is a published prospective phase 2 study investigating neoadjuvant weekly paclitaxel and carboplatin, followed by epirubicin and cyclophosphamide in 63 patients with triple-negative breast cancer. Pathological complete response (pCR) was 54%. A secondary endpoint was to correlate pCR rate to the presence of germline pathogenic variants in DNA damage response (DDR) genes and in core genes involved in Homologous Recombination (HR).

Methods: Peripheral blood from 60 TNBC patients was collected for germline DNA analysis. Whole Exome Sequencing was performed; we considered only rare variants (minor allelic frequency < 0.01) in 276 DDR genes of which 88 HR and 21 HR core genes. The correlation between pCR rate and mutations in DDR or HR genes was analyzed using the Fisher's exact test. The same was done for the correlation between DDR gene mutations and the presence of hematologic toxicities.

Results: Thirty-five out of 60 patients (58.3%) carried a protein disrupting germline mutation in a DDR gene. Twenty-four of these 35 patients (68.6%) had a pCR, compared to 40% without a DDR mutation (p=0.026). In 14/15patients (93.3%) with a HR core gene mutation a pCR was obtained, while a pCR was present in 44.4% without a HR core gene mutation (p=0.0007). HR core gene mutations were detected in BRCA1 (5), BRCA2 (4), RAD52 (4), RAD50 (1), BARD1 (1) and EME1 (1).

Conclusions: This is the first study to demonstrate that germline pathogenic variants in genes involved in HR core genes predict for pCR after platinum-containing neoadjuvant chemotherapy.

Keywords

Breast Cancer; DNA damage

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Article Details

Introduction

Most TNBC are highly proliferative cancers that lack the expression of estrogen and progesterone receptors as well as amplification of the Her2 oncogene. [1]. Preoperative chemotherapy is the standard of care in TNBC because of the prognostic significance of the pathologic response on long-term outcome and the opportunity to tailor subsequent adjuvant therapy to the quality of the response obtained [3-5]. Several studies have indicated that patients with TNBC benefit from the addition of platinum to the neoadjuvant chemotherapy, however impact on survival is still uncertain [6-9]. Given the fact that platinum adds to the toxicity of the regimen, an important question is whether all TNBC do benefit to the same degree. Applying the HRDetect mutational-signature-based algorithm, fifty to sixty percent of TNBC harbour a HR repair deficiency explained by BRCA1/2 germline/somatic mutations or other genomic (germline and somatic) instabilities, which provides specific therapeutic opportunities for the use of DNA double-strand break-inducing agents, including platinum salts, anthracyclines, alkylating agents and poly-ADP-ribose polymerase (PARP) inhibitors [10]. Up to date,it is still debated whether patients with a homologous recombination deficient TNBC, more broadly defined than only BRCA1/2 mutations, benefit more than other TNBC patients from the addition of platinum. Some studies using an HRD-score, based on loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions, support that this might be the case or at least that these patients respond better to neoadjuvant platinum combinations [11,12]. This hypothesis has not been investigated using germline mutation analysis of genes involved in DDR. By performing whole exome sequencing and investigating in more details the genes involved in the DDR machinery, we tried to identify genomic germline biomarkers allowing a better selection of the patients, who will benefit from therapies with DNA damaging agents such as platinum, in order to avoid useless toxicity.

Patient and Methods

Patient population

Between June 2015 and May 2016, 65 TNBC patients were included in a previously published phase II neoadjuvant BSMO 2014-01 study [13]. The prospective, multicenter phase II trial explored the efficacy of neoadjuvant dose-dense weekly paclitaxel and carboplatin, followed by biweekly epirubicin and cyclophosphamide. The primary objective was to determine the pCR rate. One of the preplanned secondary objectives was to examine the correlation between pCR and germline carrier status of mutations in DDR or HR genes. Patients older than 18 years and with operable stage II and III were included after signing an informed consent. Two patients were excluded from the analysis because they were not assessable for the primary endpoint (one received doxorubicin instead of epirubicin and one refused surgery). As reported in the publication of the clinical results, 20 extra patients were recruited and treated with the same regimen with the purpose to have 60 samples to do whole exome sequencing. Eleven patients (patient ID 0202; 0909; 0912; 1305; 1901; 1902; 2001; 2002; 2602; 2904; 3001) from the first publication did not consent for translational research and 8 consecutive patients(patient ID: 0107; 0913; 0205; 0206; 2104; 2105; 2610; 3004) from the extra pool agreed to participate to the genomic analysis. Triple negativity was defined as estrogen and progesterone receptor expression in less than 10% of tumor cells and no Her2 amplification as defined by Her2 IHC 0-1 or FISH ratio less than two (ASCO/CAP guideline recommendations for HER2 testing) [14].

Study procedures

All patients were treated for 12 weeks with weekly paclitaxel (wP) 80mg/m² concurrent with weekly carboplatin (Cp) at an area under the curve (AUC) dose of 2, followed by epirubicin 90mg/m² and cyclophosphamide 600mg/m² (EC) biweekly for four cycles with myeloid growth factor support on day 2. Response assessment was planned at 2 time points of the neoadjuvant systemic therapy. The extent of surgery and subsequent irradiation was performed according to the local guidelines of the participating centers and no further adjuvant chemotherapy was foreseen in the study, although this was at the discretion of the investigator. Subsequently, patients were prospectively followed for recurrence and survival status.

Pathological evaluation

Histopathologic evaluation of response after neoadjuvant chemotherapy was done in accordance to the Pinder tumour response system [15]. Pathologic response was determined locally without central pathologic review. All surgical pathology reports were centrally reviewed. pCR rate was defined as no remaining invasive cancer in the breast and resected axillary lymph nodes (ypT0/isypN0).

Germline BRCA1/2 testing

Germline testing for BRCA1/2 was performed in the individual institutions utilizing available validated gene panel tests, according national guidelines. Patients with a germline BRCA1/2 mutation or other breast cancer predisposition genes were counselled as per institutional guidelines and considering the gene risk profile and familial cancer phenotype.

Whole exome sequencing

Blood samples (EDTA) were obtained at diagnosis, before any treatment from 60 TNBC patients participating in the fore mentioned clinical study. DNA was extracted and sent to BGI (www.bgi.com) for genome sequencing. Whole exome sequencing (WES) was performed using the SureSelect Human All Exon V6 kit from Agilent for target enrichment. Paired-end sequencing was performed on an Illumina instrument. The lists of genomic variants (compared to the reference genome hg19) obtained for each patient were provided as Variant Call Format (VCF) files. Further filtering was performed to retain only variants strongly affecting protein structure (nonsense, frameshift and splice-site variants) and variants with a minor allele frequency (MAF) <0.01. To exclude false positives, variants occurring in 10% (or more) of the samples were also discarded. To categorize genes as participating in the DDR or HR pathway, we refer to a recent publication by Knijnenburg et al [16].The publication qualifies 276 genes as belonging to the DDR pathway, of which 88 belongs to the HR pathway and 21 to the HR core pathway. Data available in Table 6 All reported variants were manually reviewed and validated making use of the Integrative Genomic Viewer (IGV) from the Broad Institute [17]. All patients signed an informed consent allowing germline exome sequencing and the study was approved by the institutional ethics committee.

Statistical methods

The correlation between pCR rate and germline defects in genes involved in DDR or specifically in HR, was examined using the Fisher's exact test. All reported P values are from one sided tests for pCR correlation and two sided tests for correlation with hematologic toxicity. All analyses were performed using SPSS Statistics version 27.

Results

Patient characteristics

The demographics and clinicopathologic data of the sixty evaluable patients are shown in Table 1. Most of the patients were between 40 and 60 years old, with a median age of 55 (33-76yrs; SD: 11.7). Ninety percent of the patients had stage IIA or IIB disease, with a majority of T2 tumours and clinically node negative disease. Ninety seven percent of the patients were diagnosed with an invasive ductal carcinoma and in a large majority grade 3. One patient had a lobular carcinoma and one a mixed ductal and lobular carcinoma. Mastectomy was performed in 17 patients, breast conserving surgery in 43 and axillary dissection in 36 patients.

Variable

.

Statistics N (%)

ClinicalCharacteristics

   

Age yrs

Median

55 yrs

 

Range

(33-76 yrs)

Histology

Invasiveductal carcinoma

58 (97%)

 

Invasiveductal/lobular carcinoma

1 (1.5%)

 

Lobular carcinoma

1 (1.5%)

Clinical stage

IIA

31 (51.7%)

 

IIB

23(38.4%)

 

IIIA

5 (8.4%)

 

IIIC

1 (1.5%)

Tumourgrade

2

9 (15%)

 

3

48 (80%)

 

unknown

3 (5%)

ER and PR expression

0% and 0%

48 (80%)

 

<10% and/or < 10%

12 (20%)

Breast surgery

Mastectomy

17 (28%)

 

Breast conservingsurgery

43 (72%)

Axillarysurgery

Axillarydissection

36 (60%)

 

Sentinel node sampling

23 (38.5%)

 

Unknown

1 (1.5%)

Primaryendpoints

   

ypT0/isypN0

Yes

32 (53%)

 

No

28(47%)

ypT0/isypN0 in BRCAm patients

Yes

8 (89%)

 

No

1 (11%)

Secondaryendpoints

   

gBRCA1/2 mutation

Positive

9 (15%)

 

Negative

51 (85%)

DDR gene mutation

Yes

35 (58%)

 

No

25 (42%)

HR gene mutation

yes

19 (31.5%)

 

No

41 (68.5%)

HRcore mutation

Yes

15 (25%)

 

No

45 (75%)

ypT0/isypN0 in BRCAm patients

 

8 (89%)

ypT0/isypN0 in BRCAwt patients

 

26 (51%)

ypT0/isypN0 in DDRm patients

 

24 (68.5%)

ypT0/isypN0 in DDRwt patients

 

10 (40%)

ypT0/isypN0 in HRm patients

 

16 (84%)

ypT0/isypN0 in HRwt patients

 

18 (44%)

ypT0/isypN0 in HRcorem patients

 

14 (93%)

ypT0/isypN0 in HRcorewt patients

 

20 (44%)

Table 1: Patient Characteristics (n=60)

Germline gene testing

Routine diagnostic germline gene panel testing was performed in an initial step and revealed a deleterious BRCA1/2 mutation in nine patients (15%). Subsequent whole exome sequencing (see Table 2 for an overview of the relevant data) could detect a germline DDR gene mutation in 35 (58%) of the 60 TNBC patients. In 19 of these 35 patients (31.5%) the mutated DDR gene was a HR gene. More specifically, fifteen of these 19 patients had a mutation in a HR core gene, including the nine patients with a BRCA1 or BRCA2 mutation and six patients with a deleterious mutation in the RAD50, RAD52, BARD1 or EME1 genes. One patient had a mutation in two different HR core genes (RAD50 and RAD52). Four patients had a mutation in non-core HR genes: RECQL5, RECQL4 and EME2. Sixteen patients had germline DDR mutations not involving the HR machinery (eg in CHEK2). All pathogenic BRCA1 and BRCA2 mutations found during routine testing were also detected in the subsequent WES. No additional BRCA1/2 mutations were identified. Each of the nine BRCA1 or BRCA2 mutations was found only once, whereas two different RAD52 mutations were found each in two patients.

Patient ID

Gene 1

Variant 1, Variant 2 and variant3

Gene Family*

Gene2

Gene 3

101

none

none

none

102

RAD50

NM_005732.3:p.Ser451fs/c.1353_1356delTAAG

HRcore

RAD52

NM_001297419.1:p.Ser346*/c.1037C>A

HRcore

103

BRCA2

NM_000059.3:p.Thr772fs/c.2313_2314dupAA

HRcore

NEIL1

NM_001256552.1:c.692+2T>C

DDR

104

none

none

none

105

BRCA2

NM_000059.3:p.Ala938fs/c.2808_2811delACAA

HRcore

106

none

none

none

107

RECQL5

NM_004259.6:c.1812+2T>C

HR

201

none

none

none

204

BRCA1

NM_007300.3:p.Gln563*/c.1687C>T

HRcore

205

BRCA1

NM_007300.3:p.Gln94*/c.280C>T

HRcore

206

none

none

none

301

RAD52

NM_001297419.1:p.Tyr415*/c.1245T>G

HRcore

302

ENDOV

NM_173627.4:c.364-2A>G

DDR

701

BRCA1

NM_007300.3:p.Val1734fs/c.5200delG

HRcore

801

none

none

none

802

RECQL4

NM_004260.3:p.Gln864*/c.2590C>T

HR

803

POLN

NM_181808.3:p.Lys132fs/c.395delA

DDR

804

ERCC2

NM_000400.3:p.Arg450fs/c.1347_1377+7del

DDR

805

none

none

none

901

RAD52

NM_001297419.1:p.Tyr415*/c.1245T>G

HRcore

902

none

none

none

903

none

none

none

904

EXO5

NM_022774.1:p.Arg344fs/c.1029_1030insG

DDR

FANCL

NM_001114636.1:p.Thr372fs/c.1111_1114dupATTA

DDR

905

none

none

none

906

none

none

none

907

CHEK2

NM_001005735.1:p.Thr410fs/c.1229delC

DDR

910

none

none

none

911

RAD1

NM_002853.3:p.Arg109*/c.325C>T

DDR

913

RAD52

NM_001297419.1:p.Ser346*/c.1037C>A

HRcore

1201

MSH6

NM_000179.2:p.Lys1101fs/c.3285_3300dup

DDR

1302

APLF

NM_173545.2:p.Arg510fs/c.1528delA

DDR

1303

none

none

none

1307

none

none

none

1402

none

none

none

1501

FAAP100

NM_025161.5:p.Ala816fs/c.2446_2462del

DDR

1901

none

none

none

1902

none

none

none

1903

BARD1

NM_000465.3:p.Arg406*/c.1216C>T

HRcore

PNKP

NM_007254.3:c.1029+2T>C

DDR

1905

none

none

none

1906

EME2

NM_001257370.1:p.Gln322*/c.964C>T

HR

ENDOV

NM_173627.4:c.364-2A>G

DDR

2101

APEX1

NM_001244249.1:p.Leu292fs/c.872dupT

DDR

2102

none

none

none

2103

EXO5

NM_022774.1:p.Arg344fs/c.1029_1030insG

DDR

2105

none

none

none

2401

BRCA1

NM_007300.3:p.Glu787fs/c.2359dupG

HRcore

2402

EME1

NM_001166131.1:p.Arg504*/c.1510C>T

HRcore

2601

ENDOV

NM_173627.4:c.364-2A>G

DDR

2603

none

none

none

2604

none

none

none

2605

BRCA2

NM_000059.3:p.Val464fs/c.1389_1390delAG

HRcore

EME2

NM_001257370.1:p.Gly55fs/c.164delG

HR

ALKBH3

NM_139178.3:p.Arg70*/c.208C>T

DDR

2606

none

none

none

2607

NEIL1

NM_001256552.1:c.692+2T>C

DDR

ENDOV

NM_173627.4:c.364-2A>G

DDR

2610

APLF

NM_173545.2:p.Arg510fs/c.1528delA

DDR

2701

none

none

none

2702

none

none

none

2703

BRCA2

NM_000059.3:p.Asn1784fs/c.5351dupA

HRcore

2901

none

none

none

2902

EXO5

NM_022774.1:p.Arg344fs/c.1029_1030insG

DDR

3001

none

none

none

3002

BRCA1

NM_007300.3:p.Arg1203*/c.3607C>T

HRcore

3003

none

none

none

3004

EXO5

NM_022774.1:p.Arg344fs/c.1029_1030insG

DDR

• (*) In this colomn, a gene assigned to the family “DDR” is a DDR gene not belonging to the subgroup of HR genes. Also, a gene assigned to the family “HR” is a HR gene not belonging to the subgroup of HR core genes.

Table 2: List of the pathogenic variants identified in DDR genes of 60 TNBC patients

Correlation between germline defects and pathologic complete response:

Association of DDR versus HR gene mutation and response to platinum-based chemotherapy

A pathologic complete remission was obtained in 68.5% of the DDR mutated patients compared to 40% in the non-DDR mutated population (p=0.026). When we restricted our analyses to the patients with a mutation in the HR genes, the pCR rates increased to 84% in comparison to 44% to the patients lacking a HR gene mutation (p = 0.003). When further considering only the HR core genes, a pCR was observed in 93% (14/15) of the patients and in 44% (20/45) of the patients without a HR core gene mutation (p = 0.0007).The only patient not presenting a pCR in this subgroup carried a BRCA1 mutation. For the patients with a DDR gene mutation not included in the HR core gene panel, the pCR dropped to 50% (10/20), which was much closer to what we found in patients without a DDR mutation (40%) as shown in Table 3 and Table 4.

Patients with a DDR mutation

pCR

Febrile NP G3/G4

NP G3/G4

Anemia G3

Trombopenia G3/G4

Yes 35

Yes 24

Yes 10

Yes 27

Yes 10

Yes 5

No 11

No 25

No 8

No 25

No 30

No 25

Yes 10

Yes 8

Yes 13

Yes 7

Yes 5

No 15

No 17

No 12

No 18

No 20

P (one sided)

0.026

0.717

0.04

0.598

0.826

P (two sided)

0.036

0.783

0.055

1

0.728

Patients with a DDR mutation but not a HR core mutation 20

Yes 10

Yes 5

Yes 17

Yes 4

Yes 1

No 10

No 15

No 3

No 16

No 19

Patients without a DDR mutation

Yes 10

Yes 8

Yes 13

Yes 7

Yes 5

25

No 15

No 17

No 12

No 18

No 20

P (one sided)

0.356

0.8

0.02

0.833

0.978

P (two sided)

0.557

0.745

0.027

0.729

0.204

Patients with a HR mutation

pCR

Febrile NP G3/G4

NP G3/G4

Anemia G3

Trombopenia

G3/G4

Yes 19

Yes 16

Yes 6

Yes 13

Yes 6

Yes 5

No 3

No 13

No 6

No 13

No 14

No 41

Yes 18

Yes 12

Yes 27

Yes 11

Yes 5

No 23

No 29

No 14

No 30

No 36

P (one sided)

0.003

0.542

0.544

0.465

0.16

P (two sided)

0.005

1

1

0.763

0.263

Patients with a HR core mutation

pCR

Febrile NP G3G4

NP G3/G4

Anemia G3

Trombopenia G3/G4

Yes 15

Yes 14

Yes 5

Yes 10

Yes 6

Yes 4

No 1

No 10

No 5

No 9

No 11

No 45

Yes 20

Yes 13

Yes 30

Yes 11

Yes 6

No 25

No 32

No 15

No 34

No 39

P (one sided)

7E-04

0.491

0.63

0.202

0.207

P (two sided)

8E-04

0.754

1

0.324

0.25

Patients with a BRCA mutation

pCR

Febrile NP G3/G4

NP G3/G4

Anemia G3

Trombopenia G3/G4

Yes 9

Yes 8

Yes 4

Yes 7

Yes 5

Yes 4

No 1

No 5

No 2

No 4

No 5

No 51

Yes 26

Yes 14

Yes 31

Yes 12

Yes 6

No 25

No 37

No 20

No 39

No 45

P (one sided)

0.035

0.257

0.281

0.063

0.034

P (two sided)

0.064

0.431

0.464

0.101

0.034

Table 3: Correlation between germline defects in DDR genes of 60 TNBC patients and 5 clinical parameters

This table provides in the first column, the number of TNBC patients for which a germline mutation was found respectively in a DDR gene, in a DDR minus HR core gene, without a DDR germline mutation, in a HR gene, a HR core gene or the BRCA 1/2 genes. In the five subsequent columns the number of patients presenting the characteristics specific for each of five different clinical parameters are indicated. Statistical correlations between mutation carriership and each of the five clinical parameters were investigated using Fisher’s Exact tests.

Patient ID

Variant 1

Gene family*

Variant 2

Gene family*

Variant 3

Gene family*

Pathologic response

 

101

none

 

none

 

none

 

PR

 

102

RAD50 frameshift

HRcore

RAD52

HRcore

none

 

CR

 

Stop gain

 

103

BRCA2 frameshift

HRcore

NEIL1

DDR

none

 

CR

 

splice

 

104

none

 

none

 

none

 

CR

 
   

105

BRCA2 frameshift

HRcore

none

 

none

 

CR

   
   

106

none

none

none

 

none

 

No response

   
   

107

RECQL5 splice

HR

none

 

none

 

CR

   
   

201

none

none

none

 

none

 

No response

   
   

204

BRCA1 stop gain

HRcore

none

 

none

 

CR

   
   

205

BRCA1 stop gain

HRcore

none

 

none

 

CR

   
   

206

none

none

none

 

none

 

CR

   
   

301

none

none

none

 

none

 

CR

   
   

302

none

none

none

 

none

 

CR

   
   

701

BRCA1 frameshift

HRcore

none

 

none

 

CR

   
   

801

none

none

none

 

none

 

PR

   
   

802

RECQL4 stop gain

HR

none

 

none

 

CR

   
   

803

POLN frameshift

DDR

none

 

none

 

No response

   
   

804

ERCC2 frameshift

DDR

none

 

none

 

CR

   
   

805

none

none

none

 

none

 

CR

   
   

901

RAD52

HRcore

none

 

none

 

CR

   

stop gain

   

902

none

none

none

 

none

 

CR

   
   

903

none

none

none

 

none

 

No response

   
   

904

EXO5 frameshift

DDR

FANCL

DDR

none

 

CR

   
   

905

none

none

none

 

none

 

PR

   
   

906

none

none

none

 

none

 

PR

   
   

907

CHECK2 frameshift

DDR

none

 

none

 

PR

   
   

910

none

none

none

 

none

 

CR

   
   

911

RAD1 stop gain

DDR

none

 

none

 

PR

   
   

913

RAD52

HRcore

none

 

none

 

CR

   

stop gain

   

1201

MSH6 frameshift

DDR

none

 

none

 

CR

   
   

1302

APLF frameshift

DDR

none

 

none

 

CR

   
   

1303

none

none

none

 

none

 

PR

   
   

1307

none

none

none

 

none

 

PR

   
   

1402

none

none

none

 

none

 

PR

   
   

1501

FAAP100 frameshift

DDR

none

 

none

 

No response

   
   

1903

BARD1

HRcore

PNKP splice

DDR

   

CR

   

stop gain

   

1905

none

none

none

 

none

 

PR

   
   

1906

EME2

HR

ENDOV

DDR

none

 

PR

   

stop gain

splice

   

2101

APEX1 frameshift

DDR

none

 

none

 

PR

   
   

2102

none

none

none

 

none

 

CR

   
   

2103

EXO5 frameshift

DDR

none

 

none

 

No response

   
   

2104

RECQL5

HR

none

 

none

 

PR

   

splice

   

2105

none

none

none

 

none

 

CR

   
   

2401

BRCA1 frameshift

HRcore

none

 

none

 

CR

   
   

2402

EME1

HRcore

none

 

none

 

CR

   

stop gain

   

2601

ENDOV

DDR

none

 

none

 

CR

   

splice

   

2603

none

none

none

 

none

 

No response

   
   

2604

none

none

none

 

none

 

PR

   
   

2605

BRCA2 frameshift

HRcore

EME2 frameshift

HR

ALKBH3 stop gain

DDR

CR

   
   

2606

none

none

none

 

none

 

PR

   
   

2607

NIEL1

none

ENDOV

DDR

   

No response

   

DDR

splice

   

2610

APFL frameshift

DDR

       

PR

   
   

2701

none

none

       

CR

   
   

2702

none

none

       

PR

   
   

2703

BRCA2 frameshift

HRcore

       

CR

   
   

2901

none

none

       

CR

   
   

2902

EXO5 frameshift

DDR

       

CR

   
   

3002

BRCA1 stop gain

HRcore

       

PR

   
   

3003

none

none

       

CR

   
   

3004

EXO5 frameshift

DDR

       

CR

   
   

• (*) In these columns, a gene assigned to the family “DDR” is a DDR gene not belonging to the subgroup of HR genes. Also, a gene assigned to the family “HR” is a HR gene not belonging to the subgroup of HR core genes.

   

Table 4: List of pathogenic variants in DDR genes of 60 TNBC patients and pathologic response.

Association of DDR versus HR gene mutation and hematologic toxicities.

DDR neither HR germline gene mutations did clearly predict for hematologic toxicities, such as febrile neutropenia G3 and G4 (p=0.78; p=1), neutropenia G3 and G4 (p=0.05; p=1), anemia G3 (p=1; p=0.76), trombopenia G3 and G4 (p = 0.73; p=0.26) as shown in Table 3 and Table 5. Since neutropenia G3 and G4 appeared to occur somewhat less frequently in patients without a DDR mutation (13/25) than in patients with such mutation (27/35; p=0.055, which is at limit of significance), we further compared patients without a DDR mutation to patients with a DDR mutation that did not benefit well from the therapy (excluding the patients with a HR core gene mutation). Patients with such a mutation suffered clearly more from neutropenia G3 and G4 (13/25) than patients without a DDR mutation (13/25; P=0.027, see Table 3).

Patient ID

Variant 1 Variant2 Variant 3

Gene family*

Febrile neutropenia G3/G4

Neutro
penia G3/G4

Anemia G3

Trombopenia
G3/G4

101

none

none

1

1

0

1

102

RAD50

HRcore

0

1

0

0

103

BRCA2

HRcore

1

1

0

0

104

none

none

0

0

0

0

105

BRCA2

HRcore

0

1

1

0

106

none

none

1

1

0

1

107

RECQL5

HR

0

1

0

1

201

none

none

1

0

1

1

204

BRCA1

HRcore

1

0

0

1

205

BRCA1

HRcore

0

1

0

0

206

none

none

1

1

1

1

301

RAD52

HRcore

0

0

0

0

302

ENDOV

DDR

0

1

1

0

701

BRCA1

HRcore

1

0

1

1

801

none

none

0

1

0

0

802

RECQL4

HR

0

1

0

0

803

POLN

DDR

0

1

0

0

804

ERCC2

DDR

0

1

0

0

805

none

none

1

0

0

0

901

RAD52

HRcore

0

1

0

0

902

none

none

0

1

0

0

903

none

none

0

1

0

0

904

EXO5

DDRDDR

1

1

0

0

905

none

none

0

0

1

0

906

none

none

0

0

0

0

907

CHEK2

DDR

0

0

0

0

910

none

none

0

1

1

0

911

RAD1

DDR

0

1

0

0

913

RAD52

HRcore

1

0

1

0

1201

MSH6

DDR

1

0

1

0

1302

APLF

DDR

0

1

0

0

1303

none

none

0

1

0

0

1307

none

none

1

1

0

0

1402

none

none

0

1

0

0

1501

FAAP100

DDR

0

1

1

0

1903

BARD1

HRcore

0

1

0

0

1905

none

none

1

0

1

0

1906

EME2

HR

1

1

0

0

2101

APEX1

DDR

1

1

0

0

2102

none

none

1

0

1

1

2103

EXO5

DDR

0

1

1

0

2104

RECQL5

HR

0

0

0

0

2105

none

none

0

0

0

0

2401

BRCA1 frameshift

HRcore

0

1

1

0

2402

EME1

HRcore

0

0

0

0

2601

ENDOV

DDR

0

1

0

0

2603

none

none

0

1

0

0

2604

none

none

0

0

0

0

2605

BRCA2

HRcore

1

1

1

1

2606

none

none

0

0

0

0

2607

NIEL1

DDR

0

1

0

0

2610

APFL

DDR

0

1

0

0

2701

none

none

0

0

0

0

2702

none

none

0

0

0

0

2703

BRCA2

HRcore

0

1

1

0

2901

none

none

0

1

0

0

2902

EXO5

DDR

0

1

0

0

3002

BRCA1

HRcore

0

1

0

1

3003

none

none

0

1

1

0

3004

EXO5

DDR

1

1

0

0

(*)In this colomn, a gene assigned to the family “DDR” is a DDR gene not belonging to the subgroup of HR genes. Also, a gene assigned to the family “HR” is a HR gene not belonging to the subgroup of HR core genes.

Table 5: List of pathogenic variants and hematologic toxicities.

DDR (DNA damage repair)

HR (Homologous Recombination, pathway membership

HR (Homologous Recombination, core pathway membership

APLF

LIG1

MRE11A

APTX

MRE11A

NBN

ASCC3

NBN

RAD50

DNTT

PARG

TP53BP1

LIG1

PARP1

XRCC2

LIG3

PARPBP

XRCC3

LIG4

RAD50

BARD1

MRE11A

TP53BP1

BLM

NBN

XRCC2

BRCA1

NHEJ1

XRCC3

BRCA2

PARG

EXO1

BRIP1

PARP1

PCNA

EME1

PARP3

POLD1

GEN1

PARPBP

POLD2

MUS81

PNKP

POLD3

PALB2

POLB

POLD4

RAD51

POLL

RFC1

RAD52

POLM

RFC2

RBBP8

PRKDC

RFC3

SHFM1

RAD50

RFC4

SLX1A

RNF168

RFC5

TOP3A

RNF8

RPA1

 

TP53BP1

RPA2

 

XRCC1

RPA3

 

XRCC2

RPA4

 

XRCC3

BARD1

 

XRCC4

BLM

 

XRCC5

BRCA1

 

XRCC6

BRCA2

 

UBE2A

BRIP1

 

EXO1

DMC1

 

HMGB1

DNA2

 

MLH1

EID3

 

MLH3

EME1

 

MSH2

EME2

 

MSH3

ERCC1

 

MSH6

FANCM

 

PCNA

FEN1

 

PMS1

GEN1

 

PMS2

H2AFX

 

POLD1

HELQ

 

POLD2

HFM1

 

POLD3

INO80

 

POLD4

KAT5

 

RFC1

MUS81

 

RFC2

NFATC2IP

 

RFC3

NSMCE1

 

RFC4

NSMCE2

 

RFC5

NSMCE3

 

RPA1

NSMCE4A

 

RPA2

PALB2

 

RPA3

PARP2

 

RPA4

PAXIP1

 

ALKBH1

POLH

 

ALKBH2

POLQ

 

ALKBH3

PPP4C

 

APEX1

PPP4R1

 

APEX2

PPP4R2

 

APITD1

PPP4R4

 

ATM

RAD51

 

ATR

RAD51B

 

ATRIP

RAD51C

 

ATRX

RAD51D

 

BARD1

RAD52

 

BLM

RAD54B

 

BRCA1

RAD54L

 

BRCA2

RBBP8

 

BRE

RDM1

 

BRIP1

RECQL

 

CCNH

RECQL4

 

CDK7

RECQL5

 

CETN2

RMI1

 

CHAF1A

RMI2

 

CHEK1

RTEL1

 

CHEK2

SHFM1

 

CLK2

SLX1A

 

CUL3

SLX1B

 

CUL4A

SLX4

 

CUL5

SMARCAD1

 

DCLRE1A

SMC5

 

DCLRE1B

SMC6

 

DCLRE1C

SPO11

 

DDB1

SWSAP1

 

DDB2

TOP3A

 

DMC1

TOP3B

 

DNA2

UIMC1

 

DUT

WRN

 

EID3

ZSWIM7

 

EME1

   

EME2

   

ERCC1

   

ERCC2

   

ERCC3

   

ERCC4

   

ERCC5

   

ERCC6

   

ERCC8

   

FAAP100

   

FAAP24

   

FAAP20

   

FAM175A

   

FAN1

   

FANCA

   

FANCB

   

FANCC

   

FANCD2

   

FANCE

   

FANCF

   

FANCG

   

FANCI

   

FANCL

   

FANCM

   

FEN1

   

GADD45A

   

GADD45G

   

GEN1

   

GTF2H1

   

GTF2H2

   

GTF2H3

   

GTF2H4

   

GTF2H5

   

H2AFX

   

HELQ

   

HES1

   

HFM1

   

HLTF

   

HMGB2

   

HUS1

   

INO80

   

KAT5

   

MAD2L2

   

MBD4

   

MDC1

   

MGMT

   

MMS19

   

MNAT1

   

MPG

   

MPLKIP

   

MRPL40

   

MUS81

   

MUTYH

   

NABP2

   

NEIL1

   

NEIL2

   

NEIL3

   

NFATC2IP

   

NSMCE1

   

NSMCE2

   

NSMCE3

   

NSMCE4A

   

NTHL1

   

NUDT1

   

NUDT15

   

NUDT18

   

RRM1

   

RRM2

   

OGG1

   

PALB2

   

PARP2

   

PARP4

   

PAXIP1

   

PER1

   

POLA1

   

POLE

   

POLE2

   

POLE3

   

POLE4

   

POLG

   

POLH

   

POLI

   

POLK

   

POLN

   

POLQ

   

PPP4C

   

PPP4R1

   

PPP4R2

   

PPPR4

   

PRPF19

   

RAD1

   

RAD17

   

RAD18

   

RAD23A

   

RAD23B

   

RAD51

   

RAD51B

   

RAD51C

   

RAD51D

   

RAD52

   

RAD54B

   

RAD54L

   

RAD9A

   

RBBP8

   

RBX1

   

RDM1

   

RECQL

   

RECQL4

   

RECQL5

   

REV1

   

REV3L

   

RIF1

   

RMI1

   

RMI2

   

RNMT

   

RRM2B

   

RTEL1

   

SETMAR

   

SHFM1

   

SHPRH

   

SLX1A

   

SLX1B

   

SLX4

   

SMARCAD1

   

SMC5

   

SMC6

   

SMUG1

   

SPO11

   

STRA13

   

SWSAP1

   

TCEA1

   

TCEB1

   

TCEB2

   

TCEB3

   

TDG

   

TDP1

   

TELO2

   

TOP3A

   

TOP3B

   

TOPBP1

   

TP53

   

TREX1

   

TREX2

   

TYMS

   

UBE2B

   

UBE2N

   

UBE2T

   

UBE2V2

   

UIMC1

   

UNG

   

USP1

   

UVSSA

   

WDR48

   

WRN

   

XAB2

   

XPA

   

XPC

   

ZSWIM7

   

PTEN

   

TDP2

   

ENDOV

   

SPRTN

   

RNF4

   

SMARCA4

   

IDH1

   

SOX4

   

WEE1

   

RAD9B

   

AEN

   

PLK3

   

EXO5

   

CDC5L

   

BCAS2

   

PLRG1

   

YWHAB

   

YWHAG

   

YWHAE

   

CDC25A

   

CDC25B

   

CDC25C

   

BABAM1

   

BRCC3

   

TTK

   

SMARCC1

   

SWI5

   

MORF4L1

   

RNF169

   

HERC2

   

Table 6: List of 276 DDR genes, 88 HR genes and 21 HR core genes to be sequenced.

Discussion

Triple-negative breast cancer is generally more sensitive to neoadjuvant platinum-based chemotherapy than other subtypes of breast cancer [18]. Several reports indicated an increased effectiveness of preoperative platinum based systemic treatment in BRCA1/2 mutant and non-BRCA mutant HRD-positive breast cancer [11, 12, 18, 19]. In these studies, BRCA1/2 sequencing with or without an HRD-scoring was used [where the HRD score is the sum of three metrics of chromosomal level aberration: LOH (loss of heterozygosity), TAI (telomeric allelic imbalance) and LST (large-scale state transitions)]. It is so far unclear whether BRCA1/2 mutations or HRD as defined by an HRD score select for patients that benefit more from the addition of platinum. There are also no publications that examined the correlation of broad germline analysis of DDR or HR genes with response to neoadjuvant chemotherapy. In the current study we investigated to what extent a dose-dense platinum containing regimen was more efficacious in triple-negative breast cancer patients with or without a germline defect in the DNA repair machinery as defined from the sequencing of a panel of 276 DDR genes. Finding a predictive biomarker is essential as the inclusion of platinum significantly adds to the toxicity of the chemotherapy. On the other hand, striving for the highest efficacy is important as obtaining a pCR has crucial prognostic significance in terms of the risk of relapse and survival [4, 5]. We used whole-exome sequencing to maximize the discriminative power between cancer patients that have no DNA repair defect and those that do. Therefore, in this study the cohort without a germline DNA damage repair defect is less likely to be diluted by non-identified repair defects. For the design of the virtual DDR gene panel, we relied on a recent publication by Knijnenburg et al [16].The proportion of TNBC patients with a germline HR defect as defined in our study is 31.5 %, (25% if considering only HR core genes). The proportion of patients with any DDR germline defect was 58%. This means that a large fraction of TNBC patients have a proven or probable genetic etiologic factor. We did find a high pCR rate in the overall population (53%) consistent with other studies. A higher pCR rate was observed in patients with a DDR gene germline defect (68.5%). This increased pCR rate was driven by the patients with HR gene mutations (pCR rate of 84%), and more specifically by the patients with HR core gene defects (pCR rate of 93%). The pCR rate observed in the patients without a HR core gene defect was 44,4% and within the range of pCR rates found when platinum is not included in the neoadjuvant chemotherapy [20]. DDR defects other than HRD have also been proposed to sensitize for DNA damaging chemotherapy including cisplatinum. Our study does not support this as the pCR rates observed in patients without a germline DDR mutation and patients with a DDR gene mutation not including a HR core gene mutation are in the same range: 10/25 (40%) versus 20/45 (44.4%) respectively.Therefore, a logical proposal would be to restrict the addition of platinum to TNBC patients having a germline HR core gene mutation. It is clear that the current prospective phase 2 study does not prove that platinum is needed to achieve this result, and it could be that these tumours are simply more chemo-responsive cancers. However, our results are in line with other studies that show a high pCR rate in patients with BRCAness, which was defined in different manners [11, 12]. The GEPARsixto trial showed a significant benefit only in HRD triple negative breast cancers, although the authors did not consider these data as definitive because of the cohort size and there was no cyclophophamide included [12]. Comprehensive gene sequencing of the germline as in this study might enrich the specific HRD population and the discriminative power of the studies. A recent meta-analysis of Chai Y et al found a significant higher efficacy of platinum-based regimens in BRCA-mutated TNBC compared to BRCA wild type patients (p =0.002) and the same was true for the HRD-positive versus HRD-negative tumors with a p < 0.001 [21]. Another meta-analysis comparing platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients showed no significant increase in pCR rate with the addition of platinum in the BRCA-mutated patients. In this last study, the authors underlined that the number of included BRCA patients was too small to correctly evaluate the effect of platinum compounds in mutated versus non-mutated patients [22].These studies have less than optimal discriminative power as the non-BRCA1/2 mutant cohorts also include patients with other HRD defects. Also the predictive value of HRD remains controversial as in the TNT phase 3 clinical trial there was no correlation between carboplatin response and a high score in a Myriad HRD assay [23]. Moreover only a HRD score threshold of 42 had the potential to identify patients who might benefit from platinum based preoperative systemic therapy and the HRD status is more suitable for variation between the groups.

The ongoing PEARL phase 3 trial comparing anthracyclines followed by a taxane with anthracyclines followed by taxane plus carboplatin as neoadjuvant treatment in TNBC patients, stratified by BRCA 1/2 mutation status will be published in 2023, but this study will have the same limitation of incomplete HRD specification.

Conclusion

The present study using a comprehensive germline DDR gene mutation analysis is hypothesis generating, and suggest that platinum addition in the neoadjuvant treatment of TNBC could be restricted to patients with a germline HR core gene mutation. However prospective phase 3 trials should include broad HR gene characterization beyond BRCA1/2 to confirm our finding. This study also indicated that a high proportion of TNBC has a possible genetic etiology. Finally, in accordance with these data, additional studies should be performed to investigate whether a clear correlation between germline mutation carriership in a HR core gene and a response to therapies targeting cells with double strand DNA break repair deficiency can also be found in other cancer types, such as prostate cancer.

Acknowledgements

We want to acknowledge all the co-investigators of the BSMO, the pathology department of UZ Brussel, the Laboratory of Medical and Molecular Oncology and the patients.

Funding

The study was financially supported by Amgen and Teva

Compliance with ethical standards

Conflict of interest

All authors declare to have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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