Skip to main content
Top

23-04-2024 | Ovarian Cancer | Original Article

Exploring the effect of BRCA1/2 status on chemotherapy-induced hematologic toxicity in patients with ovarian cancer

Authors: In Hee Lee, Soo Jung Lee, Juhyung Kim, Yoon Hee Lee, Gun Oh Chong, Jong Mi Kim, Juhun Lee, Nan Young Lee, Seo Young Park, Dea Gy Hong, Yee Soo Chae

Published in: Cancer Chemotherapy and Pharmacology

Login to get access

Abstract

Objective

BRCA1/2 are integral to the DNA repair mechanism and their germline pathogenic variants (gBRCA) result in a high risk for developing breast and ovarian cancer. Patients with gBRCA mutations showed increased sensitivity to DNA cross-linking agent but might have increased treatment-related toxicities. Thus, we hypothesized that gBRCA mutation ovarian cancer patients who underwent platinum-based chemotherapy might be at higher risk of developing chemotherapy-induced hematologic toxicity.

Methods

This study enrolled 160 patients with ovarian cancer who received frontline platinum-based chemotherapy between 2011 and 2019 in Kyungpook National University Chilgok Hospital. Incidence rate and severity of chemotherapy-induced hematologic toxicity (neutropenia, anemia, thrombocytopenia) was compared for BRCA mutation and wild patients.

Results

160 women, including 62 BRCA1/2 (38 BRCA1, and 25 BRCA2) mutation group, and 98 noncarriers, were analyzed. A higher frequency of G2 anemia was noted in the BRCA -mutant group (22% vs. 1%, p = 0.07). Furthermore, G3 anemia was significantly common among BRCA group (12.9% vs. 3%, p = 0.02). In the subgroup analysis according to BRCA1/2 status, BRCA1 mutated patients showed a significantly higher frequency of G1 anemia than BRCA2 (89% vs. 60%, p = 0.01). In terms of neutropenia and thrombocytopenia, BRCA mutated patients and noncarriers had similar hematologic toxicity.

Conclusion

Germline BRCA mutations were associated with a higher frequency of G2/3 anemia in ovarian cancer patients who underwent first-line platinum-based chemotherapy. Moreover, the BRCA1 mutation appeared to be more strongly associated with the incidence of chemotherapy-induced anemia. Our findings warrant further investigation in larger, prospective studies to confirm these current findings and determine whether preventive interventions may be necessary.
Literature
2.
go back to reference Daly MB, Axilbund JE, Buys S, Crawford B, Farrell CD, Friedman S, Garber JE, Goorha S, Gruber SB, Hampel H, Kaklamani V, Kohlmann W, Kurian A, Litton J, Marcom PK, Nussbaum R, Offit K, Pal T, Pasche B, Pilarski R, Reiser G, Shannon KM, Smith JR, Swisher E, Weitzel JN (2010) Genetic/familial high-risk assessment: breast and ovarian. J Natl Compr Canc Netw 8(5):562–594. https://doi.org/10.6004/jnccn.2010.0043CrossRefPubMed Daly MB, Axilbund JE, Buys S, Crawford B, Farrell CD, Friedman S, Garber JE, Goorha S, Gruber SB, Hampel H, Kaklamani V, Kohlmann W, Kurian A, Litton J, Marcom PK, Nussbaum R, Offit K, Pal T, Pasche B, Pilarski R, Reiser G, Shannon KM, Smith JR, Swisher E, Weitzel JN (2010) Genetic/familial high-risk assessment: breast and ovarian. J Natl Compr Canc Netw 8(5):562–594. https://​doi.​org/​10.​6004/​jnccn.​2010.​0043CrossRefPubMed
7.
go back to reference Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, McCormick C, Lorusso D, Hoskins P, Freyer G, Baumann K, Jardon K, Redondo A, Moore RG, Vulsteke C, O’Cearbhaill RE, Lund B, Backes F, Barretina-Ginesta P, Haggerty AF, Rubio-Perez MJ, Shahin MS, Mangili G, Bradley WH, Bruchim I, Sun K, Malinowska IA, Li Y, Gupta D, Monk BJ, Investigators PE-OG- (2019) Niraparib in patients with newly diagnosed Advanced Ovarian Cancer. N Engl J Med 381(25):2391–2402. https://doi.org/10.1056/NEJMoa1910962CrossRefPubMed Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, McCormick C, Lorusso D, Hoskins P, Freyer G, Baumann K, Jardon K, Redondo A, Moore RG, Vulsteke C, O’Cearbhaill RE, Lund B, Backes F, Barretina-Ginesta P, Haggerty AF, Rubio-Perez MJ, Shahin MS, Mangili G, Bradley WH, Bruchim I, Sun K, Malinowska IA, Li Y, Gupta D, Monk BJ, Investigators PE-OG- (2019) Niraparib in patients with newly diagnosed Advanced Ovarian Cancer. N Engl J Med 381(25):2391–2402. https://​doi.​org/​10.​1056/​NEJMoa1910962CrossRefPubMed
8.
go back to reference Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, Gonzalez-Martin A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P (2018) Maintenance Olaparib in patients with newly diagnosed Advanced Ovarian Cancer. N Engl J Med 379(26):2495–2505. https://doi.org/10.1056/NEJMoa1810858CrossRefPubMed Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, Gonzalez-Martin A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P (2018) Maintenance Olaparib in patients with newly diagnosed Advanced Ovarian Cancer. N Engl J Med 379(26):2495–2505. https://​doi.​org/​10.​1056/​NEJMoa1810858CrossRefPubMed
9.
go back to reference Ray-Coquard I, Pautier P, Pignata S, Perol D, Gonzalez-Martin A, Berger R, Fujiwara K, Vergote I, Colombo N, Maenpaa J, Selle F, Sehouli J, Lorusso D, Guerra Alia EM, Reinthaller A, Nagao S, Lefeuvre-Plesse C, Canzler U, Scambia G, Lortholary A, Marme F, Combe P, de Gregorio N, Rodrigues M, Buderath P, Dubot C, Burges A, You B, Pujade-Lauraine E, Harter P, Investigators P- (2019) Olaparib plus Bevacizumab as First-Line maintenance in Ovarian Cancer. N Engl J Med 381(25):2416–2428. https://doi.org/10.1056/NEJMoa1911361CrossRefPubMed Ray-Coquard I, Pautier P, Pignata S, Perol D, Gonzalez-Martin A, Berger R, Fujiwara K, Vergote I, Colombo N, Maenpaa J, Selle F, Sehouli J, Lorusso D, Guerra Alia EM, Reinthaller A, Nagao S, Lefeuvre-Plesse C, Canzler U, Scambia G, Lortholary A, Marme F, Combe P, de Gregorio N, Rodrigues M, Buderath P, Dubot C, Burges A, You B, Pujade-Lauraine E, Harter P, Investigators P- (2019) Olaparib plus Bevacizumab as First-Line maintenance in Ovarian Cancer. N Engl J Med 381(25):2416–2428. https://​doi.​org/​10.​1056/​NEJMoa1911361CrossRefPubMed
10.
go back to reference Orsi G, Di Marco M, Cavaliere A, Niger M, Bozzarelli S, Giordano G, Noventa S, Rapposelli IG, Garajova I, Tortora G, Rodriquenz MG, Bittoni A, Penzo E, De Lorenzo S, Peretti U, Paratore C, Bernardini I, Mosconi S, Spallanzani A, Macchini M, Tamburini E, Bencardino K, Giommoni E, Scartozzi M, Forti L, Valente MM, Militello AM, Cascinu S, Milella M, Reni M (2021) Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey. ESMO Open 6(5):100238. https://doi.org/10.1016/j.esmoop.2021.100238CrossRefPubMedPubMedCentral Orsi G, Di Marco M, Cavaliere A, Niger M, Bozzarelli S, Giordano G, Noventa S, Rapposelli IG, Garajova I, Tortora G, Rodriquenz MG, Bittoni A, Penzo E, De Lorenzo S, Peretti U, Paratore C, Bernardini I, Mosconi S, Spallanzani A, Macchini M, Tamburini E, Bencardino K, Giommoni E, Scartozzi M, Forti L, Valente MM, Militello AM, Cascinu S, Milella M, Reni M (2021) Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey. ESMO Open 6(5):100238. https://​doi.​org/​10.​1016/​j.​esmoop.​2021.​100238CrossRefPubMedPubMedCentral
11.
go back to reference Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, Cybulski C, Marczyk E, Chrzan R, Eisen A, Lubinski J, Narod SA (2012) Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 14(4):R110. https://doi.org/10.1186/bcr3231CrossRefPubMedPubMedCentral Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, Cybulski C, Marczyk E, Chrzan R, Eisen A, Lubinski J, Narod SA (2012) Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 14(4):R110. https://​doi.​org/​10.​1186/​bcr3231CrossRefPubMedPubMedCentral
12.
go back to reference Deshpande M, Paniza T, Jalloul N, Nanjangud G, Twarowski J, Koren A, Zaninovic N, Zhan Q, Chadalavada K, Malkova A, Khiabanian H, Madireddy A, Rosenwaks Z, Gerhardt J (2022) Error-prone repair of stalled replication forks drives mutagenesis and loss of heterozygosity in haploinsufficient BRCA1 cells. Mol Cell 82(20):3781–3793e3787. https://doi.org/10.1016/j.molcel.2022.08.017CrossRefPubMed Deshpande M, Paniza T, Jalloul N, Nanjangud G, Twarowski J, Koren A, Zaninovic N, Zhan Q, Chadalavada K, Malkova A, Khiabanian H, Madireddy A, Rosenwaks Z, Gerhardt J (2022) Error-prone repair of stalled replication forks drives mutagenesis and loss of heterozygosity in haploinsufficient BRCA1 cells. Mol Cell 82(20):3781–3793e3787. https://​doi.​org/​10.​1016/​j.​molcel.​2022.​08.​017CrossRefPubMed
14.
go back to reference Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Keller PJ, Glover E, Richardson AL, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Näär AM, Blasco MA, Hinds PW, Kuperwasser C (2015) Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat Commun 6:7505. https://doi.org/10.1038/ncomms8505CrossRefPubMed Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Keller PJ, Glover E, Richardson AL, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Näär AM, Blasco MA, Hinds PW, Kuperwasser C (2015) Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat Commun 6:7505. https://​doi.​org/​10.​1038/​ncomms8505CrossRefPubMed
16.
go back to reference Konishi H, Mohseni M, Tamaki A, Garay JP, Croessmann S, Karnan S, Ota A, Wong HY, Konishi Y, Karakas B, Tahir K, Abukhdeir AM, Gustin JP, Cidado J, Wang GM, Cosgrove D, Cochran R, Jelovac D, Higgins MJ, Arena S, Hawkins L, Lauring J, Gross AL, Heaphy CM, Hosokawa Y, Gabrielson E, Meeker AK, Visvanathan K, Argani P, Bachman KE, Park BH (2011) Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc Natl Acad Sci USA 108(43):17773–17778. https://doi.org/10.1073/pnas.1110969108CrossRefPubMedPubMedCentral Konishi H, Mohseni M, Tamaki A, Garay JP, Croessmann S, Karnan S, Ota A, Wong HY, Konishi Y, Karakas B, Tahir K, Abukhdeir AM, Gustin JP, Cidado J, Wang GM, Cosgrove D, Cochran R, Jelovac D, Higgins MJ, Arena S, Hawkins L, Lauring J, Gross AL, Heaphy CM, Hosokawa Y, Gabrielson E, Meeker AK, Visvanathan K, Argani P, Bachman KE, Park BH (2011) Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc Natl Acad Sci USA 108(43):17773–17778. https://​doi.​org/​10.​1073/​pnas.​1110969108CrossRefPubMedPubMedCentral
18.
go back to reference Hu-Heimgartner K, Lang N, Ayme A, Ming C, Combes JD, Chappuis VN, Vazquez C, Friedlaender A, Vuilleumier A, Bodmer A, Viassolo V, Sandoval JL, Chappuis PO, Labidi-Galy SI (2023) Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature. Fam Cancer 22(3):283–289. https://doi.org/10.1007/s10689-023-00331-6CrossRefPubMedPubMedCentral Hu-Heimgartner K, Lang N, Ayme A, Ming C, Combes JD, Chappuis VN, Vazquez C, Friedlaender A, Vuilleumier A, Bodmer A, Viassolo V, Sandoval JL, Chappuis PO, Labidi-Galy SI (2023) Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature. Fam Cancer 22(3):283–289. https://​doi.​org/​10.​1007/​s10689-023-00331-6CrossRefPubMedPubMedCentral
22.
go back to reference Kotsopoulos J, Willows K, Trat S, Kim RH, Volenik A, Sun P, Narod SA, Boyd J, May T (2018) BRCA mutation status is not Associated with increased hematologic toxicity among patients undergoing platinum-based chemotherapy for ovarian Cancer. Int J Gynecol cancer: Official J Int Gynecol Cancer Soc 28(1):69–76. https://doi.org/10.1097/igc.0000000000001144CrossRef Kotsopoulos J, Willows K, Trat S, Kim RH, Volenik A, Sun P, Narod SA, Boyd J, May T (2018) BRCA mutation status is not Associated with increased hematologic toxicity among patients undergoing platinum-based chemotherapy for ovarian Cancer. Int J Gynecol cancer: Official J Int Gynecol Cancer Soc 28(1):69–76. https://​doi.​org/​10.​1097/​igc.​0000000000001144​CrossRef
24.
go back to reference Furlanetto J, Mobus V, Schneeweiss A, Rhiem K, Tesch H, Blohmer JU, Lubbe K, Untch M, Salat C, Huober J, Klare P, Schmutzler R, Couch FJ, Lederer B, Gerber B, Zahm DM, Bauerfeind I, Nekljudova V, Hanusch C, Jackisch C, Link T, Hahnen E, Loibl S, Fasching PA (2021) Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy. Eur J cancer (Oxford England: 1990) 145:44–52. https://doi.org/10.1016/j.ejca.2020.12.007CrossRef Furlanetto J, Mobus V, Schneeweiss A, Rhiem K, Tesch H, Blohmer JU, Lubbe K, Untch M, Salat C, Huober J, Klare P, Schmutzler R, Couch FJ, Lederer B, Gerber B, Zahm DM, Bauerfeind I, Nekljudova V, Hanusch C, Jackisch C, Link T, Hahnen E, Loibl S, Fasching PA (2021) Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy. Eur J cancer (Oxford England: 1990) 145:44–52. https://​doi.​org/​10.​1016/​j.​ejca.​2020.​12.​007CrossRef
Metadata
Title
Exploring the effect of BRCA1/2 status on chemotherapy-induced hematologic toxicity in patients with ovarian cancer
Authors
In Hee Lee
Soo Jung Lee
Juhyung Kim
Yoon Hee Lee
Gun Oh Chong
Jong Mi Kim
Juhun Lee
Nan Young Lee
Seo Young Park
Dea Gy Hong
Yee Soo Chae
Publication date
23-04-2024
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-024-04670-8
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine