Skip to main content
Download PDF

Selected features of breast and peritoneal cancers diagnosed in BRCA1 carriers after risk-reducing salpingo-oophorectomy

Hereditary Cancer in Clinical Practice volume 17, Article number: 10 (2019) Cite this article

Abstract

Background

Since more than two decades Risk-reducing salpingo-oophorectomy (RRSO) is recommended and widely accepted by BRCA1/2 carriers as a method reducing ovarian cancer risk and improving survival rate. After RRSO, there remains a risk of breast cancer and peritoneal cancer. The characteristics of these neoplasms are not well known. In this study, we determined the selected parameters such as age at cancer diagnosis, time from RRSO to the diagnosis of cancer, and significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up.

Methods

The material comprised of 195 BRCA1 carriers who performed RRSO between years 1999–2012. In this period, 16 patients developed cancer (6-primary breast cancer, 3-contralateral breast cancer, 5-relapse of breast cancer, 2-peritoneal cancer). They were subject of the further analysis.

Results

During the follow-up period mean age of patients after RRSO at the time of cancer diagnosis was 53.19. The mean age of patients diagnosed with primary breast cancer was 50, contralateral breast cancer – 58.67, recurrence of breast cancer - 51 and peritoneal cancer 60. The mean time periods from RRSO to the diagnosis of primary, contralateral, recurrence breast cancer were 53, 58.67 and 25,4 months respectively and of peritoneal cancer 46 months. BRCA1 c.5266dupC mutation carriers demonstrated significantly shorter time of cancer development compared to patients carrying c.181T > G and c.4035delA mutations. Peritoneal cancer was only observed in two c.181T > G BRCA1 mutation carriers.

Conclusions

The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.

Peer Review reports

Introduction

It was shown that diagnostic methods for ovarian cancer early-stage detection are ineffective [1]. Intensive screening tests in groups with the highest risk of ovarian cancer, such as carriers of the BRCA1 and BRCA2 mutations, have also low efficacy [1,2,3,4,5,6]. For these reasons, patients who are carriers of the BRCA1/2 mutation are offered risk-reducing salpingo-oophorectomies (RRSO), which is widely accepted by BRCA1/2 carriers and have been performed for decades in hospitals and gynecological clinics all around the world. At the moment, such management is considered the best possible option for reducing ovarian cancer risk and improving the survival rate [1, 7, 8]. However, after this surgery, there remains a risk of breast cancer and risk of peritoneal cancer. Data about characteristics of these cancers developing after RRSO are pure. In this study, we analyzed characteristics of breast or peritoneal cancer after RRSO. Follow-up was conducted over the course of 12 years. The analysis included: age at cancer diagnosis, time from RRSO to the diagnosis of cancer, significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up.

Material and methods

The material comprised of 195 BRCA1 carriers from the West Pomeranian Voivodship in Poland who performed RRSO between 15.09.1999–31.12.2012 at the Department of Gynecological Surgery and Oncology of Adults and Adolescents of the Pomeranian Medical University in Szczecin. No malignancy was found in the histopathological examination of the excised material. 80 of 195 (41.03%) patients were treated for breast cancer before risk-reducing surgery. All patients carried one of three BRCA1 mutations most commonly occurring in the Polish population (c.5266dupC – 128 patients, c.4035delA – 19 patients and c.181T > G – 48 patients) [9]. Median follow-up time for the group of 195 patients amounted to 80 months.

At the time of observation 16 out of 195 patients were diagnosed with cancer. 6 (3.1%) cases with primary breast cancer (PBC); 3 (1.5%) cases contralateral primary breast cancer (CPBC); 5 (2.56%) cases with cancer cells diagnosed in a scar after mastectomy defined as relapse of breast cancer (RBC); 2 (1.03%) cases with peritoneal cancer. The detailed characteristics of 16 patients from the study group are shown in Table 1. Ten (62.5%) of these patients had been treated for breast cancer also before the RRSO. The median age of affected patients (n = 16) at the time of RRSO was 46.5 years (36–63 years), which did not deviate from median age for the whole group (n = 195) – 47 years (31–78 years).

Table 1 Characteristics of 16 patients who developed cancer after risk-reducing salpingo-oophorectomy
Full size table

Histopathological examination of tissues excised during RRSO was performed with extraordinary caution in order to rule out the presence of cancerous foci in the ovary or the salpinx, which have been described in the literature and could have been missed in the primary histopathological assessment [10, 11]. Repeated histopathological examination of excised material failed to reveal micro-invasive foci in both of our patients diagnosed with primary peritoneal cancer during the follow-up period.

The patient analysis included: age at cancer diagnosis, time from RRSO to the diagnosis of cancer, significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up. The data has been subjected to statistical analysis.

Statistical analysis

All variables were checked for normal distribution using the Shapiro-Wilk test. They were described as means, standard deviations, medians, quartiles, as well as minimal and maximal values. We checked for statistically significant differences in quantitative variables using Student’s t-test or Mann-Whitney test and Fisher’s exact test were used in order to calculate differences in proportions. For all tests, the differences were considered statistically significant at p-value < 0.05. Statistical analyses were performed using STATA 11 software (license no. 30110532736).

Results

Summary of selected features of BRCA1 carriers diagnosed with cancer during the follow-up period is shown in Table 2. The mean age of cancer diagnosis in 16 patients who were subject of the study, was 53.19. Peritoneal cancer observed in two patients was diagnosed significantly later at a mean age of 60. Both patients were previously treated (before RRSO) due to breast cancer. With regards to breast cancer, the PBC was diagnosed in 6, CPBC in 3 and RBC in 5 out of 16 cases. The peritoneal cancer was diagnosed almost 7 months earlier than PBC (46 months vs. 53 months), but this difference was not statistically significant. Breast cancer recurrence was diagnosed almost twice as fast as primary breast cancer and peritoneal cancer (25.4 vs. 53 months), but this difference was also not statistically significant.

Table 2 Summary of selected features of BRCA1 carriers diagnosed with cancer during the follow-up period
Full size table

Peritoneal cancers diagnosed during the follow-up period were observed only in two c.181T > G BRCA1 mutation carriers. We performed a statistical analysis of the frequency of peritoneal cancer in c.181T > G BRCA1 mutation carriers in comparison to other mutation carriers. Statistical significant differences were observed for this characteristic (p = 0.0392; OR = 29.00; 95% CI: 1.048–802.64).

The time to any cancer diagnosis after RRSO was significantly shorter for c.5266dupC mutation carriers compared to c.181T > G and c.4035delA mutation carriers (30.45 vs. 75.6 months; p = 0.021).

The c.5266dupC BRCA1 mutation was most frequent among patients who developed any cancer – 68.75% (11/16), followed by c.181T > G mutation – 25% (4/16), and c.4035delA observed in 6,25% (1/16) of patients. This reflects the frequency of these mutations in the Polish population.

Discussion

In our material, we observed relatively advanced age of cancer diagnosis among BRCA1 carriers after RRSO. It is most likely associated with particularly late age of undergoing this surgery. In our study, the average age of undergoing such an operation is 46–49 years [12,13,14]. The reason for delayed RRSO was that, in a significant number of breast cancer patients, BRCA1 mutation was diagnosed after diagnosis of breast cancer. In our study group, 62.5% of patients had been previously treated due to breast cancer. As indicated in our previous studies, patients treated for breast cancer undergo RRSO at a later age compared to patients without the diagnosis of breast cancer (50 vs. 46 years; p = 0.0003) [13].

In our study, we found that the mean age at diagnosis of any breast cancer was similar to those observed by Ramon et al. and equaled 52.2 vs. 51.8 years of age. The mean time from RRSO to diagnosis of breast cancer was also similar and amounted to 44,35 vs. 40.8 months [15]. Fakkert et al. reported breast cancer diagnosis among BRCA1 patients after RRSO at a significantly younger age – 45.25 years, and somewhat longer time from RRSO to the diagnosis of breast cancer – 52.8 months [16]. Kauff et al. indicated significantly shorter time to diagnosis of breast and peritoneal cancer among patients after RRSO – 10.3 and 16.3 months, respectively [17].

Finch et al. showed that mean time to development of peritoneal cancer among BRCA1 carriers after RRSO amounted to 63.6 months, although they emphasize that in three cases the diagnosis was made before the end of three years. The mean age of those patients at the time of diagnosis equalled 51.5 years [18], which approximates our data. In another study, Finch et al. reported similar mean age at diagnosis of peritoneal cancer - 51.6 years, but the mean time to diagnosis extended to 73.2 months. Possibly, prolonged time to the diagnosis of peritoneal cancer might have been influenced by the inclusion of four patients with BRCA2 mutation into the study group of 32 patients [19]. In case of particularly short time to diagnosis of peritoneal cancer after RRSO, one should very carefully assess the excised material in order to rule out micro-invasive foci, which is described in the literature [10, 11].

Rhiem et al. observed a case of peritoneal cancer in a 57-year-old woman 26.4 months after RRSO [20]. Rebbeck et al. diagnosed peritoneal cancer in patients 45.6 and 103.2 months after RRSO [21]. Kiely et al. showed peritoneal cancer in a 70-year-old patient eight 96 months after RRSO [22]. In another publication, Kauff et al. reported peritoneal cancers among patients after RRSO on average after 41.16 months and breast cancers after 36.36 months [23]. Powell et al. demonstrated equally short time of diagnosis of peritoneal cancer in a patient after RRSO as Kauff [17]. The diagnosis was made as early as a year after the procedure [24]. In our material, the mean age of patients diagnosed with peritoneal cancer was 60 and the mean time from RRSO to the diagnosis of peritoneal cancer amounted to 46 months.

Influence of particular BRCA1 gene mutation on studied characteristics is a very difficult topic to discuss. Although c.5266dupC, the most common mutation in the Polish population, is also often identified in the Ashkenazi Jewish population [25], available literature lacks data for discussion. The frequency of particular BRCA1 mutations observed between carriers who were diagnosed with any cancer reflects the frequency of these mutations in the Polish population. However, we found peritoneal cancer in two BRCA1 carriers with c.181T > G mutation, only. These two patients also developed breast cancer before RRSO. We observed that the time to any cancer diagnosis after RRSO was significantly shorter for c.5266dupC BRCA1 mutation carriers. We think that these are interesting observations important for future analyses on significance of particular BRCA1 gene mutation, however, for more general conclusions studies on larger groups should be performed.

Conclusions

The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.

Abbreviations

CI:

Confidence interval

CPBC:

Contralateral primary breast cancer

OR:

Odds ratio

PBC:

Primary breast cancer

RBC:

Relapse of breast cancer

RRSO:

Risk-reducing salpingo-oophorectomy

References

  1. Walker JL, Bethan Powell C, Chen L-M, Carter J, Bae Jump VL, et al. Society of Gynecologic Oncology Recommendations for the prevention of ovarian Cancer. Cancer. 2015;121:2108–20.

    Article  Google Scholar 

  2. Goff BA, Lowe KA, Kane JC, Robertson MD, Gaul MA, Andersen MR. Symptom triggered screening for ovarian cancer: a pilot study of feasibility and acceptability. Gynecol Oncol. 2012;24:230–5.

    Article  Google Scholar 

  3. Goff BA. Ovarian cancer: screening and early detection. Obstet Gynecol Clin N Am. 2012;39:183–94.

    Article  Google Scholar 

  4. Goff BA, Matthews B, Andrilla CH, Miller JW, Trivers KF, Berry D, et al. How are symptoms of ovarian cancer managed? A study of primary care physicians. Cancer. 2011;117:4414–23.

    Article  Google Scholar 

  5. Goff B. Symptoms associated with ovarian cancer. Clin Obstet Gynecol. 2012;55:36–42.

    Article  Google Scholar 

  6. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. JAMA. 2011;305:2295–303.

    Article  CAS  Google Scholar 

  7. Gilbert L, Basso O, Sampalis J, Karp I, Martins C, Feng J, et al. Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project. Lancet Oncol. 2012;13:285–91.

    Article  Google Scholar 

  8. Synowiec A, Wcisło G, Bodnar L, Gasowska-Bodnar A, Szczylik C. Screening for ovarian cancer in BRCA1/BRCA2 mutations carriers. Ginekol Pol. 2014;85(5):377–81.

    Article  Google Scholar 

  9. Górski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, Gronwald J, et al. Founder mutations in the BRCA1 gene in polish families with breast-ovarian cancer. Am J Hum Genet. 2000;66(6):1963–8.

    Article  Google Scholar 

  10. Rabban JT, Krasik E, Chen LM, Powell CB, Crawford B, Zaloudek CJ. Multistep level sections to detect occult fallopian tube carcinoma in risk-reducing salpingo-oophorectomies from women with BRCA mutations: implications for defining an optimal specimen dissection protocol. Am J Surg Pathol. 2009;33:1878–85.

    Article  Google Scholar 

  11. Reitsma W, de Bock GH, Oosterwijk JC, Bart J, Hollema H, Mourits MJ. Support of the ‘fallopian tube hypothesis’ in a prospective series of risk-reducing salpingo-oophorectomy specimens. Eur J Cancer. 2013;49:132–41.

    Article  Google Scholar 

  12. Menkiszak J, Chudecka-Głaz A, Bedner R, Gronwald J, Wężowska M, Kojs Z, et al. Genital malignant tumors and precancerous conditions in female carriers of constitutional BRCA 1 gene mutations undergoing prophylactic adnexectomy. Curr Gynecol Oncol. 2012;10(4):270–85.

    Google Scholar 

  13. Menkiszak J, Chudecka-Głaz A, Gronwald J, Bedner R, Cymbaluk-Płoska A, Wężowska M, et al. Characteristics of selected clinical features in BRCA1 mutation carriers affected with breast cancer undergoing preventive female genital tract surgeries. Ginekol Pol. 2013;84(9):758–64.

    Article  Google Scholar 

  14. Menkiszak J, Chudecka-Głaz A, Gronwald J, Cymbaluk-Płoska A, Celewicz A, Świniarska M, et al. Prophylactic salpingo-oophorectomy in BRCA1 mutation carriers and postoperative incidence of peritoneal and breast cancers. J Ovarian Res. 2016 Feb;29(9):11. https://doi.org/10.1186/s13048-016-0220-4.

    Article  CAS  Google Scholar 

  15. Ramon Y, Cajal T, Torres A, Alonso C, Fisas D, Ojeda B, et al. Risk factors associated with the occurrence of breast cancer after bilateral salpingo-oophorectomy in high-risk women. Cancer Epidemiol. 2011 Feb;35(1):78–82.

    Article  Google Scholar 

  16. Fakkert IE, Mourits MJ, Jansen L, van der Kolk DM, Meijer K, Oosterwijk JC, et al. Breast Cancer incidence after risk-reducing Salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Cancer Prev Res (Phila). 2012;5(11):1291–7.

    Article  CAS  Google Scholar 

  17. Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):1609–15.

    Article  Google Scholar 

  18. Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296(2):185–92.

    Article  CAS  Google Scholar 

  19. Finch AP, Lubinski J, Møller P, Singer CF, Karlan B, Senter L, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547–53.

    Article  Google Scholar 

  20. Rhiem K, Foth D, Wappenschmidt B, Gevensleben H, Büttner R, Ulrich U, et al. Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Arch Gynecol Obstet. 2011;283(3):623–7.

    Article  Google Scholar 

  21. Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, et al. Prevention and observation of surgical end points study group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616–22.

    Article  Google Scholar 

  22. Kiely BE, Friedlander ML, Milne RL, Stanhope L, Russell P, Jenkins MA, et al. Adequacy of risk-reducing gynaecologic surgery in BRCA1 or BRCA2 mutation carriers and other women at high risk of pelvic serous cancer. Familial Cancer. 2011;10(3):505–14.

    Article  CAS  Google Scholar 

  23. Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331–7.

    Article  Google Scholar 

  24. Powell CB, Chen LM, McLennan J, Crawford B, Zaloudek C, Rabban JT, et al. Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer. 2011;21(5):846–51.

    Article  Google Scholar 

  25. Satagopan JM, Boyd J, Kauff ND, Robson M, Scheuer L, Narod S, et al. Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res. 2002;8(12):3776–81.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors thank for support to Breast Cancer Campaign Estée Lauder Companies.

Funding

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

  1. Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland

    Janusz Menkiszak, Anita Chudecka-Głaz, Aneta Cymbaluk-Płoska, Aleksander Celewicz & Ryszard Bedner

  2. Department of Gynecologic Oncology, Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Branch, Cracow, Poland

    Zbigniew Kojs

  3. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

    Mariusz Szajda, Monika Cieszyńska, Jan Lubiński & Jacek Gronwald

  4. Department of the Clinical Oncology the West Pomeranian Centre of the Oncology in Szczecin, Szczecin, Poland

    Maria Świniarska

  5. Department of Clinical Nursing, Pomeranian Medical University, Szczecin, Poland

    Anna Jurczak

  6. Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland

    Marta Celewicz

Authors
  1. Janusz Menkiszak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anita Chudecka-Głaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aneta Cymbaluk-Płoska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aleksander Celewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zbigniew Kojs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mariusz Szajda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Świniarska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryszard Bedner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Jurczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marta Celewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Monika Cieszyńska
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jan Lubiński
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jacek Gronwald
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JM the study design, database management, data collection and computing results, writing manuscript; AC-G sample collection, the manuscript review and approval; AC-P data collection, the manuscript review and approval; AC data collection, data collection and computing results, writing manuscript; ZK the study design, the manuscript review and approval; MS computing results, the manuscript review and approval, MŚ sample collection, the manuscript review and approval; RB sample collection, the manuscript review and approval; AJ sample collection, the manuscript review and approval; MC sample collection, the manuscript review and approval; MC sample collection, the manuscript review and approval; JL the study design, the manuscript review and approval; JG: the study design, database management, sample collection and computing results, molecular analysis, writing manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jacek Gronwald.

Ethics declarations

Ethics approval and consent to participate

All participants gave informed written consent prior blood donating. The study was approved by Ethics Committee of the Pomeranian Medical University in Szczecin, Poland (decision No. BN-001/174/05).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Menkiszak, J., Chudecka-Głaz, A., Cymbaluk-Płoska, A. et al. Selected features of breast and peritoneal cancers diagnosed in BRCA1 carriers after risk-reducing salpingo-oophorectomy. Hered Cancer Clin Pract 17, 10 (2019). https://doi.org/10.1186/s13053-019-0109-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13053-019-0109-5

Keywords

  • BRCA1 mutation
  • Cancer
  • Prophylactic surgery

Hereditary Cancer in Clinical Practice

ISSN: 1897-4287