COVID-19 vaccination uptake and safety profile among germline BRCA1 and BRCA2 pathogenic variant carriers in Singapore

doi:10.21203/rs.3.rs-1749535/v1

Download PDF

Research Article

COVID-19 vaccination uptake and safety profile among germline BRCA1 and BRCA2 pathogenic variant carriers in Singapore

https://doi.org/10.21203/rs.3.rs-1749535/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 12 Apr, 2023

Read the published version in Hereditary Cancer in Clinical Practice →

You are reading this latest preprint version

Background: Cancer patients infected with the Coronavirus disease 2019 (COVID-19) have demonstrated increased mortality rates compared to non-cancer patients. While COVID-19 vaccination remains voluntary in Singapore, it remains highly encouraged to provide better protection at the community level. At our Cancer Genetics Service, we see patients with germline genetic alterations, with the majority being BRCA1/2 pathogenic/likely pathogenic variant (PV/LPV) carriers. Currently, there is insufficient data to suggest if this group should be managed differently from others.

Methods: We conducted a survey of COVID-19 vaccination uptake rates and toxicity in a prospective cohort of 189 participants with germline BRCA1/2 PV/LPV between 1^st Sept 2021 and 30^th Sept 2021.

Results: Our study demonstrated that the vaccination rates in our cohort is consistent with the general population and has a similar side effects profile.

Conclusion: Recommendations with regards to vaccination for eligible individuals should not differ from non-carriers and be encouraged by their healthcare providers.

genetics

BRCA

COVID-19

vaccination

Cancer patients infected with the Coronavirus disease 2019 (COVID-19) have demonstrated increased mortality rates at 1.5 to 2 times compared to non-cancer patients(1)(2). Postulated causes include malignancy-driven processes or treatment related complications leading to an immune-compromised state(3)(4)(5). These result in cancer patients being more susceptible to COVID-19 and its associated complications. Around 5–10% of the cancer population are patients with germline genetic alterations in cellular DNA repair pathways that predisposed them to developing malignancies(6)(7). While studies had demonstrated that the COVID-19 vaccination appears safe for cancer patients(8)(9), there are limited reports on outcomes of individuals with germline pathogenic/likely pathogenic variants (PV/LPV) infected with COVID-19, or their safety profile with regards to vaccination. Currently, there is insufficient data to suggest if this group, with or without the diagnosis of cancer, should be managed differently.

As of September 2021, more than 4000 patients were seen at our Cancer Genetics Service (CGS), National Cancer Centre Singapore (NCCS), with breast and ovarian cancers accounting for 62% of the observed tumour types. Seventy-one percent of the consulted patients had genetic testing, of which 16.3% were identified with pathogenic variants. Majority of these patients (43%) are BRCA1/2 PV/LPV carriers with Hereditary Breast and Ovarian Cancer syndrome (HBOC). Pathogenic variants in these tumour suppressor genes leads to ineffective DNA repair, resulting in increased lifetime risk of breast, ovarian, pancreatic and prostate cancers(10).

The purpose of this study is to evaluate the safety profile of COVID-19 vaccination among those with HBOC seen at the CGS. It is not known how these genetic alterations affect their immune system and its impact on the COVID-19 infection, as well as efficacy of vaccination.

We hypothesize that patients seen at the CGS with underlying HBOC have similar uptake rates and safety profile of COVID-19 vaccination as the general population.

There are currently no guidelines to suggest that patients with hereditary genetic alterations should be managed differently from the general population. We believe that these data will be useful in raising awareness and addressing concerns regarding safety of the COVID-19 vaccination. This would encourage more patients to go for vaccination if they have not done so.

The CGS at the NCCS sees both paediatric and adult patients with a genetic predisposition to malignancies. Between 1st September 2021 and 30th September 2021, we conducted a phone call survey of COVID-19 vaccination uptake rates and toxicity in a cohort of 265 participants with germline BRCA1/2 PV/LPV, who had previously undergone genetic testing at the CGS. All participants were above 21 years of age and fulfilled the following criteria: a) Singapore resident, b) carrier of BRCA1/2 germline PV/LPV identified through genetic testing performed by a Clinical Laboratory Improvement Amendments (CLIA)/ College of American Pathologists (CAP) certified laboratory, and c) with or without a history of cancer. This study was approved by the SingHealth Centralised Institutional Review Board (IRB: 2021–2593). Individuals who declined the survey or did not respond after five calls were dropped out from the study.

All responders completed our Questionnaire (Appendix A) to evaluate their participation in the national COVID-19 vaccination programme in Singapore. Unvaccinated participants were invited to disclose their reason for declining vaccination. Vaccinated participants were requested to document the vaccine type, number of doses and dates administered along with any associated side effects (Appendix A). They were also given the option to elaborate on any other side effects not within the questionnaire or permitted to report no symptoms. Participants were also asked to declare their history of COVID-19 infection.

Our primary outcome was the proportion of individuals with germline BRCA1/2 pathogenic variants who received the COVID-19 vaccine, and our secondary outcome was to evaluate the proportion and type of side effects after vaccination.

Between 1st and 30th September 2021, a total of 265 pathogenic BRCA1/2 PV/LPV carriers were contacted by phone, of which 189 (71.3%) participate in the survey (Tables 1 and 2). There were 97 BRCA1 PV/LPV carriers and 92 BRCA2 PV/LPV carriers. Of the 170 (89.5%) vaccinated participants, 144 (84.7%) received Pfizer, 20 (11.8%) received Moderna, three (1.8%) received Sinovac, and three (1.8%) were unable to recall type of vaccines received (Table 2). Majority (92.3%) of vaccinated participants had completed the two-dose vaccine schedule, with 7 (4.1%) having received only one dose. Of the seven, five planned to receive the second dose as scheduled, one declined the second dose for reasons undisclosed, and one had history of COVID-19 infection and was advised that the second dose was not required at that time of the questionnaire.

Among the 19 unvaccinated participants, the most common reason for decline was being on active cancer treatments (31.6%). Three (15.8%) responders felt uncertain as they had not consulted a physician, whereas three (15.8%) were advised to wait for other types of vaccines in view of allergies to messenger ribonucleic acid (mRNA) vaccines (Table 3). One unvaccinated participant had a history of COVID-19 infection.

Ninety-two (54.1%) responders developed symptoms to the COVID-19 vaccines, with myalgia (56.5%) being the most common side effect. Other symptoms include fever (40.2%), headache (16.3%), fatigue (11.2%), and rashes (6.5%) (Tables 2 and 4). Overall, fifty-one (55.4%) responders experienced 1 side effect, thirty-three (35.9%) experienced 2 side effects, and the remaining (8.7%) experiencing more than 2 side effects post vaccination. There were no major severe adverse events of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 and above.

In Singapore, patients with cancer on active treatment, or those in remission, are given the assurance to receive the COVID-19 vaccine if deemed eligible by their primary physician. Patients on active treatment are considered to be at least moderately immunocompromised and are further encouraged to receive a third dose of vaccine two months after their second dose(11). Unless there is a cancer diagnosis, there are no studies to suggest germline carriers of BRCA1/2 PV/LPV being more vulnerable than average population to COVID-19 or vaccination adverse effects.

Our study on pathogenic BRCA1/2 PV/LPV carriers showed COVID-19 vaccine uptake rate of approximately 90%, which is consistent with the general population in Singapore as of December 2021(11)(12). Majority of the responders opted for either Pfizer or Moderna mRNA vaccine and had received two doses of vaccination at the time of our survey.

At least half of the responders developed side effects, with myalgia being the most common, followed by fever, consistent with side effects typically observed following flu vaccinations (Tables 2 and 4). The remaining responders who received the COVID-19 vaccine did not experience any side effects. There were no major adverse events such as anaphylaxis or hospitalizations. The nature of symptoms post vaccination from our survey were similar to the vaccine studies reported on the Centre for Disease Control and Prevention (CDC) website, with the most common being fatigue, headache and myalgia regardless of age(13). The frequency of adverse effects on CDC was in the range of 70.6–82.8% depending on age groups for the Pfizer-BioNTech COVID-19 vaccine and was approximately 55% in our cohort with a median age of 50 years old.

One adverse effect that is clinically relevant for our patients is the enlargement of axillary lymph nodes on the ipsilateral arm that had received COVID-19 vaccination. In a literature review of 15 studies, the reported incidence of regional lymphadenopathy was between 14.5% and 53.0% and persisted for more than 6 weeks in 29.0% of recipients(14). Most lymphadenopathies (32%) in the study were picked up on imaging with only 1.8% being self-reported. Our cohort had 3 (1.8%) vaccinated participants with reported lymphadenopathy. Given the increased lifetime risk of developing breast cancers, pathogenic BRCA1/2 PV/LPV carriers are recommended to undergo more intensive surveillance for breast cancer which includes annual breast magnetic resonance imaging (MRI) and breast mammogram (MMG) from a young age of 25. As such, it may be prudent for physicians to advise COVID-19 vaccine recipients to defer scans minimally a few weeks post-vaccination to avoid false positives for pathological conditions on imaging.

At least a quarter of the BRCA1/2 carriers from our database declined the survey or did not pick up the call, contributing to non-response. In addition, given the nature of the study, replies from participants may contribute to measurement bias through inaccurate reporting.

Our study demonstrated that BRCA1/2 PV/LPV carriers have a similar side effect profile as the general population post COVID-19 vaccination, with no major adverse events reported. Recommendations with regards to vaccination for eligible individuals with BRCA1/2 PV/LPV carriers should not differ from non-carriers and should be encouraged by their healthcare providers.

COVID-19: Coronavirus disease 2019

PV: Pathogenic variant

LPV: Likely pathogenic variant

CGS: Cancer Genetics Service

NCCS: National Cancer Centre Singapore

HBOC: Hereditary Breast and Ovarian Cancer syndrome

CLIA: Clinical Laboratory Improvement Amendments

CAP: College of American Pathologists

mRNA: Messenger ribonucleic acid

CTCAE: Common Terminology Criteria for Adverse Events

CDC: Centre for Disease Control and Prevention

MRI: Magnetic resonance imaging

MMG: Mammogram

Ethics approval and consent to participate

This study was approved by the SingHealth Centralised Institutional Review Board (IRB: 2021-2593).

Consent for publication

N/A

Availability of data and materials

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

Competing interests

Joanne Ngeow receives research funding from Astra Zeneca for research.

Funding

N/A

Author’s contributions

Conception and design

Zewen Zhang, Nur Diana Binte Ishak, Jianbang Chiang, Joanne Ngeow

Provision of study materials or patients

Zewen Zhang, Nur Diana Binte Ishak, Sock Hoai Chan, Frances Victoria Fajardo Que, Jianbang Chiang, Joanne Ngeow

Collection and assembly of data

Zewen Zhang, Nur Diana Binte Ishak, Sock Hoai Chan, Frances Victoria Fajardo Que, Zi Yang Chua

Data analysis and interpretation

Zewen Zhang, Sock Hoai Chan, Frances Victoria Fajardo Que, Zi Yang Chua, Joanne Ngeow

Manuscript writing

All authors

Final approval of manuscript

All authors

Acknowledgements

We would like to thank colleagues from the National Cancer Centre Singapore, especially individuals working at the Cancer Genetics Service, for their continued support and contribution to the study. We also thank the participants who gave their valued time and responses, making this study possible.

Leonetti A, Facchinetti F, Zielli T, Brianti E, Tiseo M. COVID-19 in lung cancer patients receiving ALK/ROS1 inhibitors. Eur J Cancer [Internet]. 2020 Jun;132:122–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0959804920301933
Rüthrich MM, Giessen-Jung C, Borgmann S, Classen AY, Dolff S, Grüner B, et al. COVID-19 in cancer patients: clinical characteristics and outcome—an analysis of the LEOSS registry. Ann Hematol [Internet]. 2021 Feb 7;100(2):383–93. Available from: http://link.springer.com/10.1007/s00277-020-04328-4
Kalinsky K, Accordino MK, Hosi K, Hawley JE, Trivedi MS, Crew KD, et al. Characteristics and outcomes of patients with breast cancer diagnosed with SARS-Cov-2 infection at an academic center in New York City. Breast Cancer Res Treat [Internet]. 2020 Jul 14;182(1):239–42. Available from: https://link.springer.com/10.1007/s10549-020-05667-6
Kuderer NM, Choueiri TK, Shah DP, Shyr Y, Rubinstein SM, Rivera DR, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet [Internet]. 2020 Jun;395(10241):1907–18. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673620311879
Garassino MC, Whisenant JG, Huang L-C, Trama A, Torri V, Agustoni F, et al. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. Lancet Oncol [Internet]. 2020 Jul;21(7):914–22. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1470204520303144
Foulkes WD. Inherited Susceptibility to Common Cancers. N Engl J Med [Internet]. 2008 Nov 13;359(20):2143–53. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMra0802968
Gennery AR, Cant AJ, Jeggo PA. Immunodeficiency associated with DNA repair defects. Clin Exp Immunol [Internet]. 2001 Dec 24;121(1):1–7. Available from: https://academic.oup.com/cei/article/121/1/1/6461538
Monin L, Laing AG, Muñoz-Ruiz M, McKenzie DR, del Molino del Barrio I, Alaguthurai T, et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Oncol [Internet]. 2021 Jun;22(6):765–78. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1470204521002138
Naranbhai V, Pernat CA, Gavralidis A, St Denis KJ, Lam EC, Spring LM, et al. Immunogenicity and Reactogenicity of SARS-CoV-2 Vaccines in Patients With Cancer: The CANVAX Cohort Study. J Clin Oncol [Internet]. 2022 Jan 1;40(1):12–23. Available from: https://ascopubs.org/doi/10.1200/JCO.21.01891
Chiang J, Ngeow J. The management of BRCA1 and BRCA2 carriers in Singapore. Chinese Clin Oncol [Internet]. 2020 Oct;9(5):62–62. Available from: http://cco.amegroups.com/article/view/49615/html
Singapore Cancer Society. COVID-19 Vaccines and Cancer [Internet]. Available from: https://www.singaporecancersociety.org.sg/covid-19.html
Ministry of Health S. COVID-19 Vaccination Frequently Asked Questions [Internet]. Available from: https://www.vaccine.gov.sg/faq
Centre for Disease Control and Prevention. Pfizer-BioNTech COVID-19 Vaccine Reactions & Adverse Events [Internet]. Available from: https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/reactogenicity.html
Garreffa E, Hamad A, O’Sullivan CC, Hazim AZ, York J, Puri S, et al. Regional lymphadenopathy following COVID-19 vaccination: Literature review and considerations for patient management in breast cancer care. Eur J Cancer [Internet]. 2021 Dec;159:38–51. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0959804921011333

Table 1: Demographics of patients contacted

Demographics (n=265)

Gender

Female

Male

227 (85.7%)*

38 (14.3%)

Race

Chinese

Malay

Indian

Others

Unspecified

164 (61.9%)

38 (14.3%)

20 (7.5%)

42 (15.8%)

1 (<0.1%)

Age, years (n=264)

Median (Range)

Mean (SD)

50 (22 – 79)

50.8 (±13.0)

Genes with pathogenic variant

BRCA1

BRCA2

134 (50.6%)

131 (49.4%)

Personal history of cancer

Yes

Unspecified

182 (68.7%)

82 (30.9%)

1 (<0.1%)

Type of cancer (n=182)

Breast

Ovarian

Others

More than 1 cancer

Unspecified

106 (58.2%)

40 (22.0%)

10 (5.5%)

25 (21 for Breast & Ovarian ca.) (13.7%)

1 (<0.1%)

Completed questionnaire

Yes

189 (71.3%)

76 (28.7%)

*Data are n(%) unless otherwise stated

Table 2: Respondents and Vaccination details

Completed COVID questionnaire (n=189)

Personal history of cancer (N=130)

Nil history of cancer

(N=59)

Gender

Female

Male

124 (95%)

6 (5%)

38 (64%)

21 (36%)

Race

Chinese

Malay

Indian

Others

Unspecified

84 (65%)

21 (16%)

13 (10%)

12 (9%)

44 (75%)

7 (12%)

3 (5%)

4 (7%)

1 (2%)

Age, years

Median (Range)

Mean (SD)

53.5 (28-79)

53.5 (±11.7)

42.5 (22-77)

45.7 (±14.0)

Germline pathogenic gene

BRCA1

BRCA2

65 (50%)

32 (54%)

27 (46%)

Types of cancer

Breast

Ovarian

Others

More than 1 cancer

Unspecified/No cancer

78 (60%)

28 (22%)

7 (5%)

16 (12%)

1 (1%)

COVID Vaccination

Yes

1 dose

2 doses

Unspecified

116 (89%)

11 (8%)

105 (81%)

0 (0%)

14 (11%)

54 (92%)

1 (2%)

51 (86%)

2 (3%)

5 (8%)

Previous COVID-19

Yes

Unspecified

2 (2%)

125 (96%)

3 (2%)

0 (0%)

59 (100%)

0 (0%)

Vaccinated individuals

Type of Vaccination

Pfizer

Moderna

Sinovac

Unspecified

N=116

97 (84%)

13 (11%)

3 (3%)

N=54

47 (87%)

7 (13%)

0 (0%)

Side effects post vaccination

Yes

1 side effect

2 side effects

Multiple (>2) side effects

Unreported

64 (55%)

36 (31%)

20 (17%)

8 (7%)

50 (43%)

2 (2%)

29 (54%)

15 (28%)

14 (26%)

0 (%)

25 (46%)

0 (%)

Table 3: Reasons for not receiving COVID-19 vaccination

Unvaccinated	N=19
Active treatment including chemotherapy	6
Have not consulted Physician	3
Just received Physician’s recommendation	1
Vaccine not recommended	1
Allergic/advised to wait	3
Have not had time to do it	1
Does not believe in the vaccine	1
Prefer not to disclose	2
Unknown	1

Table 4: Side effects experienced post vaccination

Individuals with side effects post vaccination	N = 92
Headache	15
Fever	37
Body aches	52
Rashes	6
Others:	33
Chills	6
Itch	1
Fatigue	11
Flushing	1
Swollen arm, hands	6
Nausea	3
Swollen lymph node (breast, neck)	3
Eczema flare, allergy	2
Breathing difficulty	1
Affected period cycle	1
Patients without side effects	N = 76

Appendix A: COVID Vaccination Questionnaire

Name:

IC:

Date of clinic visit:

1) Have you had your COVID Vaccination (Yes/No) – if no please proceed to Question 4

2) When did you receive your vaccination?

#1 ____________ dd/mm/year

#2____________ dd/mm/year

3) Name of COVID Vaccine (Pfzier/Moderna/Sinovac/Others/Unsure)

4) Reason for not receiving vaccination: _______________

5) Have you experienced any side effects from the vaccination? (Yes/No)

If “Yes” please select the appropriate answers, you may choose more than one

A) Headache

B) Fever

C) Body aches

D) Rashes

E) Others__________ (please specify)

6) Have you ever been tested positive for COVID? (Yes/No)

If “Yes”, when was it ___________ (dd/mm/year)

Competing interest reported. Joanne Ngeow and Zhang Zewen received funding from Astra Zeneca for research and conference respectively, while all other authors of the manuscript have no conflict of interests and no financial disclosures to be made.

Download PDF

Journal Publication

published 12 Apr, 2023

Read the published version in Hereditary Cancer in Clinical Practice →

Editorial decision: Major revision
10 Oct, 2022
Reviews received at journal
07 Jul, 2022
Reviewers agreed at journal
06 Jul, 2022
Reviewers invited by journal
05 Jul, 2022
Editor assigned by journal
21 Jun, 2022
Submission checks completed at journal
13 Jun, 2022
First submitted to journal
12 Jun, 2022

You are reading this latest preprint version

COVID-19 vaccination uptake and safety profile among germline BRCA1 and BRCA2 pathogenic variant carriers in Singapore

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Appendix

Additional Declarations

Status:

Journal Publication

Version 1