Oncologists´ perspectives and practice on exogenous reproductive hormone use in breast cancer patients

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Örebro University School of Medical Sciences Degree project, 15 ECTS

June 2020

Oncologists´ perspectives and practice on

exogenous reproductive hormone use in breast

cancer patients

Version

1

Author: Sofie Nisbeth Supervisor: Antonios Valachis, Associate Professor of Oncology, Örebro University Hospital

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Abstract

Purpose: the study aimed to investigate oncologists´ perspectives and practices on their

prescription of oral hormonal contraceptives (OHC), menopausal hormone therapy (MHT) and local estrogen therapy in patients with prior breast cancer diagnosis or BRCA-mutation carriers

Method: The study was a web-based survey, based on fictional patient cases that was sent out

to 134 breast oncologists in Sweden. Thirty-six oncologists responded and included in the analysis.

Results: Most oncologists would not recommend MHT after breast cancer diagnosis except

from the case of estrogen-receptor negative disease where 38.9% would recommend. Similarly, non-hormonal contraceptives were recommended from most oncologists in different clinical scenarios. Regarding MHT in BRCA-mutations carriers, 11.1% would recommend MHT in patients without mastectomy whereas 50% would recommend MHT in patients who have undergone prophylactic mastectomy. Non-hormonal treatment followed by low-dose estriol were the most common treatment strategies for dry vagina after breast cancer diagnosis among oncologists whereas estriol-containing treatment was also a relatively common approach in patients treated with tamoxifen.

Conclusion: We found unanimous practices in some clinical scenarios where there is some

evidence, and more variable practice where the evidence is weak or completely absent. The presence of guidelines for some clinical scenarios seems to increase the common view among oncologists.

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Abbreviations

MHT: Menopausal hormone therapy OHC: Oral hormonal contraceptive CEE: Conjugated equine estrogen

BRCA1: Breast cancer susceptibility gene 1 BRCA2: Breast cancer susceptibility gene 2 ER: Estrogen receptor

HER2: Human epidermal growth factor receptor 2 BOF: Bröst onkologisk förening

IUD: Intra uterine devices

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Innehållsförteckning

1 INTRODUCTION 5

1.1 A BRIEF HISTORY OF ORAL HORMONAL CONTRACEPTIVES (OHC) 5

1.2 OHC AND ITS POSSIBLE CORRELATION TO CANCER 5

1.3 A BRIEF HISTORY OF MENOPAUSAL HORMONE THERAPY (MHT) 6

1.4 MHT AND ITS POSSIBLE CORRELATION WITH CANCER 6

1.5 MHT IN PATIENTS WITH PRIOR HISTORY OF BREAST CANCER 6

1.6 OHC AND MHT IN BRCA- MUTATION CARRIERS 7

1.7 LOCAL ESTROGEN THERAPY IN PATIENTS WITH HISTORY OF BREAST CANCER 7

1.8 PURPOSE 7

2 METHODS 8

2.1 QUESTIONNAIRE:THE QUESTIONNAIRE WAS BASED IN 6 CLINICAL VIGNETTES. 8

2.2 STATISTICAL ANALYSIS 9

3 RESULTS 10

3.1 CHARACTERISTICS OF STUDY COHORT 10

3.2 CASE I 11 3.3 CASE II 12 3.4 CASE III 13 3.5 CASES IVA-IVC 14 4 DISCUSSION 15 5 CONCLUSION 16 6 ACKNOWLEDGEMENTS 16 7 LIST OF REFERENCES 17 8 APPENDICES 20 8.1 QUESTIONNAIRE 20

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1 Introduction

1.1 A brief history of oral hormonal contraceptives (OHC)

Enovid™-10, produced by the Searle Company, was approved for the American market by the Federal Drug Administration (FDA) in 1957 as a treatment for menstrual disorders[1]. It was a combined OHC which consisted of 9.85 mg norethynodrel (a progestin) and 150 µg mestranol (an estrogen) which is a significantly higher dose than the modern day pill[2]. Both estrogen and progesterone can on their own inhibit ovulation but medications that contain both estrogen and progestin (synthetic analogue to progesterone) are more efficient. Combined OHC also controls vaginal bleeding better [3].It would take until 1961 for the Searle Company to get it approved by FDA as a contraceptive drug: This version of Enovid™ contained 5 mg norethynodrel and 75 mg mestranol. It was only available to married women. [1]Within a year of its release, FDA would receive reports of 6 deaths and 20 non-fatal cases of thromboembolism following usage of the drug [4]. Thromboembolism, due to the effects of estrogen (especially ethinylestradiol) on clotting factors, would become the main issue

regarding side effects caused by the drug until now. Gradual reductions in dosage in newer versions of the drug was made to reduce this pro-thrombotic effect[1].In Great Britain, the pill became available in 1961 to married women. In Sweden, oral contraceptives became available in 1964; to both married and unmarried women [5, 6].

1.2 OHC and its possible correlation to cancer

A Swedish-Norwegian study, published in 2002, pointed to an increased risk for breast cancer in patients who currently used or had recently used combined OHCs. This association was, however, not evident in patients who received progestin-only OHCs [7].On the other hand a British study, published in 2010, pointed to a decreased mortality in all types of cancers that the study covered including colorectal-, endometrial-, breast-, and ovarian cancers in “ever users” of oral contraceptives [8].Another British study published in 2010, found no major increase in risk of developing breast cancer due to OHCs. However a small increase was seen when OHCs had been used for a long period of time in early years. This risk was correlated to hormonal effects on less differentiated tissues. This risk was shown to progressively

disappeared after the patient had stopped using OHCs [9].A study published in 2013 confirmed that there was a slight increase in incidence of breast cancer in “ever users” of OHC. However, 10 years after stopping the risk seemed to be equivalent to those of “never users”[10].

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1.3 A brief history of menopausal hormone therapy (MHT)

In 1886, two studies were published in Germany showing that women who were suffering from postmenopausal symptoms experienced relief when injected with ovarian tissue [11]. In 1933 the first MHT product, Emmenin, was produced and released on the American market. It contained estrogen from the urine of pregnant women. Later, Premarin, containing conjugated estrogen derived from urine of pregnant horses was released. Premarin was less expensive than Emmenin. Usage of different MHTs rose steadily with an especially high peak between 1960 and mid 1970s. This peak was promoted by several books one of which was “Feminine Forever” by Robert Wilson; published in 1968. “Feminine Forever” encouraged the use of estrogens to treat “emotional complaints” and menopause [11].

1.4 MHT and its possible correlation with cancer

The rise of MHT was halted in the 1970s due to a reported 4-14 times increased risk of developing endometrial cancer when using estrogen, depending on length of exposure [12, 13].Studies in the 1980s identified progesterone as the agent that could reverse this effect which resuscitated MHT. A a result, use of estrogen now in combination with progestin rose once again in women with uteri. This increased trend on MHT use was continued up until the 1990s [11].In 2002, two parallel studies made by the “Women’s Health Initiative” (WHI) were published, both focused on the possible risks and benefits of different hormone therapies [14, 15]. The two studies would somewhat contradict one another. In one trial where the patients were treated with conjugated equine estrogen (CEE) plus medroxyprogesterone, an increase in invasive breast cancer could be seen [14]. In the other trial, women who had undergone a previous hysterectomy were treated with CEE alone. Surprisingly, a decrease in breast cancer incidence was seen in comparison to the trials placebo group. The authors concluded that this unanticipated result would need more research to be fully explained [15]. In 2019, a meta-analysis of available evidence was published and showed that a large part of post-menopausal women who had developed breast cancer had been using MHT with a mean treatment duration of 10 years. The meta-analysis also showed that the risk of developing breast cancer increased steadily with prolonged duration of MHT treatment [16].

1.5 MHT in patients with prior history of breast cancer

Three studies have investigated the safety of MHT in patients with prior history of breast cancer [17, 18]. The HABITS trial found an increased risk for breast cancer recurrence in

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patients treated with MHT after breast cancer diagnosis and the trial was prematurely stopped. The Stockholm trial was also prematurely stopped due to the results of HABITS trial.

However, the Stockholm study did not show any increased risk for breast cancer recurrence [17]. The third study originally sought to demonstrate the alleviating effect of Tibolone on

postmenopausal symptoms. But due to an unexpected, clearly elevated, recurrence risk the trial had to end prematurely[18].

1.6 OHC and MHT in BRCA- mutation carriers

Carriers of breast-cancer susceptibility gene 1 (BRCA1) and breast- cancer susceptibility gene 2 (BRCA2) have an elevated lifetime risk of developing breast cancer [19]. Regarding the use of OHC in BRCA-mutation carriers, extended duration (≥ 5 years) of OHC use could not be excluded as a potential factor that increase the risk for breast cancer in BRCA 1 and BRCA 2 mutation carriers [20]. Regarding MHT, BRCA1- or BRCA2- mutation carriers are often

recommended to undergo a prophylactic salpingo-oophorectomy to prevent ovarian cancer. Use of MHT, to alleviate subsequent menopausal symptoms, seems to be safe in regard to the risk of developing breast cancer. [19]

1.7 Local estrogen therapy in patients with history of breast cancer

Vaginal atrophy and dyspareunia are examples of troublesome symptoms that can occur under or after menopause as well as during endocrine treatment for breast cancer and local estrogen therapy is effective in reducing the local symptoms[21]. Studies conducted so far have not been able to show an increased breast cancer recurrence when using vaginal estrogen therapy. [22, 23]. Given the lack of high-quality evidence on the potential effect of exogenous

reproductive hormones, as OHC, MHT and local estrogen therapy, on breast cancer risk in patients with prior breast cancer or in BRCA-mutation carriers, the current recommendations are weak. As a result, how the oncologists are dealing with these clinical challenging

questions is more a matter of each oncologist´s perception and local tradition rather than an evidence-based decision.

1.8 Purpose

This study aimed to investigate the oncologists´ practice on prescription of different hormone therapies to patients that have undergone breast cancer or patients with high risk for breast cancer as BRCA-mutation carriers.

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2 Methods

A web-based survey, based on fictional patient cases, was sent out to 134 breast oncologists in Sweden during February- March 2020. The oncologists were identified through the membership list of the Bröst Onkologisk förening (BOF). Four cases highlighting different aspects on the potential use of OHC, MHT and local estrogens in patients with breast cancer history or BRCA- mutation carriers were constructed to showcase the oncologists perceptions and practices about a possible prescription of exogenous reproductive hormones for breast cancer patients. The questionnaire was sent from my e-mail to the participants. Brief e-mail reminders were sent on a weekly basis for up to 3 times.

2.1

Questionnaire:

The questionnaire was based in 6 clinical vignettes.

Case I: Agda was diagnosed with an estrogen receptor (ER)-positive, HER2- negative pT2N0 breast cancer at the age of 50. She was operated and

subsequently treated with radiation therapy and and an additional 5 years of endocrine treatment. She seeks help for postmenopausal symptoms.

Aim: This question aimed to investigate the perception about MHT use in general and

based on ER-status and time since diagnosis.

Case II: Berit was diagnosed with an ER-positive and HER2- negative pT1N0 breast cancer at the age of 32. She was operated with breast conserving surgery and sentinel node biopsy. She received adjuvant chemotherapy and then

endocrine treatment for 5 years. No BRCA1- or BRCA2-mutation was found. Now, at the age 35, she seeks advice for contraceptives.

Aim: This question aimed to investigate the perception about OHC use in cancer

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Case III: Carita is 48 years old. Both her mother and grandmother were diagnosed with breast cancer around the age of 50. No BRCA1- or BRCA2-mutation was found. She seeks help for postmenopausal symptoms.

Aim: This question aimed to investigate the perception about MHT use in patients

with a family history of breast cancer. Alternative scenario was presented which included detected BRCA- mutations with or without prophylactic mastectomy. Cases IVa-IVc: These cases aimed to investigate the perception about locally applied hormonal or nonhormonal therapies in patients previously operated for ER-positive tumors depending on the type of endocrine therapy.

Case IVa: Denise was operated 2 years ago for an ER-positive breast cancer and is

treated with adjuvant endocrine therapy with aromatase-inhibitors. She seeks help for vaginal dryness.

Case IVb: Ellen was operated 2 years ago for an ER-positive breast cancer. She is

being treated with Tamoxifen. She seeks help for vaginal dryness.

Case IVc: Frideborg was operated 2 years ago for an ER-positive breast cancer. She

currently has no adjuvant treatment. She seeks help for vaginal dryness. 2.2 Statistical analysis

Responses were summarized in numbers and percentages. For cases I, II, and III more than one answer was able for each question. Due to the relatively limited number of responders, no subgroup analyses were performed based on responders´ characteristics. The diagrams were created using the Infogram visualization tool or Microsoft Excel.

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3 Results

3.1 Characteristics of study cohort

In total, 134 email addresses to oncologists were included in the BOF membership list.

Twenty-six addresses were inactive or blocked. In total, 108 oncologists with active addresses were identified and received an e-mail with the questionnaire and reminders. Thirty-six oncologists (response rate 33.3%) answered the questionnaire and were included in the analysis. All responders were specialists in oncology. The characteristics of oncologists are presented in Table 1. 16 20 12 10 10 4 21 12 3 22 4 10 16 15 5 36

>75% of workin time spent with breast cancer patients 50-75% of workin time spent with breast cancer patients 25-50% of workin time spent with breast cancer patients <25% of workin time spent with breast cancer patients Working with oncology for >15years Working with oncology for 10-15 years Working with oncology for 5-10 years Working at a University hospital Working at a middle sized hospital Working at a smaller hospital Active in Götaland Active in Svealand Active in Norrland Men Women Total Table 1

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3.2 Case I

Figure 1 illustrates the distribution of answers in the case I. None of the oncologist would recommend MHT after breast cancer diagnosis for an ER-positive breast cancer whereas 38.9% would recommend MHT if the breast cancer was ER-negative.

Figure 1: Distribution of answers in Case I. Would you recommend menopause hormonal therapy in a breast cancer patient with ER-positive breast cancer, ER-positive with > 5 years from diagnosis, or ER-negative breast cancer?

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3.3 Case II

The recommended contraceptive options after breast cancer diagnosis are presented in Figure 2. Copper IUD and other non-hormonal contraceptives were the most common recommended options in all three clinical scenarios, positive disease within 5 years from diagnosis, ER-positive > 5 years from diagnosis, and ER-negative disease, respectively.

In ER-negative disease, 6 oncologists would recommend progesterone-only pills compared to 1 in ER-positive disease. Similarly, hormonal IUD would be recommended from 13

oncologist in ER-negative disease compared to 8 in ER-positive disease.

Figure 2 Distribution of answers in Case II. Which contraceptive option would you recommend in ER-positive breast cancer; ER-ER-positive > 5 years from diagnosis; ER-negative breast cancer?

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3.4 Case III

Most of the oncologists would not recommend MHT either in patients with family history of breast cancer (69.4%) or in BRCA-mutation carriers who have not undergone prophylactic mastectomy (88.9%) (Figure 3). In BRCA-mutation carriers with prophylactic mastectomy, 50% of oncologists would recommend MHT.

Figure 3. Distribution of answers in Case III: Would you recommend menopausal hormone therapy in patients with family history of breast cancer, mutation carriers without mastectomy, BRCA-mutation carriers after mastectomy?

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3.5 Cases IVa-IVc

Hormone-free treatment was the treatment of choice for most of the oncologists in all three clinical scenarios (patients treated with aromatase-inhibitors, those treated with tamoxifen, those without adjuvant endocrine therapy) with 34, 33, and 34 positive answers, respectively followed by low-dose estriol containing treatment with 26, 31, and 25 positive answers, respectively (Figure 4). The number of oncologists that would recommend estriol- or

estradiol-containing treatment was higher for patients treated with tamoxifen (n=15 and n=7, respectively), or patients without adjuvant endocrine therapy (n=6 and n=3, respectively) compared to patients treated with aromatase-inhibitors (n=1 and n=0, respectively)(Figure 4).

Figure 4: Distribution of answers in cases IVa-IVc: Which local treatment strategy would you recommend against vaginal dryness in patients treated with aromatase-inhibitor, tamoxifen, or no adjuvant endocrine therapy?

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4 Discussion

Considering the lack of strong recommendations about the use of exogenous reproductive hormones in patients with prior breast cancer or BRCA-mutation carriers, how the oncologists implement the current evidence and recommendations in their clinical practice is an important aspect in understanding the pattern of prescribing practices in Sweden. Our study sought to capture the oncologists´ perception on the use of OHC, MHT, or local estrogen treatment in different clinical scenarios from daily clinical practice.

Regarding MHT after prior breast cancer, a unanimous approach was found because the vast majority of oncologist would not recommend MHT in patients with ER-positive breast cancer irrespectively the time since diagnosis. This approach is in line with the current evidence of an increased risk for breast cancer due to MHT after breast cancer in 2 of 3 available randomized trials [17, 18]and the subsequent recommendation from the Swedish National Guidelines for breast cancer [24]. However, the results about the use of MHT after ER-negative breast was less unanimous, which can reflect the lack of evidence in this breast cancer subtype.

The National Guidelines do not recommend hormonal contraceptives in women with a history of breast cancer, mainly based on the theoretical risk of hormonal contraceptives to influence prognosis rather than on a true evidence [24]. The oncologists´ approach to these cases were in line with the current guidelines since regardless of the time from diagnosis and ER- status, the vast majority opted for hormone-free contraceptives.

According to the National Guidelines, premenopausal women that are carriers of BRCA-mutations, and have undergone a risk reducing salpingo-oophorectomy can be offered MHT up to the age of 50 [24]. Despite this, when oncologists were faced with a case meeting the requirements for treatment, the vast majority seem not to recommend systemic MHT.

However, this prescribing pattern seems to be different in patients who undergo prophylactic mastectomy where MHT would be recommended from half of the oncologists.

Regarding local estrogen treatments, the National Guidelines do not recommend locally applied estradiol-containing treatment for breast cancer patients. In patients treated with aromatase inhibitors, the first choice according to the National Guidelines is hormone-free options, followed by low-dose estriol containing treatment. In patients treated with tamoxifen, the two above options are available along with the possibility to use estriol-containing

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in line with current recommendations for patients treated with aromatase-inhibitors or tamoxifen.

The study has several limitations that need to be discussed. First, the number of responders was relatively low which might impact the generalizability of prescription patterns. Since the number of respondents was low, individual answers could have had a bigger impact on the results. A bigger response rate might therefore have given a more accurate picture of how the general oncologist would have answered. However, we only included oncologists with special interest to breast cancer in order to capture the perceptions of oncologists who are working with breast cancer patients in daily clinical practice. In addition, no subgroup analyses based on oncologists´ characteristics was able due to the relatively low number of responders. Furthermore, our results are mostly a descriptive analysis of prescription patterns rather than a more detailed analysis on the reasons behind these patterns.

5 Conclusion

Our study investigated the prescription patterns of exogenous reproductive hormones after breast cancer or in BRCA-mutation carriers among oncologists. We found unanimous practices in some clinical scenarios where there is some evidence and more variable practice where the evidence is weak or completely absent. The presence of guidelines for some clinical scenarios seems to increase the common view among oncologists.

6 Acknowledgements

Ett varmt tack till handledare Antonios Valachis för stort tålamod och vägledning. Tack!

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7 List of references

1. Dhont M. History of oral contraception. Eur J Contracept Reprod Health Care. 2010 Dec;15 Suppl 2:S12-8. Available from: https://doi.org/10.3109/13625187.2010.513071

2. Liao PV, Dollin J. Half a century of the oral contraceptive pill: historical review and view to the future. Can Fam Physician. 2012 Dec;58(12):e757-60. Available from:

http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3520685/

3. Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol. 1999 Nov;181(5 Pt 1):1263-9. Available from: https://doi.org/10.1016/s0002-9378(99)70120-1

4. Christin-Maitre S. History of oral contraceptive drugs and their use worldwide. Best Pract Res Clin Endocrinol Metab. 2013 Feb;27(1):3-12. Available from:

https://doi.org/10.1016/j.beem.2012.11.004

5. S. Andersson. Skjuta myggor med elefantbössa [Internet]. RFSU 2017 [Citerad 2020-05-25]. Available from:

https://www.rfsu.se/sex-och-relationer/for-dig-som-undrar/preventivmedel/p-piller/p-pillrets-historia/

6. Contraceptive pill 1961 [Internet]. NHS Graduates [Citerad 2020-05-25]. Available from:

http://www.nhsgraduates.co.uk/about-the-nhs/history/1960s/contraceptive-pill-1961/

7. Kumle M, Weiderpass E, Braaten T, Persson I, Adami HO, Lund E. Use of oral

contraceptives and breast cancer risk: The Norwegian-Swedish Women's Lifestyle and Health Cohort Study. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1375-81. Available from: https://cebp.aacrjournals.org/content/11/11/1375.long

8. Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee AJ. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners' Oral Contraception Study. BMJ. 2010 Mar 11;340:c927. Available from:

https://doi.org/10.1136/bmj.c927

9. Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, et al. Hormonal contraception and risk of cancer. Hum Reprod Update. 2010 Nov-Dec;16(6):631-50. Available at: https://doi.org/10.1093/humupd/dmq022

10. Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013 Nov;22(11):1931-43. Available at: https://doi.org/10.1158/1055-9965.epi-13-0298

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11. Kohn GE, Rodriguez KM, Hotaling J. The History of Estrogen Therapy. Sexual Medicine Reviews Volume 7, Issue 3 July 2019 Pages 416- 421. Available at:

https://doi.org/10.1016/j.sxmr.2019.03.006

12. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med. 1975 Dec 4;293(23):1164-7. Available at:

https://doi.org/10.1056/nejm197512042932302

13. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med. 1975 Dec 4;293(23):1167-70. Available at:

https://doi.org/10.1056/nejm197512042932303

14. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. Available at: https://doi.org/10.1001/jama.288.3.321

15. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the

Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. Available at: https://doi.org/10.1001/jama.291.14.1701 16. Type and timing of menopausal hormone therapy and breast cancer risk: individual

participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 09 28;394(10204):1159-68. Available at:https://doi.org/10.1016/S0140-6736(19)31709-X 17. von Schoultz E, Rutqvist LE. Menopausal hormone therapy after breast cancer: the

Stockholm randomized trial. J Natl Cancer Inst. 2005 Apr 6;97(7):533-5. Available at:

https://doi.org/10.1093/jnci/dji071

18. Speroff L. The LIBERATE tibolone trial in breast cancer survivors. Maturitas. 2009 May 20;63(1):1-3. Available at: https://doi.org/10.1016/j.maturitas.2009.03.001

19. Marchetti C, De Felice F, Boccia S, Sassu C, Di Donato V, Perniola G, et al. Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta-analysis. Crit Rev Oncol Hematol. 2018 Dec;132:111-5. Available at:

https://doi.org/10.1016/j.critrevonc.2018.09.018

20. Narod SA, Dubé MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, et al. Oral

contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2002 Dec 4;94(23):1773-9. Available at:

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21. Vaz-Luis I, Partridge AH. Exogenous reproductive hormone use in breast cancer survivors and previvors. Nat Rev Clin Oncol. 2018 04;15(4):249-61. Available at:

https://doi.org/10.1038/nrclinonc.2017.207

22. Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric. 2003 Mar;6(1):45-52. Available at:

https://pubmed.ncbi.nlm.nih.gov/12725664/

23. Le Ray I, Dell'Aniello S, Bonnetain F, Azoulay L, Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study. Breast Cancer Res Treat. 2012 Sep;135(2):603-9. Available at:

https://doi.org/10.1007/s10549-012-2198-y

24. Nationellt vårdprogram bröstcancer; version 3.0 [Internet]. Regionala cancercentrum i samverkan 2020. [Citerad 2020-05-25]. Available from:

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8 Appendices

8.1 Questionnaire

Fall I:

Agda insjuknade med ER-positiv, HER2-negativ bröstcancer vid 50 års ålder. Hon blev opererad med bröstbevarande kirurgi och sentinel node biopsi och tumören visade sig vara pT2N0. Patienten fick postoperativ cytostatikabehandling, strål-behandling och därefter 5 års antihormonell strål-behandling. Fyra år efter bröstcancer-diagnos får patienter klimakterieliknande besvär och patienten önskar få prova en systemisk hormonell behandling mot sina postmenopausala besvär. Patienten är recidivfri.

Skulle du rekommendera systemisk hormonell behandling?

Ja

Sannolikt ja Sannolikt nej Nej

Vet ej

Om nej/ sannolikt nej; skulle du rekommendera systemisk hormonell behandling om Agda kommit till dig > 5 år efter bröstcancerdiagnos?

Ja / Sannolikt ja, om 5 – 9 år efter bröstcancerdiagnos Ja / Sannolikt ja, om 10 – 15 år efter bröstcancerdiagnos Ja / Sannolikt ja, om > 16 år efter bröstcancerdiagnos Sannolikt nej, oavsett tiden från bröstcancerdiagnos Nej, oavsett tiden från bröstcancerdiagnos

Vet ej.

Om patienten istället skulle ha haft en ER-negativ tumör, skulle du rekommendera henne systemisk hormonell behandling?

Ja

Vet ej

Fall II:

Berit insjuknade vid 32 års ålder i ER-positiv, HER2-negativ bröst-cancer. Hon blev opererad med bröstbevarande kirurgi och sentinel node biopsi (ej bevisad BRCA1 eller BRCA2 mutation). Tumören var pT1N0 och Berit fick postoperativ cytostatikabehandling, strålbehandling och antihormonell

behandling i 5 år. Hon söker nu, vid 35 års ålder, till din mottagning för råd om preventivmedel.

Vilket preventivmedel skulle du rekommendera? (mer än ett alternativ kan väljas)

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P-piller P-stav P-spruta P-ring P-plåster Minipiller Hormonspiral Kopparspiral

Annan hormonfri preventivmetod utöver kopparspiral (pärlspiral, pessar, kondom) Vet ej

Om patienten istället skulle ha haft en ER negativ tumör, vilket preventivmedel skulle du rekommendera? (mer än ett alternativ kan väljas)

Om patienten ställde frågan om preventiv medel > 5 år efter bröstcancerdiagnos (patienten är recidivfri), vilket preventivmedel skulle du rekommendera? (mer än ett alternativ kan väljas)

Fall III:

Carita är 48 år och frisk sedan tidigare. Hennes mor och mormor

drabbades båda av bröstcancer runt 50 års ålder. Genetisk utredning är genomfört utan att bevisa någon BRCA1 eller BRCA2 mutation. Har nu börjat uppleva postmenopausala problem som svettningar, sömnsvårigheter, torra slemhinnor och trötthet. Hon önskar nu systemisk hormonell behandling mot sina post-menopausala besvär.

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Ja

Vet ej

Om Carita hade en BRCA1 eller BRCA2 mutation och postmenopausala besvär till följd av profylaktisk salpingo-ooforektomi, men patienten är inte

profylaktiskt bilateralt mastektomerad, skulle du rekommendera systemisk hormonell behandling? Ja Sannolikt ja Sannolikt nej Nej Vet ej

Om nej/ sannolikt nej; skulle du rekommendera systemisk hormonell behandling om patienten var bilateralt mastektomerad i förebyggande syfte?

Ja

Vet ej

Fall IVa:

Denise blev opererad på grund av en ER-positiv bröstcancer för 2 år sedan och behandlas med aromatashämmare som adjuvant behandling. Hon besväras av torra slemhinnor och önskar nu behandling mot detta.

Vilken av följande skulle du välja att behandla henne med (mer än ett alternativ kan väljas):

Östradiol-innehållande preparat (Vagifem®) Östriol-innehållande preparat (Ovesterin®) Lågdos östriol-innehållande preparat (Blissel®)

Annat hormonfritt preparat (Replens®, Repadina®, Vagisan®) Vet ej

IVb:

Ellen blev också opererad på grund av en ER-positiv bröstcancer för 2 år sedan men hon behandlas med tamoxifem. Hon besväras också av torra

slemhinnor.

Östradiol-innehållande preparat (Vagifem®) Östriol-innehållande preparat (Ovesterin®)

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Lågdos östriol-innehållande preparat (Blissel®)

IVc:

Frideborg blev också opererad på grund av en ER-positiv bröstcancer för 2

år sedan och har ingen pågående adjuvant behandling. Hon besväras också av torra slemhinnor.

Östradiol-innehållande preparat (Vagifem®) Östriol-innehållande preparat (Ovesterin®) Lågdos östriol-innehållande preparat (Blissel®)