Breast Cancer and Pregnancy

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1 Breast Cancer and Pregnancy F. Cardoso, MD Director, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal ESO Breast Cancer Program Coordinator ESMO Board of Directors & NR Committee Chair EORTC Breast Group Past-Chair

2 DISCLOSURES SLIDE Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva. Institutional financial support for clinical trials from: Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi, Eisai, Fresenius GmbH, Genentech, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Tigris, Wilex, Wyeth. Non-Financial disclosures: Chair ABC Global Alliance and ABC Consensus Conference and Guidelines. Member/Committee Member of ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC

3 3 ISSUES TO DISCUSS: Fertility preservation Pregnancy after breast cancer Breast cancer during pregnancy

4 3 ISSUES TO DISCUSS: Fertility preservation Pregnancy after breast cancer Breast cancer during pregnancy

5 FERTILITY PRESERVATION All young women should be counseled about the risks and associated symptoms and outcomes of treatment-related amenorrhea and premature menopause before the onset of systemic therapy (either CT or ET) and referred for special counseling/consultation if interested in fertility preservation. TAKE HOME MESSAGE Do not forget to discuss fertility issues BEFORE starting the planned treatment

Pregnancy rate after cancer: not all alike Thyroid cancer Melanoma Non-Hodgkin's lymphoma Hodgkin's lymphoma All cancers Brain tumors Analysis adjusted for education level, previous pregnancy age

6 Pregnancy rate after cancer: not all alike Thyroid cancer Melanoma Non-Hodgkin's lymphoma Hodgkin's lymphoma All cancers Brain tumors Analysis adjusted for education level, previous pregnancy age Germ cell tumors Acute leukemia Cervical cancer Epithelial ovarian cancer Breast cancer % of young patients with breast cancer have a pregnancy Stensheim et al; Int J Cancer 2011 Courtesy F. Peccatori

TAKE HOME MESSAGES Inform the patient about the

endocrinologist asap Consider egg/embryo freezing

chemotherapy Offer participation in clinical

7 TAKE HOME MESSAGES Inform the patient about the risk of infertility Refer her to the reproductive endocrinologist asap Consider egg/embryo freezing before chemotherapy Consider LHRHa during chemotherapy Offer participation in clinical trials Consider adapting CT regimens Adapted from F. Peccatori

8 Neo/adjuvant systemic treatment No age-specific neo/adjuvant CT regimen regarding efficacy and longterm tolerance is currently known. As for all stage I-III breast cancer patients, the preferred regimens are standard anthracycline, alkylating, and taxane based regimens. It is however possible to SPARE ALKYLATING AGENTS in many cases (specially non-tnbc)

9 Neoadjuvant systemic treatment In patients with TNBC or BRCA-associated tumors the incorporation of platinum agents increases pcr rates and may be considered when neoadjuvant chemotherapy is indicated. Data on the impact of incremental increases in pcr on long term outcome are not conclusive. (LoE: 2A) (77%) The use of platinum has potential additional impact on fertility and increased toxicity that may compromise standard duration and dosing of standard systemic treatment, and this needs to be clearly communicated to patients.

10 Consider LHRHa during chemo Lambertini et 2015, Annals of Oncology

11 Consider LHRHa during chemo Lambertini et 2015, Annals of Oncology

12 Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropinreleasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients Matteo Lambertini 1, Halle C.F. Moore 2, Robert C.F. Leonard 3, Sibylle Loibl 4, Pamela Munster 5, Marco Bruzzone 6, Luca Boni 7, Joseph M. Unger 8, Richard A. Anderson 9, Keyur Mehta 4, Susan Minton 10, Francesca Poggio 6, Kathy S. Albain 11, Douglas J.A. Adamson 12, Bernd Gerber 13, Amy Cripps 14, Gianfilippo Bertelli 15, Sabine Seiler 4, Marcello Ceppi 6, Ann H. Partridge 16, and Lucia Del Mastro 6 Abstract GS4-01 Presented at San Antonio Breast Cancer Symposium, December 5-9, Slides are used with the permission of Dr Matteo Lambertini

Definition of premature ovarian insufficiency (POI) PROMISE- GIM6 1,2 No resumption of menstrual activity and postmenopausal levels of FSH and E2 POEMS/SWOG Moffitt-led trial 4 GBG-37 ZORO 5 Anglo

periods within 21 to 35 days Amenorrhea with elevated FSH Timing of POI after chemotherapy 12 months 24 months 24 months 6 months Between 12 and 24 months Sample size 281 257 48 60 227 ER status for

13 Definition of premature ovarian insufficiency (POI) PROMISE- GIM6 1,2 No resumption of menstrual activity and postmenopausal levels of FSH and E2 POEMS/SWOG Moffitt-led trial 4 GBG-37 ZORO 5 Anglo Celtic S Group OPTION 6 Amenorrhea for the prior 6 months and postmenopausal levels of FSH No maintenance of menses and no resumption of menses No reappearance of two consecutive menstrual periods within 21 to 35 days Amenorrhea with elevated FSH Timing of POI after chemotherapy 12 months 24 months 24 months 6 months Between 12 and 24 months Sample size ER status for eligibility Upper age limit for eligibility ER-positive and ER-negative ER-negative only ER-positive and ER-negative ER-negative only ER-positive and ER-negative 45 years 49 years 44 years 45 years None Type of GnRHa Triptorelin Goserelin Triptorelin Goserelin Goserelin Del Mastro L et al, JAMA 2011;306: Lambertini M et al, JAMA 2015;314: Moore HCF et al, N Engl J Med 2015;372: Munster P et al, J Clin Oncol 2012;30: Gerber B et al, J Clin Oncol 2011;29: Leonard RCF et al, Ann Oncol 2017;28:

Premature-Ovarian Insufficiency Rate 50% 40% OR* 0.38 (95% CI 0.26 0.57) P<.001 14.1% 30.

14 Premature-Ovarian Insufficiency Rate 50% 40% OR* 0.38 (95% CI ) P< % 30.9% Meta-analysis approach 30% 20% 10% 0% GnRHa Group n = 363 Control Group n = 359 *Odds ratio (OR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.

15 Post-Treatment Pregnancy Rate GnRHa Group: 37/359 (10.3%) vs Control Group: 20/367 (5.5%) Meta-analysis approach IRR* 1.83 (95% CI ) P =.030 Age distribution, years Estrogen receptor status Positive Negative GnRHa Group n = 37 Number (%) 37 (100) 0 (0.0) 6 (16.2) 31 (83.8) Control Group n = 20 Number (%) 20 (100) 0 (0.0) 2 (10.0) 18 (90.0) IRR, Incidence rate ratio Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.

16 Disease-Free Survival/Overall Survival Median follow-up = 5.0 years (IQR, years) Disease-Free Survival, % HR* 1.01 (95% CI ) P =.999 Overall Survival, % HR* 0.67 (95% CI ) P =.083 Time Since Random Assignment, Years Time Since Random Assignment, Years *Hazard ratio adjusted for age, estrogen receptor status, type and duration of chemotherapy administered and tumor stage IQR, interquartile range Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.

17 3 ISSUES TO DISCUSS: Fertility preservation Pregnancy after breast cancer Breast cancer during pregnancy

18 TAKE HOME MESSAGE IS PREGNANCY AFTER BREAST CANCER SAFE? YES Same risk of recurrence and death Even in hormone-dependent tumors

19 Pregnancy after Breast Cancer Meta-analysis Differences in DFS between the pregnant group and matched non-pregnant group Healthy mother effect Azim H A et al. JCO 2013;31:73-79

20 SUPPORTIVE CARE PREGNANCY AFTER BREAST CANCER Pregnancy after breast cancer should not be discouraged even in patients with HR positive disease, although all available data have limitations. Prospective data from a global clinical trial are being collected (POSITIVE Trial).

Screening/eligibility: Patients with ER+ early breast cancer 18 and 42 years at enrollment Completing 18-30 months of ET (SERMs alone, GnRH analogue + SERM or AIs) 1

complete 5 (-10) yrs Follow-up Pregnancy desire 1 + CT 2 No more than 1 month prior enroll.

21 Screening/eligibility: Patients with ER+ early breast cancer 18 and 42 years at enrollment Completing months of ET (SERMs alone, GnRH analogue + SERM or AIs) 1 Stop ET 2 E N R O L L M E N T 3 months wash out POSITIVE STUDY The Baby Trial Up to 2 years break to allow conception, delivery ± breast feeding ET resumption to complete 5 (-10) yrs Follow-up Pregnancy desire 1 + CT 2 No more than 1 month prior enroll mos 10 yrs Ovarian function evaluation Translational research Uterine evaluation Circulating tumor DNA (ctdna) Genomic evaluation of primary breast tumor Psycho-oncology companion psychological distress, fertility concerns, decisional conflict

22 Open questions PREGNANCY AFTER BREAST CANCER What is the ideal interval between ET interruption and pregnancy? When is it considered safe to interrupt ET? What is the impact of different ETs in fertility? Tamoxifen, Aromatase Inhibitor Ovarian Function Suppression

23 ADVANCED BREAST CANCER (ABC) (i.e. metastatic disease diagnosed before the age of 40) Is pregnancy always out of the question in advanced breast cancer?

24 3 ISSUES TO DISCUSS: Fertility preservation Pregnancy after breast cancer Breast cancer during pregnancy

25 BREAST CANCER DIAGNOSED DURING PREGNANCY Epidemiology - 1/100 cancers in reproductive age are diagnosed during pregnancy - 1/1000 pregnancies are complicated with cancer de Haan J et al, Lancet Oncol 2018 Courtesy F. Peccatori

26 EPIDEMIOLOGY 1/3.000 pregnancies, 5-10% breast cancer < 40 y/o Berry DL et al, JCO 1999 Courtesy F. Peccatori

27 Possible causes: Increasing age at pregnancy Courtesy F. Peccatori

28 Possible causes: Increasing incidence of breast cancer in young women Courtesy F. Peccatori

29 Matching variables (1 case: 2 controls) Age (±2 years) Year of surgery (±2 years) pt (1a vs. 1b vs. 1c vs. 2 vs. 3 vs. X) # of positive nodes (0 vs. 1-3 vs. 4-9 vs. 10+) Neoadjuvant chemotherapy (Yes vs. No) Azim HA Jr et al; Acta Oncol 2012

30 Clinical characteristics Age (years) Year of Surgery pt pn < Pregnant Cases N = (30.8) 33 (50.8) 12 (18.5) Controls N = (31.5) 61 (46.9) 28 (21.5) Median 36 (28-47) 36 (28-47) a-b 1c 2 3 X pn0 pn1 pn2 pn3 pnx 16 (24.6) 20 (30.8) 16 (24.6) 13 (20.0) 37 (28.5) 35 (26.9) 36 (27.7) 22 (16.9) Median (7.6) 21 (32.3) 31 (47.7) 6 (9.2) 2 (3.1) 28 (43.1) 19 (29.2) 10 (15.4) 6 (9.2) 2 (3.1) 10 (7.6) 42 (32.3) 62 (47.7) 12 (9.2) 4 (3.1) 56 (43.1) 38 (29.2) 20 (15.4) 12 (9.2) 4 (3.1) Azim HA Jr et al; Acta Oncol 2012 Courtesy F. Peccatori

31 Biological characteristics: no major differences Pregnant Cases N = 65 Controls N = = 130 p Estrogen Receptor Present Absent 43 (66.1) 22 (33.9) 98 (75.4) 32 (24.6) Progesteron Receptor Present Absent 42 (64.6) 23 (35.4) 87 (66.9) 43 (33.1) Grade (7.5) 18 (34.0) 31 (58.5) 4 (3.6) 43 (39.1) 63 (57.3) Ki-67 % < (28.6) 45 (71.4) 30 (23.4) 98 (76.6) Her2/neu Negative Positive 54 (83.1) 11 (16.9) 103 (81.1) 24 (18.9) Perivascular Invasion Absent Present 31 (47.7) 34 (52.3) 70 (55.1) 57 (44.9) Molecular subtypes Luminal A Luminal B Her2/Neu Triple Negative 8 (12.3) 37 (56.9) 6 (9.2) 14 (21.5) 13 (10.3) 82 (65.1) 4 (3.2) 27 (21.4) Azim HA Jr et al; Acta Oncol 2012 Courtesy F. Peccatori

32 Molecular subtypes (IHC): similar distribution Basal Luminal-A Luminal-B HER2 Chi-square: p=0.68 Azim HA Jr et al; Acta Oncol 2012 Courtesy F. Peccatori

33 TILS 50% Pregnant: 2/86 patients (2.3%) Non-pregnant: 11/116 (9.6%), p<0.001 Courtesy F. Peccatori

34 Managing Breast Cancer during Pregnancy TAKE HOME MESSAGE TREATMENT MUST BE PERFORMED IN A SPECIALISED CENTER BY AN EXPERIENT MULTIDISCIPLINARY TEAM!

35 BREAST CANCER DURING PREGNANCY FIRST QUESTION: TO CONTINUE OR TO STOP THE PREGNANCY? Only when diagnosis happens very early (first trimester) this hypothesis needs consideration However, this is always a parents decision (independently of the time of pregnancy) NO IMPACT ON PROGNOSIS

36 BREAST CANCER DURING PREGNANCY 1 st QUESTION: To Continue or To Stop the Pregnancy? INTERRUPTING THE PREGANCY DOESN T ADD ANY BENEFIT TO THE MOTHER Azim HA Jr et al; Acta Oncol 2012 TAKE HOME MESSAGE DO NOT advise the patient that she must terminate pregnancy!

37 BREAST CANCER DURING PREGNANCY If the decision is to continue pregnancy: TAKE HOME MESSAGE AVOID PREMATURE DELIVERY! TAKE HOME MESSAGE TREAT AS YOU WOULD IN A NON-PREGNANT CASE (only few exceptions: ET, anti-her2)

38 BREAST CANCER DURING PREGNANCY Which type of exams can you perform during pregnancy? Breast Chest Safe Ultrasound Mammogram X-rays, Low dose CT scan (first trimester) DW-MRI* Not safe MRI with gadolinium X-rays, CT scan (beyond first trimester) Abdomen Ultrasound /DW-MRI* CT scan Bone DW-MRI* Bone scan Brain DW-MRI* Whole body DW-MRI* PET scan * Without gadolinium Courtesy F. Peccatori Note: EVERYTHING THAT IS NOT INDISPENSIBLE, POSTPONE!

40 BREAST CANCER DURING PREGNANCY Which type of treatments are possible during pregnancy? SURGERY: YES CHEMOTHERAPY: YES RADIOTHERAPY: Yes, with protection but preferable after delivery Hormonal and biological treatments: NO

41 BREAST CANCER DURING PREGNANCY SURGERY Breast Conservative Surgery is possible and preferable. Identical indications as in non-pregnant women. Sentinel node biopsy is feasible but without using blue dye. Radioisotope dosing should be the minimum possible.

42 SURGERY No difference in the surgical approach of breast cancer during pregnancy, but: - careful anesthesiological evaluation - fetal monitoring, when appropriate Picture courtesy of Prof F Amant Courtesy F. Peccatori

Sentinel lymph node during pregnancy is safe Number 145 Age 35 (28 45) Technique -99m TC albumin nanocolloid only -Blue dye only -Combined -Unknown 96 (66%) 14 (10%) 15 (10%) 20 (14%) Successful

43 Sentinel lymph node during pregnancy is safe Number 145 Age 35 (28 45) Technique -99m TC albumin nanocolloid only -Blue dye only -Combined -Unknown 96 (66%) 14 (10%) 15 (10%) 20 (14%) Successful mapping 144 (99%) Mean number of SLN 3.2 Positive SLN 43 (30%) Loco regional events at median FU: 48m Neonatal adverse events 11 (7%) (only 1 case of axillary recurrence) NONE Courtesy F. Peccatori

44 Breast reconstruction during pregnancy is safe

45 RADIOTHERAPY BREAST CANCER DURING PREGNANCY Usually contra-indicated Associated to serious adverse impact on the fetus Wait until after delivery (no problem with the needed time)

46 BREAST CANCER DURING PREGNANCY SYSTEMIC TREATMENTS: crucial importance of GESTACIONAL AGE 1st TRIMESTER Risk of malformations is 20% Cardonick E & Iacobucci; Lancet Oncol 2004

47 CHEMOTHERAPY DURING PREGNANCY The placenta Courtesy F. Peccatori

4 ± 0.8 Docetaxel 9 0 0 Cyclophosphamide 4 3 25.1 ± 6.3 Carboplatin 7 7 57.5 ± 14.

48 Maternal/fetal transfer of chemotherapy (apes) Number Drug detected in fetus (n) % drug detected in fetus Doxorubicin ± 3.2 Epirubicin ± 1.6 Paclitaxel ± 0.8 Docetaxel Cyclophosphamide ± 6.3 Carboplatin ± 14.2 DOXORUBICIN EPIRUBICIN Kristel van Calsteren et al; Gynecol Oncol 2011 Courtesy F. Peccatori

49 BREAST CANCER DURING PREGNANCY CHEMOTHERAPY RECOMMENDATIONS MDT team (including also obstetrics and neonatology) Treat as similar as possible to a non pregnant patient Prefer sequential CT (less toxic, identical efficacy) e.g. Epirubicin followed by weekly Paclitaxel Dosing according to real weight (not excluding the baby) Support measures (ex: antiemetics yes; growth factors no) Pregnancy Surveillance: Ultrasound after each cycle of CT

50 Chemotherapy effects on pregnancy and fetus Loibl et al; Lancet Oncol 2012

51 Chemotherapy effects on newborns Loibl et al; Lancet Oncol 2012

52 CHILD LONG TERM EFFECTS Lancet Oncol 2012; 13: Fetal exposure to chemotherapy was not associated with increased CNS morbidity.compared with the general population.

53 CHILD LONG TERM EFFECTS MAIN MESSAGE: AVOID PREMATURE DELIVERY! Long term cognitive function is related with date of delivery but not with the number of CT cycles Each additional pregnancy month is associated to a rise of 11.6 points in the Intelligence Coefficient Scale

54 Anthracycline (N=328), Taxanes (N=84), Platinum (N=74) No impact on short-term fetal mortality

55 Peccatori FA, Corrado G, Fumagalli M. Nat Rev Clin Oncol 2015

56 BREAST CANCER DURING PREGNANCY SYSTEMIC TREATMENT: HORMONAL THERAPY NO! HIGH RISK OF MALFORMATIONS! SYSTEMIC TREATMENT: TRASTUZUMAB NO! HIGH RISK OF MALFORMATIONS! (anidramnios) Specially in the 2nd e 3rd trimester (different from other drugs)

57 MOTHER PROGNOSIS (Young women!)

58 Prognosis (DFS & OS) DFS OS p-value: p-value: Pregnant cases (n=65) Controls (n=120) Median follow up: 51 months Azim HA Jr et al; Acta Oncol 2012 Courtesy F. Peccatori

59 NEED FOR MORE INFORMATION: EUROPEAN REGISTRIES Registry for breast cancer during pregnancy GBG-29 BIG www. germanbreastgroup.de/pregnancy With support of the BANSS-Foundation

60 BREAST CANCER DURING PREGNANCY: CONCLUSIONS Courtesy F. Peccatori

Dear doctor, what about a baby? Myths and facts

Dear doctor, what about a baby? Myths and facts OLIVIA PAGANI BREAST UNIT AND INSTITUTE OF ONCOLOGY OF SOUTHERN SWITZERLAND IBCSG Background About 15% of patients with BC are diagnosed during their reproductive