Biology of Young Breast Cancer and Management in Pregnant Women

19 th BSMO Annual Meeting 2017 Breast Cancer Task Force Biology of Young Breast Cancer and Management in Pregnant Women Matteo Lambertini, MD ESMO Fellow Institut Jules Bordet, Brussels Diegem, Belgium February 24, 2017

Disclosure Information Relationship Relevant to this Session Lambertini, Matteo: No relevant relationship to disclose.

Introduction Plan of the Talk Biology of breast cancer in young women Young age, pathological breast cancer subtypes and prognosis Young age, molecular breast cancer subtypes and genomic alterations Breast cancer and pregnancy Breast cancer during pregnancy Pregnancy after breast cancer Concluding remarks

Breast Cancer in Young Women: Epidemiology Considerations Female Brain cancer (all ages) 10,000/y Female Stomach cancer (all ages) 10,000/y Female Liver cancer (all ages) 11,500/y Female Soft tissue sarcoma (all ages) 5,500/y DeSantis CE et al, CA Cancer J Clin 2016;66:290-308. Siegel RL et al, CA Cancer J Clin 2017;67:7-30

Breast Cancer in Young Women: Epidemiology Considerations Ghiasvand R et al, BMC Cancer 2014;14:343

Breast Cancer in Young Women: Young Women Advocates Statement Fertility preservation and pregnancyrelated issues is one of the five priority areas of concern for young women with breast cancer

Breast Cancer in Young Women: Clinical Practice Guidelines Partridge AH et al, The Breast 2014;23:209-20. Paluch-Shimon S et al, The Breast 2016;26:87-99

Pathological Features and Prognosis N=243,012 (Year 1988 2003) < 40 (n=15,548) 40 (n=227,464) P-value T > 2cm 49.5% 35.5% <0.0001 Node-positive 39.2% 25.2% <0.0001 ER-negative 28.0% 14.2% <0.0001 PgR-negative 30.1% 20.4% <0.0001 Grade 3 42.6% 25.9% <0.0001 Gnerlich JL et al, J Am Coll Surg 2009; 208:341-7

Pathological BC Subtype and Prognosis Higher incidence of TNBC and HER2-positive subtypes in young patients Azim HA et al, Breast Cancer Res 2014; 16:427

Pathological Features and Prognosis Young age as an independent factor associated with higher risk of disease relapse and death despite more aggressive treatments Increased risk of survival events Azim HA et al, Breast Cancer Res 2014; 16:427

Pathological BC Subtype and Prognosis Young patients have greater breast cancer mortality The effect of age on survival varies by breast cancer subtype: young age is particularly prognostic in women with luminal disease Breast cancer subtype Results in young patients Luminal A HR, 1.7; 95% CI, 1.1 2.7 Luminal B HR, 1.2; 95% CI, 0.9 1.7 HER2-positive HR, 1.1; 95% CI, 0.7 1.7 Triple negative HR, 1.3; 95% CI, 0.9 1.7 Partridge AH et al, J Clin Oncol 2016; 34:3308-14

Luminal BC Subtype and Prognosis Some young patients with luminal disease do have good outcomes SOFT Study No Chemotherapy TEXT Study No Chemotherapy Francis PA et al, N Engl J Med 2015;372:436-46. Pagani O et al, N Engl J Med 2014;371:107-18

Luminal BC Subtype and Prognosis 1 Increased risk of non-adherence 2 Importance of OFS in higher-risk patients Huiart L et al, Eur J Cancer 2012;48:1939-46. Burstein HJ et al, J Clin Oncol 2016;34:1689-701

Luminal BC Subtype and Prognosis 3 Young patients with luminal disease remain at increased risk of late relapse Slide 15 Pan H et al, ASCO 2016

Luminal BC Subtype and Prognosis 3 Premenopausal patients may derive greater benefit from extended adjuvant endocrine therapy Goss PE et al, Ann Oncol 2013;24:355-61

Molecular BC Subtype and Prognosis Higher incidence of basal-like and HER2-enriched tumors in young patients Azim HA et al, Breast Cancer Res 2014; 16:427

Molecular BC Subtype and Prognosis The effect of age on survival varies by breast cancer subtype: young age remains particularly prognostic in women with luminal disease Azim HA et al, Clin Cancer Res 2012; 18:1341-51

Molecular Profiling of BC Gene-Expression Differences in Young Patients Enrichment of biological processes related to immature mammary cell population Higher expression of signatures related to endocrine resistance RANKL expression Mammary Stem cells Young patients Young patients Azim HA et al, Clin Cancer Res 2012; 18:1341-51. Azim HA et al, BMC Med 2015; 13:266

Genomic Alterations Somatic Mutations Azim HA et al, BMC Med 2015; 13:266

Genomic Alterations Somatic Mutations GATA3 mutations.. Affect ER binding to DNA Modulate response of BC cells to estrogen signaling Promote tumor growth Associated with endocrine resistance Potential biologic reason of poorer prognosis of ER+ BC in young patients?? Courtesy of Azim HA Gaynor K et al, Horm Cancer 2013;4:123-39. Adomas AB et al, BMC Cancer 2014;14:278

Genomic Alterations Germline Mutations Tung N et al, J Clin Oncol 2016;34:1460-8

Genomic Alterations Germline Mutations 16 Eccles D et al, SABCS 2016;S2-3

Can Current Knowledge of Biology Translate in New Therapeutic Options for Young Patients? Target Rationale Agent RANKL GATA3 Stem cells / luminal progenitors BRCA COX-2 Courtesy of Azim HA High expression Modulation by pregnancy High prevalence in young Poor outcome of ER+ in young Involved in endocrine resistance High content in tumors arising at young age High mutation rates in young patients Implicated in post-pregnancy progression of cancer Denosumab (NCT01864798) Denosumab (ACTRN12614000694617)?? Notch inhibitors?? Platinum salts (in clinical practice) PARPi (NCT02032823) Cox-2 inhibitors (NCT01881048)

Breast Cancer During Pregnancy: Clinical Practice Guidelines Loibl S et al, Cancer 2006;106:237-46. Amant F et al, Eur J Cancer 2010;46:3158-68. Loibl S et al, JAMA Oncol 2015;1:1145-53

Breast Cancer During Pregnancy: Epidemiological Considerations Breast cancer is one of the most frequently diagnosed malignancy during pregnancy Rare conditions: overall incidence of 2.4-7.3 per 100,000 pregnancies Trend in mother s age at birth Trend in BC in young women Trend in BC during pregnancy Increased awareness needed! Mathews TJ et al, NCHS 2016;(232):1-8. Merlo FD et al, BCRT 2012;134:363-70. Loibl S et al, JAMA Oncol 2015;1:1145-53

Breast Cancer During Pregnancy: Biology and Prognosis BCP or BC < 5 years post-partum More aggressive pathological features and biology? More advanced stage at diagnosis? Sub-optimal treatments during pregnancy? BC < 5 years postpartum only BCP only Better OS with pregnancy Worse OS with pregnancy Hartman EK et al, Breast Cancer Res Treat 2016;160:347-60

Breast Cancer During Pregnancy: Biology and Prognosis No differences in the distribution of breast cancer subtypes Pregnant BC Patients Non-pregnant BC Patients Azim HA et al, Endocr Relat Cancer 2014;21:545-54

Breast Cancer During Pregnancy: Biology and Prognosis More advanced stage at diagnosis in women with BCP than nonpregnant patients but similar survival outcomes Amant F et al, J Clin Oncol 2013;31:2532-9

Breast Cancer During Pregnancy: Biology and Prognosis No differences in the survival outcomes between patients with BCP treated with FAC chemotherapy during pregnancy and matched control patients Disease-free survival Overall survival Litton JK et al, The Oncologist 2013;18:369-76

Breast Cancer During Pregnancy: Clinical Management Trimester of pregnancy at the time of diagnosis is the main issue! Loibl S et al, JAMA Oncol 2015;1:1145-1153

Breast Cancer During Pregnancy: Clinical Management First-Trimester Second/Third-Trimesters Amant F et al, Lancet 2012;379:570-9

Breast Cancer During Pregnancy: Systemic Therapy - Chemotherapy Anthracyclines can be safely administered after the 1 st trimester of pregnancy No. of patients receiving anthracyline Type of anthracyline regimen used Gestational age at starting CT (months) Gestational age at delivery (months) Cardonick et al. (2010) Loibl et al. (2012) Murthy et al. (2014) 103 178 81 AC, FAC, EC, FEC, anthracycline followed by taxanes A alone or E alone, AC or EC, FAC or FEC, anthracycline CMF, anthracycline taxanes 20.4 24 - FAC 35.8 37 37 Spontaneous abortion 5% 1% - Malformations 4% 4% 4% Lambertini M et al, Expert Opin Drug Safety 2015;14:1395-408

Breast Cancer During Pregnancy: Systemic Therapy - Chemotherapy Taxanes can be safely administered after the 1 st trimester of pregnancy Taxanes during pregnancy Number - Breast cancer - Other - Paclitaxel - Docetaxel - Both Neonatal outcome - Mean gestational age at delivery - Foetal weight - Early preterm delivery - Foetal complications - Foetal malformations 55 39 16 33 19 3 Week 36 2400 g 1 (2%) Anaemia (n=1), neutropenia (n=1) Pyloric stenosis (n=1) Zagouri F et al, Clin Breast Cancer 2013;13:16-23. Loibl S et al, Lancet Oncol 2012;13:887-96

Breast Cancer During Pregnancy: Systemic Therapy - Chemotherapy Loibl S et al, JAMA Oncol 2015;1:1145-1153

Breast Cancer During Pregnancy: Systemic Therapy - Chemotherapy General rules to administer chemotherapy Use standard protocol Dose according to actual body weight Maintain dose-intensity Do not increase/decrease the dose Discontinue chemotherapy at week 35-37 of gestation Loibl S et al, JAMA Oncol 2015;1:1145-1153

Breast Cancer During Pregnancy: Systemic Therapy Timing of Chemotherapy 100% In patients diagnosed in the early third trimester of pregnancy (weeks 28-33), preterm delivery in order to start anticancer treatments in the post-partum period is the preferred option 80% 60% 40% 20% 0% 57% 15% 28% Disagree Neutral Agree Lambertini M et al, in preparation

Breast Cancer During Pregnancy: Systemic Therapy Outcomes of Children 96 exposed to chemotherapy Amant F et al, N Engl J Med 2015;373:1824-34

Breast Cancer During Pregnancy: Systemic Therapy Outcomes of Children Prematurity is more important than chemotherapy exposure for the cognitive development of children Cognitive outcome and gestational age Cognitive outcome and chemotherapy Amant F et al, N Engl J Med 2015;373:1824-34

Breast Cancer During Pregnancy: Systemic Therapy Outcomes of Children No difference in cognitive outcomes according to type of chemotherapy Amant F et al, N Engl J Med 2015;373:1824-34

Breast Cancer During Pregnancy: Systemic Therapy Outcomes of Children No difference in cardiac structure and functioning Amant F et al, N Engl J Med 2015;373:1824-34

Breast Cancer During Pregnancy: Systemic Therapy Fetal and Obstetric Care Increased risk of fetal/obstetric/birth complications No. of patients (No. with breast cancer) van Calsteren et al. (2010) 62 (34) Cardonick et al. (2010) 104 (104) Loibl et al. (2012) 179 (179) Fetal weight below 10 th percentile (CT vs no CT) 22% vs. 11% 7.5% vs. 0% 9% vs. 4% Obstetric complications (CT vs no CT) 27% vs. 9% 22% vs. NR 17% vs. 9% Fetal complications at birth (CT vs no CT) 11% vs. 5% 11% vs. 16% 15% vs. 4% Lambertini M et al, Expert Opin Drug Safety 2015;14:1395-408

Breast Cancer During Pregnancy: Systemic Therapy Fetal and Obstetric Care General Recommendations: Chemotherapy is generally safe beyond the first trimester of gestation. However, increased rates of premature delivery and growth retardation have been reported. Pregnancies where the fetus has been exposed to chemotherapy starting in the second trimester should be regarded as high-risk and regular fetal monitoring during gestation should be considered. Full-term delivery (i.e. 37 weeks) should be targeted whenever possible. Early or very early delivery should be discouraged, unless maternal and/or fetal health are endangered by the postponement of delivery until term. Peccatori FA et al, Ann Oncol 2013;24:v160-70

Breast Cancer During Pregnancy: Systemic Therapy Targeted agents Opposite considerations for targeted agents and chemotherapy Lambertini M et al, Cancer Treat Rev 2015;41:301-9

Breast Cancer During Pregnancy: Systemic Therapy Targeted agents Anti-HER2 and endocrine treatments are contraindicated during pregnancy Loibl S et al, JAMA Oncol 2015;1:1145-1153

Breast Cancer During Pregnancy: Systemic Therapy Supportive Treatments Loibl S et al, JAMA Oncol 2015;1:1145-1153

Pregnancy after Breast Cancer Who Cares? Only 3-7% manage to become subsequently pregnant Letourneau JM et al, Cancer 2012;118:1710-7. Litton JK et al, Curr Treat Options Oncol 2012;13:137-45

Pregnancy after Cancer Breast cancer patients have the lowest chances among cancer survivors to become subsequently pregnant! Analysis adjusted for: -education level -previous pregnancy -age 70% lower chance of pregnancy compared to general population Peccatori F et al, Ann Oncol 2013;24:vi160-70

Inform the Patients about the Risk of Infertility: Early Referral ESMO GUIDELINES 2013 ASCO GUIDELINES 2013 Loren AW et al, J Clin Oncol 2013;31:2500-10. Peccatori F et al, Ann Oncol 2013;24:vi160-70.

Pregnancy after Breast Cancer Is It Safe? 100% A pregnancy in breast cancer survivors may increase the risk of recurrence 80% 60% 40% 20% 0% 71% 17% 12% Disagree Neutral Agree Lambertini M et al, in preparation

Pregnancy after Breast Cancer Is It Safe? Better OS with pregnancy Worse OS with pregnancy Azim HA Jr et al, Eur J Cancer 2011;47:74-83

Pregnancy after Breast Cancer Is It Safe in ER+ Patients? Azim HA Jr et al, J Clin Oncol 2013;31:73-9

Pregnancy after Breast Cancer Is It Safe? Lambertini M et al, BMC Med 2016;14:1

Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine resposive breast cancer (POSITIVE) Target accrual: 514 patients Pagani O et al, Breast 2015;24:201-7

Take Home Messages (1/2) Age per se should not be considered a reason to administer more aggressive therapies Breast cancer arising in young women is biologically distinct beyond differences in breast cancer subtypes Specific attention should be paid in the management of young patients with luminal disease The investigation of tailored therapeutic strategies is warranted given their unique biology

Take Home Messages (2/2) Breast cancer during pregnancy should be managed in center with the adequate expertise The goal of treatments is to achieve full-term delivery Following available guidelines, the treatment of breast cancer during pregnancy is safe for both the mother and the baby Pregnancy after breast cancer can be considered safe also in patients with ER+ disease