La personalizzazione terapeutica: quanto influisce l età

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1 La personalizzazione terapeutica: quanto influisce l età PierFranco Conte University of Padova Department of Surgery, Oncology and Gastroenterology IOV Istituto Oncologico Veneto I.R.C.C.S.

2 Breast Cancer in Young Women - Outline Epidemiology Biology of breast cancer in young patients Implications for local treatment Adjuvant therapy in young women: - Efficacy - Tolerability - Needs

3 Nuovi casi di tumore maligno stimati in Veneto nel Distribuzione per fasce di età e sesso Dati registro tumori Veneto

4 I tumori più frequenti in età anni. Femmine. Casi annui stimati in Veneto nel 2014 e % sul tot. tumori anni. SEDE Casi/anno tot tumori % Mammella % Cute melanomi % Tiroide % Utero % Linfoma di Hodgkin % Totale (eccetto cute non melanoma) % Dati registro tumori Veneto

5 Trend di incidenza Le sedi più frequenti nelle femmine. Età anni Dati registro tumori Veneto

6 Sopravvivenza relativa dei casi di tumore in età anni. Casi incidenti nel periodo Le sedi più frequenti nelle femmine Dati registro tumori Veneto

7 Breast Cancer in Young Women - Outline Epidemiology Biology of breast cancer in young patients Implications for local treatment Adjuvant therapy in young women: - Efficacy - Tolerability - Needs

8 Proportion of breast cancer subtypes among California women by age group, BC patients diagnosed Data from the California Cancer Registry: n=112,256 (5,605 aged 15-39, 19,776 aged 40-49, and 86,875 older than 50). HR-/HER2+ HR+/HER2+ TN HR+/HER2- Keegan et al, Breast Cancer Research 2012

9 Disease Free Survival by age Anders C. K. Et al. JCO 2008

10 Reasons for worse outcome for young breast cancer patients - diagnostic delay (no screening) - association with aggressive features - POSH Prospective observational study of BC pts <40yrs: n=2956, ductal histology 86.5%, G III 58.9%, N+ 50.2% - enrichment with aggressive subtypes - More TN and HER2+ - different tumor biology in young vs older? Keegan et al, Breast Cancer Research 2012

11 Breast Cancer in Young Women - Outline Epidemiology Biology of breast cancer in young patients Implications for local treatment Adjuvant therapy in young women: - Efficacy - Tolerability - Needs

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13 Young BC patients have a higher risk of local relapse

14 Benefit from post-mastectomy RT 3131 pn+ pts with mastectomy + AND Any first recurrence (yrs 0-9) BC mortality <40yrs 40-49yrs 50-59yrs +60yrs <40yrs 40-49yrs 50-59yrs +60yrs 1314 pn1-3 pts with mastectomy + AND Any first recurrence (yrs 0-9) BC mortality <40yrs 40-49yrs 50-59yrs +60yrs <40yrs 40-49yrs 50-59yrs +60yrs EBCTCG, Lancet 2014

15 Breast Cancer in Young Women: implications for local treatment Young age, although correlated to a higher risk of local relapse, is not a contraindication to BCS Relevance of clear margins Benefit from post-mastectomy RT in N1-3 positive nodes Genetic factors influence treatment decision

16 Breast Cancer in Young Women - Outline Epidemiology Biology of breast cancer in young patients Implications for local treatment Adjuvant therapy in young women: - Efficacy - Tolerability - Needs

17 Overall survival in young (<35yrs) vs older (35-50yrs) pts according to tumor biology n tot=9885 (young n=1444); Diagnosis All HR- HR unknown HR+ Ahn J Clin Oncol 2007

18 HR+ EBC: Upfront Adjuvant Endocrine Therapy Definitive local treatment PRE & PERIMENOPAUSE? POST- MENOPAUSE Tamoxifen 5y Tam 5y + OFS 5y Still standard of care 5y DFS % Tam 84.7 Tam+OS 86.6 HR 0.83 (95% CI ) p = 0.10 Francis PA et al NEJM 2015

19 SOFT TRIAL: SELECTED AES AE Tamoxifen (N 1006) Tamoxifen + OS (N 1005) any G % G > 3 % any G % G > 3 % Hot flushes depression sweating insomnia hypertension muscoskeletal osteoporosis Vaginal dryness Decreased libido Glucose intolerance Any AE Francis PA et al NEJM 2015

20 TEXT and SOFT joint analysis TEXT trial (n=2672) Tamoxifen + OFS x 5y Exemestane + OFS x 5y SOFT trial (n=3066) Tamoxifen x 5y Joint Analysis (n=4690) median FU 5.7 y Tamoxifen + OFS x 5y Exemestane + OFS x 5y Tamoxifen + OFS x 5y Exemestane + OFS x 5y Primary endpoint: DFS Secondary endpoints: BCFI, DRFI, OS Pagani O, NEJM 2014

21 HR+ EBC: Upfront Adjuvant Endocrine Therapy Definitive local treatment PRE & PERIMENOPAUSE? POST- MENOPAUSE TEXT and SOFT joint analysis: results Tamoxifen 5y Tam 5y + OFS 5y Still standard of care AI 5y + OFS 5y Contraindication to Tam (endometrial hyperplasia or cancer, DVT, PE) High risk patients Pagani O, NEJM 2014

22 TEXT and SOFT joint analysis: selected AEs Pagani O, NEJM 2014

23 HR+ EBC: Ongoing Endocrine Therapy 5-ys TAM in PRE & PERIMENOPAUSE? 5-ys TAM in POSTMENOPAUSE 5 ys AI in POSTMENOPAUSE Stop TAM TAM up to 10y Trial Experimental arm pts # DFS Δ HR ATLAS 1 10y TAM 6, % 0.75 attom 2 10y TAM 6,953 4% Davies et al, Lancet 2013; 2 Gray et al, ASCO 2013

24 HR+ EBC: Ongoing Endocrine Therapy 5-ys TAM in PRE & PERIMENOPAUSE? 5-ys TAM in POSTMENOPAUSE 5 ys AI in POSTMENOPAUSE Stop TAM TAM up to 10y High risk patients Risk of endometrial cancer and PE Symptoms & sexuality Endometrial cancers Continue (3470) Stop (3486) P value < Endometrial cancer deaths

25 LHRHa during chemotherapy to preserve ovarian function Del Mastro L, 2014

26 Prevention Of Early Menopause Study: POEMS n= 118 Primary endpoint: Ovarian failure at 2 years Secondary endpoint: Pregnancy outcome Ovarian disfunction 1,2 yrs Exploratory: DFS/OS Moore H, NEJM 2015

27 Prevention Of Early Menopause Study: POEMS CHT CHT+Goserelin p OF 2yrs 22% 8% 0.04 Achieved pregnancy 11% 21% 0.03 DFS OS Moore H, NEJM 2015

28 Breast Cancer in Young Women Peculiar biological features Worse prognosis (even in case of HR+ disease) More efficacious endocrine therapies are available (OFS + exemestane; 10 y Tamoxifen) but side effects may be troblesome Sexuality and fertility are often overlooked by clinicians If chemotherapy is needed, OFS can preserve ovarian function and fertility