Carcinoma mammario metastatico HR+/HER2-: recidiva scheletrica durante trattamento adiuvante con Inibitore dell’Aromatasi Jennifer Foglietta

CLINICAL CASE REPORT PATIENT’S CHARACTERISTICS 49 anni Nessuna comorbidità Anamnesi familiare negativa per patologie oncologiche

PATIENT’S HISTORY OF DISEASE CLINICAL CASE REPORT PATIENT’S HISTORY OF DISEASE All’età di 49 anni… Novembre 2007: quadrantectomia destra per carcinoma duttale in situ di alto e basso grado. pTis (premenopausa) Seguiva radioterapia In a 2015 observational study that included over 100,000 patients who received a diagnosis of DCIS in the Surveillance, Epidemiology, and End Results (SEER) database, when compared with lumpectomy (with or without radiotherapy), mastectomy resulted in [2]: ●A similar 10-year breast cancer-specific mortality (multivariate hazard ratio [HR] for mastectomy versus lumpectomy 1.2, 95% CI 0.96-1.50) ●Lower rates of ipsilateral invasive recurrence (1.3 versus 3.3 percent). the risk of developing a contralateral breast cancer or DCIS is approximately 3 to 10 percent.

PATIENT’S HISTORY OF DISEASE CLINICAL CASE REPORT PATIENT’S HISTORY OF DISEASE All’età di 53 anni … Giugno 2011: mastectomia destra per carcinoma duttale G2 infiltrante di 8 mm associato a carcinoma in situ di alto e basso grado; ER=90%, PgR=60%, Ki-67=20%, HER2=neg. Ln sentinella negativo pT1b pN0 M0 (stadio IA); postmenopausa In an analysis of over 100,000 patients with DCIS enrolled in the Surveillance, Epidemiology, and End Results (SEER) database, the 20-year breast cancer mortality among women with DCIS was 3.3 percent. The risk of ipsilateral invasive recurrence at 20 years was 5.9 percent, and the risk of contralateral invasive recurrence was 6.2 percent. In this study, predictors of a higher risk of death from breast cancer included young age at diagnosis (before age 35 years, hazard ratio [HR] 2.3, 95% CI 1.6-3.2), high grade (HR 1.88, 95% CI 1.38-2.55), and black ethnicity (HR 2.55, 95% CI 2.17-3.01)

Stadio IA (pT1b) (G2, ER=90%, PgR =60%, Ki-67=20%,HER2 negativo) CLINICAL CASE REPORT Stadio IA (pT1b) (G2, ER=90%, PgR =60%, Ki-67=20%,HER2 negativo) Quale terapia adiuvante?

LG AIOM 2016

What should we fear?…adverse biology of T1a,bN0M0 BC *MAI: Mitotic Activity Index

Stadio Ia (pT1b); G2, ER=90%, PgR =60%, Ki-67=20%,HER2 negativo CLINICAL CASE REPORT Stadio Ia (pT1b); G2, ER=90%, PgR =60%, Ki-67=20%,HER2 negativo TERAPIA ADIUVANTE Giugno 2011: inizia ormonoterapia adiuvante con letrozolo Dicembre 2015: comparsa di dolore al bacino e rialzo del CEA (41 ng/ml) e CA 15-3 (38 U/ml)> esegue PET/TC

CLINICAL CASE REPORT RESTAGING DFI: 4 years Metastasi ossee multiple a livello di L2, L3, sacro, entrambi le ali iliache, IV costa destra, femore sinistro Metastasi epatiche e ln mediastino

CLINICAL CASE REPORT Biopsia osteomidollare: sostituzione midollare da carcinoma solido desmoplastico, ER=60%, PgR=10%, Ki-67=20%, HER2=2+ (FISH negativa) DFI: 4 years Metastasi epatiche e ln mediastino

CLINICAL CASE REPORT PATIENT’S HISTORY OF DISEASE Gennaio 2016 Carcinoma mammario stadio IV per metastasi ossee multiple, ER=60%, PgR=10%, Ki-67=20%, HER2=2+ (FISH negativa) DFI:4 anni 53 anni PS=0; nessuna comorbidità Postmenopausa Quale terapia di I linea?

Quale terapia di I linea? Chemioterapia Exemestane Exemestane+ everolimus Fulvestrant ….

Come scegliere il trattamento: Treatment choice should take into account at least these factors: HR and HER-2 status previous therapies and toxicities disease-free interval, tumour burden (defined as number and site of metastases) biological age performance status co-morbidities (including organ dysfunctions) menopausal status (for ET) need for a rapid disease/ symptom control socio-economic and psychological factors available therapies in the patient’s country patient preference ABC 3 Cardoso F. et al. Ann Oncol 2017

Can chemo be safely delayed to later lines of therapy? 2003

Chemotherapy vs endocrine therapy 76 phase III trials Saad ED. J Clin Oncol 2010;28:1958-1962.

Visceral disease and endocrine therapy First line endocrine therapy in 4 phase III trials: combined analysis Title: Visceral metastases from hormone receptor positive breast cancer are as sensitive to endocrine therapy as non-visceral metastases. HR+ VMs have hormone sensitivity similar to non-visceral mets – they respond as well and for as long as non-VMs. In the absence of visceral crisis (ie immediately life-threatening disease) ET would appear to be the treatment of choice for VMs in the same way as it is for non-VMs Robertson, J. San Antonio Breast Cancer Symposium 2014. Cancer Res, 2015. 75: P1-13-02.

LG AIOM 2016

PRIMARY ENDOCRINE RESISTANCE is defined as: Relapse while on the first 2 years of adjuvant ET, or PD within first 6 months of 1st line ET for MBC, while on ET. SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as: Relapse while on adjuvant ET but after the first 2 years, or Relapse within 12 months of completing adjuvant ET, or PD  6 months after initiating ET for MBC, while on ET. Note: resistance is a continuum and these definitions help mainly clinical trials and not necessarily clinical practice ABC 3 Cardoso F. et al. Ann Oncol 2017

Diverse definizioni di ormonosensibilità

520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366)

CLINICAL CASE REPORT PATIENT’S HISTORY OF DISEASE Gennaio 2016 Carcinoma mammario stadio IV per metastasi ossee multiple, ER=60%, PgR=10%, Ki-67=20%, HER2=2+ (FISH negativa) DFI:4 anni 53 anni PS=0; nessuna comorbidità Postmenopausa Inizia Everolimus+ exemestane

LG AIOM 2016

BOLERO-2 Eligible patients were postmenopausal women with ER-positive, human epidermal growth factor receptor type 2 (HER2)–nonamplified advanced breast cancer whose disease was refractory to previous letrozole or anastrozole, defined as recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 1 month after the end of treatment for advanced disease

Bolero-2

Bolero-2:OS

Chemo-like side effects of mTOR inhibition Hyperglicemia/new onset diabetes Stomatitis Fatigue Pneumonitis H. S. Rugo et al. Ann Oncol 2014;25:808-815

Ellis MJ et al ESMO 2016; LBA14_PR

Ellis MJ et al ESMO 2016; LBA14_PR

Ellis MJ et al ESMO 2016; LBA14_PR

Ellis MJ et al ESMO 2016; LBA14_PR

Ellis MJ et al ESMO 2016; LBA14_PR

INIBITORI DI CDK 4/6

ER/PgR

Per abemaciclib non ancora dati disponibili (probabilmente MONARCH 2; che prevede abemaciclib + fulvestrant, entro la prima metà del 2017)

Paloma-2: design Recidiva dopo almeno 12 mesi dalla fine dell’adiuvante Finn RS et al. N Engl J Med 2016;375:1925-1936

Paloma-2: PFS PFS= 24.8 m vs 14.5 m PFS= 30,5 m vs 19.3 m Progression-free Survival. Panel A shows progression-free survival in the intention-to-treat population, as assessed by the investigators (primary analysis); the median progression-free survival was 24.8 months (95% CI, 22.1 to not estimable) among the 444 patients in the palbociclib–letrozole group and 14.5 months (95% CI, 12.9 to 17.1) among the 222 patients in the placebo–letrozole group. Panel B shows progression-free survival in the intention-to-treat population, as assessed by means of blinded, independent central review; the median progression-free survival was 30.5 months (95% CI, 24.7 to not estimable) among the 444 patients in the palbociclib–letrozole group and 19.3 months (95% CI, 16.4 to 30.6) among the 222 patients in the placebo–letrozole group. PFS= 24.8 m vs 14.5 m PFS= 30,5 m vs 19.3 m Finn RS et al. N Engl J Med 2016;375:1925-1936

Paloma-2: toxicity Finn RS et al. N Engl J Med 2016;375:1925-1936

PALOMA 2– subgroups analysis Finn RS et al. N Engl J Med 2016;375:1925-1936

Hortobagyi GN et al. N Engl J Med 2016;375:1738-1748

63% letrozole+ribociclib 42.2% letrozole+placebo PFS at 18m: 63% letrozole+ribociclib 42.2% letrozole+placebo Hortobagyi GN et al. N Engl J Med 2016;375:1738-1748

INIBITORI DI PI3K

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CLINICAL CASE REPORT PATIENT’S HISTORY OF DISEASE Aprile 2016 PET/TC di rivalutazione: «nettissima riduzione delle note aree di patologico accumulo riscontrate a livello scheletrico. Attualmente sono visibili sono alcune piccole focalità a livello di L4, ali iliache e sfumata captazione sacrale.» CEA=5,1 ng/ml CA 15-3=31,8 U/ml

CLINICAL CASE REPORT PATIENT’S HISTORY OF DISEASE Luglio 2016-marzo 2017 Persiste sostanzialmente invariata la risposta di malattia documentata a livello osseo. CEA e CA 15-3 stabili Non eventi avversi

? CDKI4/6 ? + CDKI4/6? LG AIOM 2016