ESMO SUMMIT MIDDLE EAST 2018

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1 ESMO SUMMIT MIDDLE EAST 2018 Breast Clinical Cases Presentation Hampig Raphael Kourie, MD, MSc, MBioethics Faculty of Medicine, Saint Joseph University of Beirut, Lebanon 6-7 April 2018, Dubai, UAE

2 CONFLICT OF INTEREST DISCLOSURE No conflict of interest

3 CASE 1: Treatment-naïve ER+ metastatic breast cancer in premenopausal woman CASE 2 : Adjuvant treatment in TNBC CASE 3 : Heavily pretreated HER2+ metastatic breast cancer CASE 4 : Heavily pretreated ER+ metastatic breast cancer CASE 5: Hereditary breast cancer CASE 6 : Metastatic breast cancer in man

4 CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE- MENOPAUSAL WOMAN

5 CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE- MENOPAUSAL WOMAN HISTORY AND SYMPTOMS 40 years old woman (born in 1978) without relevant past medical history Familial History : Mother diagnosed with a breast cancer at the age of 60 and a maternal cousin with breast cancer at the age of 50 She felt a right breast nodule, 4 years ago, (2014) during her pregnancy, without doing any further investigation She presented a dorsal pain since November 2017

6 CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE- MENOPAUSAL WOMAN WORK-UP In the end of January 2018, she visited an orthopedic surgeon for investigation Persistant dorsal and lumbar pain despite the antalgic treatment Dorso-lombar MRI : secondary lesions at D12 and L2

7 CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE- MENOPAUSAL WOMAN WORK-UP Mammogram : 4 cm lesion in the right breast with supra-centimetric axillary lymph nodes TAP CT Scan : no other secondary lesion Ca 15-3 : (N)

8 CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE- MENOPAUSAL WOMAN WORK-UP Biopsy of the right breast nodule (2/2/2018) : Invasive ductal carcinoma moderately differentiated ER : positive (80%) PR : negative HER2 2+ FISH negative Ki67 : 25% Grade 2

9 Persistant dorsal pain without any response to antalgic treatment in ER+ metastatic breast cancer What to do next?

10 POSSIBLE THERAPEUTIC OPTIONS? 1)Chemotherapy followed by hormonal therapy 2)Radiation therapy followed by hormonal therapy 3)Hormonal therapy 4)Breast Surgery followed by hormonal therapy

11 REMOVAL OF THE PRIMARY IN METASTATIC BREAST CANCER

12 Radiation therapy on D12 and L2 vertebral secondary lesions (10 sessions) + Zoledronic acid What to do next?

13 POSSIBLE THERAPEUTIC OPTIONS? 1)LHRH agonists + AI 2)LHRH agonists + AI+ anti-cdk4/6 3)Bilateral oophorectomy + AI 4)Bilateral oophorectomy + AI + anti-cdk4/6 5)Tamoxifene 6)LHRH agonists + tamoxifene 7)LHRH agonists + tamoxifene + anti-cdk4/6

14 OVARIAN ABLATION VERSUS SUPPRESSION

15 eupdate ESMO Advanced Breast Cancer Algorithms, 2017

MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/nsai + goserelin Pre/perimenopausal women with HR+, HER2 ABC No prior endocrine therapy for advanced disease 1 line of

16 MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/nsai + goserelin Pre/perimenopausal women with HR+, HER2 ABC No prior endocrine therapy for advanced disease 1 line of chemotherapy for advanced disease N=672 Randomization (1:1) Stratified by: Presence/absence of liver/lung metastases Prior chemotherapy for advanced disease Endocrine therapy partner (tamoxifen vs NSAI) Ribociclib (600 mg/day; 3-weeks-on/1-weekoff) + tamoxifen/nsai + goserelin* n=335 Placebo + tamoxifen/nsai + goserelin* n=337 Primary endpoint PFS (locally assessed per RECIST v1.1) Secondary endpoints Overall survival (key) Overall response rate Clinical benefit rate Safety Patient-reported outcomes Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter Primary analysis planned after ~329 PFS events 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm 1,2 ), and a sample size of 660 patients Tripathy et al, SABCS 2017 NSAI, non-steroidal aromatase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors. *Tamoxifen = 20 mg/day; NSAI: anastrozole = 1 mg/day or letrozole = 2.5 mg/day; goserelin = 3.6 mg every 28 days; PFS by Blinded Independent Review Committee conducted to support the primary endpoint. 1. Klijn JG, et al. J Clin Oncol 2001;19: ; 2. Mourisden H, et al. J Clin Oncol 2001;19:

17 Probability of PFS (%) PRIMARY ENDPOINT: PFS (INVESTIGATOR-ASSESSED) PFS (investigator Ribociclib + tamoxifen/nsai Placebo + tamoxifen/nsai assessment) n=335 n=337 Number of events, n (%) 131 (39.1) 187 (55.5) Median PFS, months (95% CI) 23.8 (19.2 NR) 13.0 ( ) Hazard ratio (95% CI) ( ) One-sided p value No. at risk Time (months) Ribociclib + tamoxifen/nsai Placebo + tamoxifen/nsai Tripathy et al, SABCS 2017 CI, confidence interval; NR, not reached. Goserelin included in all combinations.

18 TREATMENT 16/3/2018 : bilateral oophorectomy 19/3/2018 : Started letrozole + palbociclib + zoledronic acid

19 UNMET NEED IN PREMENOPAUSAL PATIENTS WITH HR+, HER2 ABC Estimates suggest that in 2017 in the US, ~19% of invasive breast cancers will be diagnosed in women aged 49 years The proportion of patients aged <50 years may be up to 40% to 50% in the Middle East (Najjar et al) The last randomized trial focusing solely on premenopausal women with ABC was published in 2000 Young women with ABC have a distinct tumor biology, experience more aggressive disease, and are more likely to die from their cancer than older women

20 TAKE HOME MESSAGES FROM CASE ONE Premenopausal breast cancer patients represent an important public health issue in the Middle East More studies should be done in this specific population, mainly in developing countries Anti-CDK4/6 agents will certainly have their place in the algorithm of the treatment of pre-menopausal ER+ metastatic breast cancer

21 CASE 2 : ADJUVANT TREATMENT IN TNBC

22 HISTORY AND WORK-UP A 37 years old woman (born in 1981) without relevant past medical history Ultrasound of the left breast (24/1/2018) : an inferior-intern nodule of 1.8 cm (ACR4a) Breast MRI (8/2/2018) : an inferior-intern nodule of 2 cm ACR6 at left (ACR6) A biopsy was done (9/2/2018) :ductal carcinoma of unknown specificity (aspects of metaplastic carcinoma); ki67 : 70%, triple negative, grade 3

23 TUMORECTOMY 19/2/2018 : Tumorectomy Invasive ductal carcinoma, metaplastic with a squamous cell component and a ductal carcinoma NOS, grade 3, T=2.4 cm Negative margins 0/10 positive lymph nodes Absence of vascular and lymphatic invasion

24 WORK-UP PET/CTScan : negative Cardiac US : EF=70% Genetic testing : ongoing

25 HISTOLOGIC SUBTYPES : INFILTRATIVE CARCINOMA

26 METAPLASTIC CARCINOMA RARE POOR PROGNOSIS CHEMORESISTANT?

27 IN FRONT OF TNBC WITH METAPLASTIC COMPONENT? 1)SURVEILLANCE 2)ADJUVANT CHEMOTHERAPY 3)RADICAL MASTECTOMY

28 It was decided to start a chemotherapy. Dose Dense versus every 3 weeks adjuvant chemotherapy?

29 San Antonio 2017

31 Is there any role for carboplatine in the adjuvant setting if there is a BRCA mutation?

32 CARBOPLATIN BASED REGIMEN IN THE NEO- ADJUVANT SETTING Castrellon et al, 2017

33 TWO NEGATIVE TRIALS IN THE ADJUVANT SETTING ASCO 2017

34 TAKE HOME MESSAGES FROM CASE 2 TNBC is divided in different histologic and molecular subtypes ; each one having specific characteristics Dose-dense chemotherapy could be considered in the adjuvant setting, namely in TNBC 5% decrease in recurrence rate at 10 years No evidence on the use of carboplatine in the adjuvant setting in BRCA mutated triple negative breast cancer

35 CASE 3 : HEAVILY TREATED HER2+ MBC 55 years old women, without past medical history or comorbidities, diagnosed in 2003 with right breast cancer. Tumorectomy ; pathology : DCIS of 3.5 cm with positive margins, ER 8/8, PR 0/8 and HER2 3+ Right mastectomy

36 HISTORY 55 years old women, without past medical history or comorbidities, diagnosed in 2003 with right breast cancer. Tumorectomy ; pathology : DCIS of 3.5 cm with positive margins, ER 8/8, PR 0/8 and HER2 3+ Right mastectomy

42 \

44 OTHER POSSIBLE TREATMENT OPTIONS Eribuline role? with trastuzumab? Platinum-based agents? A place for pertuzumab in heavily pre-treated HER2+ patients?

46 HER2 + BC WITH BRAIN METASTASES

47 SUPPRESSION OF ANTI-HER2 PATHWAY

48 CASE 4 : HEAVILY TREATED PREMENOPAUSAL HR+ MBC

49 HISTORY AND DIAGNOSIS 45 years old woman, without past medical history, diagnosed in 1999 at the age of 28 with right breast cancer Tumorectomy + lymph node dissection : hormonal receptors and negative HER2 22 mm invasive ductal carcinoma with positive Familial history : Absence of other cancers in the family Genetic screening : Absence of BRCA1 or BRCA2 mutation

50 ADJUVANT TREATMENT Followed by adjuvant chemotherapy 4 adriamycine and 3 MF, radiation therapy and tamoxifen (stopped in 2001, after 1 year for pregnancy and restarted after that) 3MF instead of CMF : cyclophosphamide was omitted in order to decrease the risk of toxicity to the ovaries

51 PREMENOPAUSAL LUMINAL BREAST CANCER-PREGNANCY Fertility concerns influence treatment decision in an important number of patients Many patients still fear that a future pregnancy will increase their risk of recurrence

52 POSITIVE TRIAL BIG - Patients with ER+ early breast cancer - 42 years at enrolment - Completing months of ET (SERMs alone, LH-RH analogue + SERM or AIs) - Pregnancy desire ClinicalTrials.gov. Pregnancy Outcome and Safety of Interrupting Therapy for Women With Endocrine Response Breast Cancer (POSITIVE). NCT Accessed December 21, 2015.

56 The patient presented a new bone marrow progression. Suggestions? New agents Experimental therapy (phase 1?) Other?

57 Treatment by aromatase inhibitor (started 6/1/2016) and palbociclib (22/1/2016) Schedule of Palbociclib was adapted according to hematogical count during therapy

58 Good performance status during the evolution of the disease and willing to be actively treated. In addition to standard of care, access to 3 new therapies that become available during the course of the disease (eribuline, afinitor and palbociclib) and 1 experimental agent (XRP). Long ambulatory course treatment of 17 years (Her child become an adolescent of 16 years at her death) Hospitalized only for 2 times One episode of febrile neutropenia (March 2016) Death due to hepatic PD (April 2016 )

59 CASE 5 : HEREDITARY CANCERS

60 HISTORY Mrs R is a single woman, without a relevant past medical history, diagnosed at the age of 40 from a breast cancer.

61 PEDIGREE? Eugénie, Lung? Elias Lena, Melanoma at 60 Najib Suzanne, breast cancer at the age of 50 Fouad 3 2 Tony,prostate cancer at 64 Michel 5 Rabiha, CUP at 27 years old Wadih, 1939,died in 2011 Souad 1950 Jean, melanoma at the age 64 died at the age of 68 Maroun 1968 Joseph 1969 Simon 1972 Rania

62 DIAGNOSIS Pathology report (2014) : Triple negative invasive ductal carcinoma, grade 3. T=1.8cm without lymph node invasion.

63 TREATMENT Treated with neo-adjuvant chemotherapy (4AC-4T) followed by partial mastectomy and radiation therapy. She relapsed in 2016 and presented a single pulmonary nodule of 1.2 cm, treated by surgery. Now she is under surveillance.

64 Is there any indication for genetic testing? Which genes should be tested?

66 WHEN WE SHOULD SUSPECT A HEREDITARY BREAST CANCER IN A PATIENT WITH BREAST CANCER?

67 HEREDITARY BREAST CANCER GENE PANEL

68 RESULTS OF GENETIC TESTING Panel of 19 genes for breast ovarian hereditary cancer panel Presence of pathogenic BRCA1 mutation

69 CONSEQUENCES ON THE PATIENT AND HIS FAMILY Prophylactic bilateral mastectomy and salpingo-oophorectomy Targeted genetic testing in the children and brotherhood

70 PREVENTION AND SCREENING IN BRCA MUTATION CARRIERS AND OTHER BREAST/OVARIAN HEREDITARY CANCER SYNDROMES: ESMO CLINICAL PRACTICE GUIDELINES Paluch-Shimon et al, Annals of Oncology 2016

71 PREVENTION AND SCREENING IN BRCA MUTATION CARRIERS AND OTHER BREAST/OVARIAN HEREDITARY CANCER SYNDROMES: ESMO CLINICAL PRACTICE GUIDELINES Breast cancer risk reduction screening Paluch-Shimon et al, Annals of Oncology 2016

72 PREVENTION AND SCREENING IN BRCA MUTATION CARRIERS AND OTHER BREAST/OVARIAN HEREDITARY CANCER SYNDROMES: ESMO CLINICAL PRACTICE GUIDELINES Breast cancer risk reduction surgery Paluch-Shimon et al, Annals of Oncology 2016

73 OTHER BRCA-ASSOCIATED CANCER Paluch-Shimon et al, Annals of Oncology 2016

74 PREVENTION AND SCREENING STRATEGIES FOR SPECIFIC MUTATIONS Paluch-Shimon et al, Annals of Oncology 2016

75 TAKE HOME MESSAGES FOR CASE 5 Genetic counseling is necessary in : -patients with familial history of breast and ovarian cancer, -young patients with breast cancers -patient with more than one cancer from the spectrum of HBOC. Panel of genes for HBOC syndrome by NGS Prophylactic screening modalities and surgey are indicated in the presence of deleterious mutations leading to HBOC syndrome

76 CASE 6 : METASTATIC BREAST CANCER IN MALE

77 HISTORY A 43 years old patient (born in 1975) without relevant past medical history No familial history of cancer

78 DIAGNOSIS October 2016 : palpation of a lump in the right breast Total body MRI done showed a 4.4 cm nodule in the with axillary lymph nodes, 2 costal secondary lesions and diffuse small pulmonary nodules (<5 mm)

79 PATHOLOGY REPORT Invasive ductal carcinoma ER : 75% PR : 10% HER2 :- Grade 2

80 TREATMENT November 2016: He was treated with letrozole and palbociclib February 2017: Partial response ; breast lesion decreased to 2.8 cm instead of 4.4 cm ; disapparance of costal lesions, decrease and disappearance of lung lesions

82 In april 2018, after 18 months of treatment by letrozole and palbociclib, he presented a progression in the axillary lymph nodes (+20%) and appearance of a new bone lesion and progression of the costal lesions The patient tolerated very well the treatment without remarkable side effects

84 FEW CASES REPORTED IN THE LITERATURE ASCO 2017

85 What is the treatment option after progression?

86 eupdate ESMO Advanced Breast Cancer Algorithms, 2017

87 What is the treatment option after progression?

88 TAKE HOME MESSAGES A genetic counseling is necessary in every man with breast cancer Second line hormonal-based treatment is indicated after progression on 1 st line ER+ metastatic breast cancer in the absence of visceral crisis Extrapolation of the treatment of breast cancer in men from women

89 THANK YOU

RIBOCICLIB EN PRIMERA LINEA DE TRATAMIENTO. Dra. Elena Aguirre H.U. Miguel Servet

RIBOCICLIB EN PRIMERA LINEA DE TRATAMIENTO Dra. Elena Aguirre H.U. Miguel Servet INTRODUCTION ADVANCED BREAST CANCER HR+/HER2- YES Consider Chemo VISCERAL CRISIS? NO Endocrine Therapy X3 Toxicity Progresive