ESMO SUMMIT MIDDLE EAST 2018Breast Clinical Cases Presentation

Hampig Raphael Kourie , MD , MSc , MBioethics

Faculty of Medicine , Saint Joseph University of Beirut, Lebanon

6-7 April 2018, Dubai, UAE

CONFLICT OF INTEREST DISCLOSURE

No conflict of interest

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

CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE-

MENOPAUSAL WOMAN

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

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

Mammogram : 4 cm lesion in the right breast with supra-centimetric axillary lymph

nodes

TAP CT Scan : no other secondary lesion

Ca 15-3 : 20.54 (N)

CASE 1 : ER+ METASTATIC BREAST CANCER IN PRE-

MENOPAUSAL WOMAN

WORK-UP

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

Persistant dorsal pain without any response to antalgic treatment in ER+ metastatic

breast cancer

What to do next ?

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

REMOVAL OF THE PRIMARY IN METASTATIC BREAST

CANCER

Radiation therapy on D12 and L2 vertebral secondary lesions (10 sessions) +

Zoledronic acid

What to do next ?

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

OVARIAN ABLATION VERSUS SUPPRESSION

eUpdate – ESMO Advanced Breast Cancer Algorithms , 2017

MONALEESA-7: Phase III placebo-controlled study of ribociclib

and tamoxifen/NSAI + goserelin

• 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 arm1,2), and a sample size of 660 patients

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;19:343–353; 2. Mourisden H, et al. J Clin Oncol 2001;19:2596–2606.

Stratified by:

• Presence/absence of liver/lung metastases

• Prior chemotherapy for advanced disease

• Endocrine therapy partner (tamoxifen vs

NSAI)

Primary endpoint

• PFS (locally assessed per

RECIST v1.1)‡

Secondary endpoints

• Overall survival (key)

• Overall response rate

• Clinical benefit rate

• Safety

• Patient-reported outcomes

• 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)

Ribociclib(600 mg/day; 3-weeks-on/1-week-

off)

+ tamoxifen/NSAI + goserelin*

n=335

Placebo+ tamoxifen/NSAI + goserelin*

n=337

Tripathy et al , SABCS 2017

PRIMARY ENDPOINT: PFS (INVESTIGATOR-ASSESSED)

CI, confidence interval; NR, not reached.

Goserelin included in all combinations.

Pro

bab

ility

of

PF

S (

%)

Time (months)No. at risk

Ribociclib + tamoxifen/NSAI 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0

Placebo + tamoxifen/NSAI 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0

PFS (investigator assessment)

Ribociclib + tamoxifen/NSAI n=335

Placebo + tamoxifen/NSAI n=337

Number of events, n (%) 131 (39.1) 187 (55.5)

Median PFS, months (95% CI)

23.8(19.2–NR)

13.0(11.0–16.4)

Hazard ratio (95% CI) 0.553 (0.441–0.694)

One-sided p value 0.0000000983

1086420

100

80

60

40

20

0

30282624222018161412

10

30

50

70

90

Tripathy et al , SABCS 2017

TREATMENT

16/3/2018 : bilateral oophorectomy

19/3/2018 : Started letrozole + palbociclib + zoledronic acid

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

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

CASE 2 : ADJUVANT TREATMENT IN TNBC

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

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

WORK-UP

PET/CTScan : negative

Cardiac US : EF=70%

Genetic testing : ongoing

HISTOLOGIC SUBTYPES : INFILTRATIVE CARCINOMA

METAPLASTIC CARCINOMA

RARE

POOR PROGNOSIS

CHEMORESISTANT ?

IN FRONT OF TNBC WITH METAPLASTIC

COMPONENT?

1)SURVEILLANCE

2)ADJUVANT CHEMOTHERAPY

3)RADICAL MASTECTOMY

It was decided to start a chemotherapy.

Dose Dense versus every 3 weeks adjuvant chemotherapy ?

San Antonio 2017

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

?

CARBOPLATIN BASED REGIMEN IN THE NEO-

ADJUVANT SETTING

Castrellon et al , 2017

TWO NEGATIVE TRIALS IN THE ADJUVANT SETTING

ASCO 2017

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

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

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

\

OTHER POSSIBLE TREATMENT OPTIONS

Eribuline role ? with trastuzumab ?

Platinum-based agents?

A place for pertuzumab in heavily pre-treated HER2+ patients ?

HER2 + BC WITH BRAIN METASTASES

SUPPRESSION OF ANTI-HER2 PATHWAY

CASE 4 : HEAVILY TREATED PREMENOPAUSAL HR+ MBC

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 : 22 mm invasive ductal carcinoma with positive

hormonal receptors and negative HER2

Familial history : Absence of other cancers in the family

Genetic screening : Absence of BRCA1 or BRCA2 mutation

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

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

POSITIVE TRIAL – BIG

- Patients with ER+ early breast cancer

- ≤42 years at enrolment

- Completing 18-30 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). NCT02308085. https://clinicaltrials.gov/ct2/show/NCT02308085 Accessed December 21, 2015.

The patient presented a new bone marrow progression .

Suggestions ?

New agents

Experimental therapy (phase 1 ?)

Other?

Treatment by aromatase inhibitor (started 6/1/2016) and palbociclib (22/1/2016)

Schedule of Palbociclib was adapted according to hematogical count during

therapy

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 )

CASE 5 : HEREDITARY CANCERS

HISTORY

Mrs R is a single woman, without a relevant past medical history, diagnosed at the

age of 40 from a breast cancer.

PEDIGREE

? 4

Lena, Melanoma at 60

Eugénie, Lung?

Elias

2 3 4

Najib

Suzanne, breast cancer at the age of 50

2

Fouad

Tony,prostatecancer at 64

3

Michel

Rabiha, CUP at 27 years old

5

Wadih, 1939 ,died in 2011

Souad1950

2 3

Jean, melanoma at the age 64 died at the age of 68

Maroun 1968 Joseph 1969

Simon 1972

Rania 1973

1996 1993 1999 1995 2008 2010

DIAGNOSIS

Pathology report (2014) :

Triple negative invasive ductal carcinoma , grade 3.

T=1.8cm without lymph node invasion.

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.

Is there any indication for genetic testing ?

Which genes should be tested ?

WHEN WE SHOULD SUSPECT A HEREDITARY BREAST

CANCER IN A PATIENT WITH BREAST CANCER?

HEREDITARY BREAST CANCER GENE PANEL

RESULTS OF GENETIC TESTING

Panel of 19 genes for breast ovarian hereditary cancer panel

Presence of pathogenic BRCA1 mutation

CONSEQUENCES ON THE PATIENT AND HIS FAMILY

Prophylactic bilateral mastectomy and salpingo-oophorectomy

Targeted genetic testing in the children and brotherhood

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

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

Breast cancer risk reduction – screening

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

Breast cancer risk reduction – surgery

OTHER BRCA-ASSOCIATED CANCER

Paluch-Shimon et al , Annals of Oncology 2016

PREVENTION AND SCREENING STRATEGIES FOR

SPECIFIC MUTATIONS

Paluch-Shimon et al , Annals of Oncology 2016

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

CASE 6 : METASTATIC BREAST CANCER IN MALE

HISTORY

A 43 years old patient (born in 1975) without relevant past medical history

No familial history of cancer

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)

PATHOLOGY REPORT

Invasive ductal carcinoma

ER : 75%

PR : 10%

HER2 :-

Grade 2

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

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

FEW CASES REPORTED IN THE LITERATURE

ASCO 2017

What is the treatment option after progression?

eUpdate – ESMO Advanced Breast Cancer Algorithms , 2017

What is the treatment option after progression?

TAKE HOME MESSAGES

A genetic counseling is necessary in every man with breast cancer

Second line hormonal-based treatment is indicated after progression on 1st

line ER+ metastatic breast cancer in the absence of visceral crisis

Extrapolation of the treatment of breast cancer in men from women

THANK YOU