MOLECULAR BIOLOGY OF BREAST CANCER AND IDENTIFICATION AND MANAGEMENT OF HIGH

RISK PATIENT

DR.BARUN KUMAR

MOLECULAR BIOLOGY

The markers and pathways of interest in breast ca are :

• Steroid hormone receptor pathway (ER & PR)• Human epidermal growth factor receptor pathway ( HER family)• Cell cycle ( CDKs)• COX-2 • PPAR-y• IGF family• TGF-y• PDGF• p53

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STEROID HORMONE RECEPTOR PATHWAY (ER &PR)

• Belongs to the family of G-protein coupled receptors• 2 different forms- alpha (breast cancer cells) and beta

• Over- expression is seen in more than half of breast tissue biopsies

• 2 mechanisms have proposed for tumor genesisFirst, binding of oestrogen to the ER stimulates proliferation

of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations.

Second, oestrogen metabolism produces genotoxic waste.

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• Tumours are classified as oestrogen dependent and independent according to their need for oestrogen for growth

• Assessment of receptor expression helps in prognostication and decision making about endocrine therapy as chemoprevention

HER2/neu

• Human epidermal growth factor receptor 2• Member of ErbB protein family• Cell membrane bound tyrosine kinase

mediated pathway

• Approx 30% of breast cancer show over expression of her2/neu which is associated with bad prognosis

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• Co-localized with GRB7 (proto-oncogene)• Targeted by monoclonal antibody

TRANSTUZUMAB • Pertuzumab (inhibits dimerization of HER2 &

HER3 receptors) used in combination of transtuzumab

Molecular pathways in pathogenesis of breast cancer

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A classification system based on expression of ER/PR and HER2/neu has been made

However, tumours in same group don't follow similar behaviour, which warrants further sub classification system

A special category is TRIPLE NEGATIVE tumours• Express proteins common with myoepithelial

cells at the base of mammary ducts, so called BASAL LIKE CANCERS

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• High association with BRCA1 has been shown

• As no chemoprevention is effective, hard to treat

• Surgery is the treatment of choice with adjuvant chemo (very chemo sensitive) and radiotherapy

• Addition of a taxane improve outcome

HIGH RISK PATIENT RISK FACTORS THAT CANNOT

BE MODIFIED• Increasing age • Female gender• Menstrual factors• Early age at menarche• Older age at menopause• Nulliparity• Family history of breast cancer• Genetic predisposition • Personal history of breast ca• Race, ethnicity• H/O of radiation exposure

RISK FACTORS THAT COULD BE MODIFIED•Reproductive factors•Age at first live birth •Parity•Lack of breast feeding•Obesity•Alcohol consumption•Tobacco smoking•Use of hormone replacement•Decreased physical activity•Night shifts

HISTOLOGICAL FACTORS•ADH ALH •Proliferative breast disease•LCIS

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1. GENDER : female:male incidence is 100:1

2. AGE: rare in <20 years. after that, incidence progressively increases with

age

3. PERSONAL H/O OF BREAST CA (RR=6.8)4. HISTOLOGICAL RISK FACTORS: LCIS (RR=16.4) DCIS ( RR= 17.3) NON PROLIFERATIVE DISEASE (RR= 1) PROLIFERATIVE DS WITHOUT ATYPIA (RR=1.3-1.9) PROLIFERATIVE DISEASE WITH ATYPIA ( RR= 3.7-4.2)

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5. FAMILY HISTORY

• first degree relative (parent, sibling, or child) with

premenopausal breast ca (RR=3.3) postmenopausal breast ca (RR=1.8)

• Risk is more with relative having bilateral breast ca

• 2 OR MORE second-degree (grandmother, granddaughter, aunt, niece, half-sibling) relatives with breast or ovarian cancer.

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• Family history of both breast and ovarian cancer.

• One or more relatives with 2 cancers (breast and ovarian cancer or 2 independent breast cancers).

• Male relatives with breast cancer.

6. PRIOR RADIATION EXPOSURE more with high dosage given at early age <30

years as in Hodgkin's disease (RR=5.2)

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7.GENETIC PREDISPOSITION SYNDROME DEFECT ASSSOCIATED CONDITIONS

BRCA1 Chr 17q Ca breast, ovary , prostate and colon

BRCA2 Chr 13q Breast ca (including male), ovary, prostate, larynx and pancreas

LI-FRAUMENI Mutation of p53

Ca breast, brain, adrenal, soft tissue sarcoma

MUIR-TORRE DNA mismatch gene (Hmlh1&2)

Malignancy of breast and GI tractSebaceous tumour , keratocanthoma

COWDEN disease

PTEN gene Chr 10q

Ca Breast, colon uterus, thyroid, lungHamartomous polyp in GI tract

PEUTZ –JEGHERS

STK11 gene Ca breast and pancreasMucocutaneous melanin depositionHamartoma of GI tract

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8. ENDOCRINE FACTORS• EARLY MENARCHE (before 12 yrs) RR=1.3• LATE MENOPAUSE (>55yrs) RR=1.2-1.5 • Women who menstruate for >30 yrs• AGE AT FIRST CHILDBIRTH (>30 yrs ) RR=1.7-

1.9

9. EXOGENOUS HORMONE USE5 yr use has a RR of 1.3

BREAST CANCER RISK ASSESSMENT TOOLS

A. GAIL MODEL• It takes into account of 1. Age2. Age at first period3. Age at first childbirth 4. Family H/O breast cancer5. No of past breast biopsies6. No of breast biopsies showing atypical hyperplasia7. Race/ ethnicity

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• Women with 5 yr risk of 1.67% or higher are classified as HIGH RISK.

LIMITATIONS:• Women with personal H/O DCIS or LCIS• Women with strong family H/O breast cancer

who might have an inherited gene mutation

With all its limitations, it is still used as an initial scoring system

B.NSABP (national surgical adjuvant breast and bowel project)www.cancer.gov/bcrisktool

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C. CLAUSE MODEL• Based on assumptions about the high

penetrance breast cancer susceptibility genes• Provides individual estimate of breast cancer

according to decade of life.

MANAGEMENT OF HIGH RISK PATIENTS

A close surveillance for women with high risk is recommended as:

• Monthly self breast examination starting at 18-20 years of age

• Semi-annual clinical breast examination at age of 25 years

• Annual mammography beginning at age 25 years or 10 years before the onset of breast cancer in a family member

• Addition of annual MRI to mammography is optional

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CHEMOPREVENTIONTAMOXIFEN and RALOXIFEN are the currently

approved for reducing breast cancer risk

TAMOXIFEN : oestrogen antagonist • Proven benefit against ER pos breast caEBCTCG trial: 47% reductionNSABP P-1 trial: 49% reductionMETA-ANALYSIS: 38%

• Side effects include increased risk for endometrial ca (RR=2.5), deep vein thrombosis (RR=1.7), pulmonary embolism (RR=3)

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RALOXIFEN : selective ER modulator (SERM)• Has comparable efficacy in prevention of a

second primary breast carcinoma and a favourable toxicity profile

STAR trial (reported in NSABP P-2 trial)Includes finding from more than 10000 womenShowed that raloxifen usage reduced no of

uterine cancer by 36% and episodes of embolism by 29%

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PROPHYLACTIC MASTECTOMYReduce the risk of breast cancer in high risk

patients by 90%RISK REDUCING MASTECTOMY (RRM)RISK REDUCING SALPINGO-OOPHORECTOMY (SSRO)Has been advocated in patients with BRCA1 & BRCA2

mutation

CONTRALATERAL PROPHYLACTIC MASTECTOMY :Reduced mortality risk by 4.8% in 5 years

Flowchart for management of

high risk patients

THANK YOU

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