Breast Cancer

Breast Cancer

Epidemiology

·        In NZ, 1600 cases each year, 580 die.  Commonest cause of cancer death in women.

·        10% life time incidence (usually over 70)

·        Maori rate similar to non-Maori

·        75% diagnosed with breast cancer are over 50. Uncommon under 40. Mean age of diagnosis is 60 – 65. Younger if genetic risk

·        If > 70 years, more likely to be indolent and hormone responsive.  If < 35 then large and aggressive

·        Survival:

·       Risk Factors

·        Major risks:

o  Woman (100 * men)

o  Age 

o   Previous breast cancer, also previous (or family) history of endometrial, prostate, or ovarian cancer

o  Biopsy showing an at risk condition e.g. atypical hyperplasia

o  Genetic predisposition (eg BRAC1 or 2 account for 5% of breast cancers)

o  Family History:

§  Most with family history don‟t develop it, most who get it won‟t have a family history

§  Risk is above population risk for only 1% of female population

§  4% have a moderate increase in risk if:

·        A mother, sister or father developed breast cancer before 50, or in both breasts 

·        More than one close relative on the same side of the family who had breast or ovarian cancer (geneticist said only genetic if 3 or more affected relatives – it is so common have to have a high incidence in family before suspecting a family loading)

·        Minor risks:

o  Oestrogen exposure: 

§  Slight increase for OC and Depo-Provera (only while taking it – and usually young so less of an issue)

§  Longer duration between menarche and menopause

§  First child beyond 35 or no children 

o  Not having lactated ® slight ­risk of premenopausal cancer

o  Obesity 

o  HRT for more than 5 years increases risk by about 30%. Risk disappears within 5 years of stopping

o  Radiation, environmental hazards

·        Not risk factors:

o  Smoking

o  Small (now disproven?) relationship with low fat, high fibre diet

Symptoms

·        Presenting symptoms:

o  Painless mass: 66%

o  Painful mass: 11%

o  Nipple discharge: 9%

·        Usual presentation is a dominant, painless mass

·        New lump or thickening

·        Change in breast shape or size

·        Puckering or dimpling of the skin

·        Change in a nipple

·        Lumpiness in one breast soon after period ends

·        Pain in the breast that is unusual

 Investigations

·        History and clinical exam

·        Mammogram:

o   Not sensitive < age 35

o   Calcifications: low risk are coarse or rounded, high risk are clustered or branching

o   Shadows: malignant are less circumscribed

·        Ultrasound

·        FNA ® Cytology

·        Core or hook wire biopsy

Pathogenesis

·         Most tumours occur in the epithelial component lining the ducts and lobules.  Epithelial hyperplasia (1 –       2 times risk) ® Atypical hyperplasia – proliferation and atypia of ductal or lobular epithelium. Risk of subsequent cancer = 4 times.

·        Tumour cells secrete cytokines ® fibrosis ® lump. Easier to detect in an older woman (­fat and ¯intra-lobular fibrosis)

·        All breast cancers are different. Tumour growth rates vary considerably. On average takes 9 years to reach 1 cm.

·        Death is from metastases which can occur at any time

·        Spreads to lymph nodes via lymphatics and directly to distant sites via blood stream – not via lymph nodes then to distant sites (although lymph node involved Þ ­risk of blood spread as well)

·        Lots of implicated genes.  Those in familial breast cancer include:

o   BRAC1:

·        Autosomal dominant (but recessive at the level of the cell): if carrier then 65 – 75% risk (ie high penetrance)

·        A tumour suppressor gene, expressed in breast, ovary, thymus, testis

·        Accounts for 40 – 50% of familial breast cancer

o   BRAC2:

·        Associated with male breast cancer, not ovarian

·        10% of inherited breast cancer

Classification of Breast Cancer

·        Classification:

o   Most cancers are intraductal

o   Plus Paget‟s Disease of the Nipple

·        Non-infiltrating/in-situ breast cancer: Does not metastasise but recurrence is a problem. Can become infiltrative and then metastasise

o   Intraductal carcinoma (20 – 30%): 

§  Comedocarcinoma: solid intraductal proliferation, central necrosis, microcalcifications on mammogram 

§  Classified by nuclear grade (low, intermediate and high) and the presence or absence of necrosis. 

§  Can eventually become invasive: removal ® cure 

o   Paget‟s disease (a type of ductal carcinoma in situ): lesion of the nipple caused by malignant cells arising from ducts and invading the nipple epithelium. Looks inflamed (early on can look like eczema). Most often an underlying duct carcinoma. 

o   Lobular carcinoma in situ: 

§  Usually an incidental finding on biopsy affecting terminal ductules

§  Proliferation of terminal ductules and acini 

§  1% per year risk of invasive carcinoma in same or opposite breast – removal isn‟t necessarily cure

·        Invasive/infiltrating breast cancer:

o  Main risk factor: ­age

o  Infiltrative ductal carcinoma (65 – 80%): 

§  No special type: Most common. Grossly stellate or multinodular and very hard. Histologically compressed ductules in a very desmoplastic stroma

§  Medullary: Big, bulky and soft, plentiful lymphocytes, better prognosis than other types 

§  Mucinous (colloid, gelatinous) carcinoma: Grossly: gelatinous mass. Histologically: clumps of cells in lakes of mucin. Better prognosis

§  Tubular Carcinoma: well-formed glands, best prognosis

o  Infiltrative lobular carcinoma:

§  Histological: Indian files around ducts, small cells

§  Often bilateral

·        Features of invasive cancers:

o  Usually dominant mass

o  Usually painless 

o  In time fixed to deep fascia ® immobile 

o  Orange peel appearance: blocked lymphatics ® oedema + suspensory ligaments contract ® distorted shape

o  Also nipple retraction, ulceration of overlying skin

o  Majority arise in the outer quadrants – particularly the upper, outer quadrant

·        On mammography:

o  Infiltrative edge: not well demarcated 

o  ­Density compared with adipose tissue

o  Micro-calcifications: small clustered areas of necrosis

Prognosis

·        Stage: axillary metastases most important, also size. Cancers found on mammography or by self-examination are smaller Þ better prognosis

·        Grade

·        Oestrogen receptor sensitivity: if positive then better – more differentiated and Tamoxifen ® regression

Treatment of Breast Cancer

·        Can‟t cure metastases ® aim of treatment is local control

·        Options:

o  Two options (similar long-term survival):

§  Removal of the lump + radiation therapy (significant ¯ in local recurrence)

§  Mastectomy (or radical mastectomy) + reconstruction

o  +/- Radiotherapy (planned to limit dose to the heart, lung or opposite breast

o  +/- Tamoxifen (anti-oestrogen)

·        Surgery:

·        Most common metastasis is in the bone.  Bisphosphonates ® slow osteolysis

·        Risk factors for recurrence in breast cancer (Þ consider adjuvant chemo):

o  Axillary node status (strongest predictor)

o  Tumour size (> 1 cm)

o  Histological tumour type and grade

·        Adjuvant Chemotherapy:

o   Approx 25 – 30% ¯ risk of recurrence, 15 – 20% ¯ risk of death. Improves long term survival in node positive and node negative disease 

o   4 to 6 courses over 3 – 6 months optimal

o   2 agents better than one: eg 

§  AC: Adriamycin (an anthracycline) and Cyclophosphamide. „Gold standard‟. Adriamycin causes vomiting and wasn‟t used so much until 5HT3 antagonists were available

§  CMF: Cyclophosphamide, Methotrexate and Fluorouracil (another „Gold Standard‟)

·        Hormone Therapy:

o   Aim: prevent breast cancer cells from receiving stimulation from oestrogen

o   Only is oestrogen receptor sensitive

o   Oestrogen deprivation:

§  Block oestrogen receptor: eg Tamoxifen – antagonist.  Taken for 5 years.  Side-effects:

·        Largely well tolerated

·        1 in 3 have post menopausal flushes, vaginal dryness/discharge

·        Initial nausea, weight gain

·        Rare retinopathy 

·        Agonist in the uterus ® ­endometrium ® ­risk of endometrial carcinoma (1 in 1000, usually curable) 

·        PE/DVT (1 – 2 %) 

§  Suppress synthesis: aromatase inhibitors (work in adipose tissue, eg in post menopausal women), LHRH agonist (pre-menopausal, switches off the ovary)

§  Destroy ovaries (surgery or RT) 

o   Leads to ¯recurrent, ¯ 40% incidence of contralateral breast cancer (although absolute risk low)

Breast Screening

·        Of proven benefit in reducing mortality in women over 50: benefits under 50 unclear

·        2 yearly screening after 50 reduces chances of dying from breast cancer by about 1/3. Reduces a one in 42 chance to one in 60

·        In NZ is free from 50 – 64

·        Mammograms less reliable in under 50s: denser breast tissue. Higher false positives ® ­unnecessary investigations. Sensitivity for < 50 years is 50% - 60%, for > 50 years is 80+%. 5 – 10 % screened sent for further investigations. Positive predicative yield is 8.5% (high false positive rate)

·        Further investigations: ultrasound, FNA, biopsy

·        Of 1000 screened, 70 to 120 will be positive, 10 to 30 will proceed as far as open biopsy, and 5 to 10 will have cancer

·        Mammogram less accurate if on HRT

·        Interval cancers: fast growing cancers appearing between mammograms – never ignore a lump

·        Application of screening criteria (see Criteria for Screening Programmes, page 690):

o   It is an important health problem – with a significant incidence.  It is preventable

o   A screening test is available: a two yearly double view double read mammography (double reading increases cancer detection by 15% compared with single reading and reduces recall rate)

o   The screening test is available, acceptable (83% a little uncomfortable only), reasonable sensitivity, but low PPV

o   Natural history is well understood, and there is a detectable pre-symptomatic stage

o   Screening leads to interventions that increase the quality of life: relative risk reduction 10 – 30% for women in the 50 – 65 age group. However, lots of unnecessary interventions, and for a majority (>70%) whose cancer is diagnosed, the outcome is unchanged (but will live with 2 years extra knowledge of condition) 

o   Is there an appropriate infrastructure to provide screening and follow-up? There have been pilot studies

o   Is it cost effective:  Needs at least 70% screening coverage to be cost effective.