Breast cancer

• Uncommon <30yo.  1/3 are premenopausal, 2/3 are postmenopausal
• 1 in 11 women in Australia develop breast cancer
• Of those who present with local disease, about 50% will develop metastases. 

Risk Factors

• Increasing age (>40yo), Caucasian
• Pre-existing benign breast lumps
• Alcohol, Obesity
• HRT >5 years
• Personal history breast cancer
• Family history in a first degree relative (raises risk about 3 fold). 5% of cases are familial.
• Nulliparity, Childless until after 30yo, Late menopause (after 53yo), Early menarche
• Ionising radiation exposure

Screening

• Mammogram in women 50-69yo every 2 years
• Insufficient evidence for clinical breast exams (therefore cannot recommend them)
• Might start mammograms at 40 if first-degree relative <50years at diagnosis.

Clinical features

• Presenting symptoms of breast cancer
  • HARD irregular lump
  • Thickening or ridge
  • Breast or nipple asymmetry
  • Skin changes, skin dimpling, puckering
  • skin oedema (peau d’orange)
  • Nipple changes/distortion/eczema
  • Nipple discharge
  • Unilateral breast pain

• Relevant history
  • Previous breast issues/investigation
  • Risk factors
  • hormonal status, menstrual history, parity, recent pregnancies and breastfeeding 
  • current medications or recent changes in medication, especially exogenous hormones, complementary and alternative medicines 
  • lifestyle factors, including obesity, alcohol, physical activity and smoking 
  • most recent imaging results – screening or diagnostic 
  • previous radiation therapy or previous breast surgery, including cosmetic surgery 
  • recent breast trauma – symptoms still require investigation

Examination

• Inspection – upright
  • Arms by side, above head, pressing hips and leaning foward
  • Breast contours, skin changes, nipples
• Palpation
  • Upright – supraclavicular and axillary lymph nodes, breasts (particularly outer quadrants)
  • Lying flat – all quadrants, axillary tail, around and behind nipple
• Record details of any changes

• Nipple
• Benign nipple changes may include
  • Slit like retraction
  • Retraction that is easily everted
• Suspiscious nipple changes
  • Colour change
  • Fixed whole nipple inversion
  • Ulceration and eczematous changes
• Nipple discharge
  • Unilateral, spontaneous, bloody or serous discharge highly suspiscious
  • Positive cytology is indicative, but negative cytology is not sensitive
  • If bilateral, no blood – review, consider prolactin levels

Investigations

  Triple test

1. Medical history and breast examination
2. Imaging– mammography and/or ultrasound
3. Non-excision biopsy – core biopsy and/or fine needle aspiration (FNA) cytology.

• Mammography – Established benefit >50yo, possible benefit for women in 40s
• Breast ultrasound
  • Mainly used to elucidate an area of breast density, best method of defining benign breast disease, especially with cystic changes
  • USS more sensitive in young women
  • Most useful in women <35yo (as compared with mammography)
  • Also good for palpable masses at periphery (mammograms wont pick these up)

• Age Under 35
  • USS first line. Use mammogram if suspicious, malignant, indeterminate or USS not consistent with clinical findings
• Age 35 – 50
  • Do both mammography and USS
• Age> 50 years
  • Mammogram only, but in some cases USS may be useful, always useful if discrete breast lump
• Pregnancy/lactation
  • USS more useful
  • Mammogram if suspicious/indeterminate
• Biopsy
  • Core biopsy or FNA – image guided, Core biopsy preferred if suspicious
  • FNA if suspected cystic lesion or fibroadenoma, useful in solid lesions with an accuracy of 90 – 95%

• Surgical referral if
  • Any component of triple test is positive or indeterminate
  • Cyst aspiration is incomplete, bloody, or lump remains post aspiration
  • Suspicious nipple discharge
  • Eczematoid changes of the nipple/areolar which persis > 1-2 and do not respond to topical treatment
  • Inflammatory breast conditions that do not resolve after 2 weeks Abx

• if stage 1 or 2: tumour excision followed by whole breast irradiation
• Total mastectomy and breast-conservation surgery had equivalent survival
• Total mastectomy preferred for larger tumour, multifocal, previous irradiation
• Radiotherapy after surgery
  • if tumours >4cm, >3 axillary nodes involved
  • positive or close tumour margins
• Chemo has an important role
• Adjuvants:
  • anti-oestrogens (tamoxifen)
  • aromatase inhibitors (eg. anastrozole)
  • monoclonal antibodies (eg Herceptin)
  • progesterone

Risk Factors

• Sex: Being a woman is the strongest risk factor for breast cancer. Women are 100 times more likely to develop breast cancer than men
• Age
  • woman in her 30s the risk is approximately 1 in 250
  • woman in her 70s, it is approximately 1 in 30
  • Most breast cancers are diagnosed after the menopause
  • about 75% of breast cancer cases occur after 50 years of age. 
• Family history
  • Women with a mother, sister or daughter with breast cancer are, on average, at twice the risk of those with no affected first-degree relative (ie RR 2).
  • The risk increases with the number of first-degree relatives affected and, when three or more first-degree relatives are affected, the risk becomes more than three times that for women with no affected first-degree relatives (ie RR >3). 
  • The risk associated with family history increases also when relatives with breast cancer are diagnosed at a young age and when the family is of Jewish descent Ashkenazi or Eastern European Jewish ancestry
  • rare deleterious mutations in genes such as BRCA1 and BRCA2 that are associated with a high risk of the disease. 
  • A family history of ovarian cancer increases the risk of breast cancer because the risk of ovarian cancer is also associated with these genes. 
• Breast conditions
  • Women diagnosed with invasive breast cancer are at two to six times the population risk of developing cancer in the contralateral breast (other breast). 
  • preinvasive breast conditions
    • lobular carcinoma in situ
    • ductal carcinoma in situ
    • atypical ductal hyperplasia.
  • Mammographic breast density
    • Women having the highest degree of breast density are at four to six times greater risk than women with little or no breast density.
• Endogenous oestrogens
  • Postmenopausal women with high levels of circulating oestrogens (women with levels in the top 20%) have a two-fold increased risk of breast cancer compared with women with low levels of circulating oestrogens (women with levels in the bottom 20%)
• Hormonal factors
  • Factors associated with a modestly increased risk (RR 1.25–1.99) include:
    • older age at menopause (over 55 years vs 55 years or less)
    • use of combined hormone replacement therapy (current users vs never)
    • use of oral contraceptive pill (vs never, risk decreases to normal 10 years after ceasing use)
    • younger age at menarche (commencement of menstruation younger than 12 years vs 12 years or more)
    • high circulating levels of androgens (women with levels in the top 20% vs women with levels in the bottom 20% for postmenopausal women and possibly for premenopausal women)
    • high circulating levels of insulin-like growth factors (IGF-1 and IGFBP-3, women with levels in the top 25% vs women with levels in the bottom 25%, possibly only for postmenopausal women)
    • use of diethyl stilbestrol(DESPLEX)  during pregnancy and exposure to diethylstilbestrol in utero

• Factors associated with a decreased risk (RR <0.8) include:
  • parity (giving birth to at least one child vs never having carried a pregnancy; ie nulliparity)
  • earlier age at first birth (<25 years vs >29 years)
  • breastfeeding (at least 12 months’ total duration vs no breastfeeding) 
  • number of births (≥4 vs 1).
• Personal and lifestyle factors
  • Factors associated with a modestly increased risk (RR 1.25–1.99) include:
    • taller height (≥175 cm vs <160 cm)
    • overweight and obesity for postmenopausal women (body mass index >25 kg/m2  vs <21 kg/m2)
    • alcohol consumption (three or more standard drinks per day compared with none)
    • a previous personal history of some types of cancer other than breast cancer including melanoma, colorectal, ovarian, endometrial and thyroid cancer
    • high-dose ionising irradiation, especially before age 20.
  • Factors associated with a decreased risk (RR <0.8) include:
    • physical activity (two or more hours of brisk walking or equivalent per week vs no activity).

• Factors that have not been shown to impact on risk for breast cancer
  • pregnancy termination or abortion
  • tobacco smoking (study findings are inconsistent)
  • exposure to environmental tobacco smoke (study findings are inconsistent)
  • environmental pollutants
  • wearing a bra or different types of bra
  • silicone implants
  • use of underarm deodorant or antiperspirant
  • stress.

Screening

• Mammogram in women 50-69yo every 2 years
• Insufficient evidence for clinical breast exams (therefore cannot recommend them)
• Might start mammograms at 40 if first-degree relative <50years at diagnosis.

• There is insufficient evidence to assess the balance of benefits and harms of screening mammogram in women aged >75 years 
• There is insufficient evidence to recommend that clinical breast examination offers any benefits to women, of any age/ However, it is recommended that all women, whether or not they undergo mammogram screening, are aware of how their breasts normally look and feel, and promptly report any new or unusual changes (such as a lump, nipple changes, nipple discharge, change in skin colour, pain in a breast) to their GP. No one method for women to use when checking their breasts is recommended over another.
• First-degree = parents, brothers, sisters, children
• Second-degree = aunts, uncles, nieces, nephews, grandparents, grandchildren

Risk Level	Age	Relatives	Diagnosed Conditions	What should be done?	How often?
Low Risk	No age restriction	No confirmed family history	No diagnosed breast cancer in the family	Mammogram + Breast awareness	Every 2 years from 50-74y
	≥50 years	(1)x 1st-degree relative	Diagnosed with breast cancer
	Any age	(1)x 2nd-degree relative
	≥50 years	(2)x 2nd-degree relatives on the same side of the family
	≥50 years	(2)x 1st-degree or 2nd-degree relatives on different sides of the family
Moderate Risk	<60 years	(1)x 1st-degree relative	Diagnosed with breast cancer (without additional features of high-risk group)	Referral: Advise referral to a cancer specialist or family cancer clinic for:- Risk assessment- Possible genetic testing- Development of a management plan Chemoprevention: – Consider treatment with selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) for women at moderate or high risk of breast cancer. SERMs: = Tamoxifen: Greater efficacy, can be used in premenopausal women. = Raloxifene: Fewer adverse effects. Surgical Options: Consider mastectomy or salpingo-oophorectomy, especially for those at high risk: = Mastectomy: Reduces the risk of breast cancer. = Salpingo-oophorectomy: Greater effect on reducing ovarian cancer risk, also reduces the risk of breast cancer. Decision-Making: = Requires careful assessment of risks and benefits for individual women. Ongoing Surveillance: = Regular clinical breast examinations = Mammography = Magnetic resonance imaging (MRI) = Ultrasound = Consideration of ovarian cancer risk	Ages 50 to 74 years:= Frequency: At least every (2) years. Ages 40 years and older (with specific family history): = Frequency:Annual mammograms may be recommended if the woman has a 1st-degree relative diagnosed with breast cancer before age 50. Individualized Surveillance Program: = May include regular clinical breast examinations and annual breast imaging. = Mammography, MRI, or ultrasound. = Point: Tailored to individual risk factors and medical history.
	Any age	(2)x 1st-degree relatives on the same side of the family
	<60 years	(2)x 2nd-degree relatives on the same side of the family
HIGH Risk	Any age	Women at potentially high risk of ovarian cancer
	Any age	(2)x 1st-degree or 2nd-degree relatives on (1) side of the family	Diagnosed with breast or ovarian cancer, plus (1) or more of the following features: – Additional relative(s) with breast or ovarian cancer – Breast cancer diagnosed before age 40 years – Bilateral breast cancer – Breast and ovarian cancer in the same woman – Ashkenazi Jewish ancestry – Breast cancer in a male relative
	<45 years	(1) 1st-degree or 2nd-degree relative	Diagnosed with breast cancer AND – another 1st-degree OR – 2nd-degree relative on the same side of the family with sarcoma (bnoe/soft tissue) aged <45 years
	Any age	Member of a family with a known high-risk breast cancer gene mutation	Established presence of a high-risk breast cancer gene

Hereditary conditions predisposing to breast cancer

			%
Disease	Other tumour susceptibility	Inheritance	BC	HPBC	Location
Familial breast BRCA1	Ovary, prostate	AD	1.7	50	17q21
Familial breast BRCA2	Ovary, prostate, male breast cancer	AD	1.2	35	13q12
Li-Fraumeni TP53	Sarcoma, brain, adrenocortical	AD	0.1	1	17p13.1
Ataxia-telangectasia ATM	Homozygotes (leukaemias)	AR	0	0	11q22.3
	Heterozygotes (gastric)		2	4–8
Cowden PTEN	Skin, thyroid, bowel	AD	<1	<1	10q23.3
Reifenstein	?	XLR	<1	0	Xq11
Hras variant		AD	?8	0	11p15.5
hCHK2	Breast	AD	4	0	22q12.

AD, Autosomal dominant

AR, autosomal recessive

XLR, X linked recessive

HPBC, highly penetrant hereditary breast cancer (eg >3 affected relatives).

Ductal Carcinoma in situ

• Precursor to invasive breast cancer
• Non-invasive abnormal proliferation of milk duct epithelial cells
• Readily detected on mammography
• Now comprises 20% of breast cancer
• May present clinically with a palpable mass or nipple discharge
• Management is challenging decision – total mastectomy vs breast-conserving therapy with or without radiotherapy
• Excellent outcomes, with low local recurrence rates and survival of at last 98%