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2 BREAST CANCER Epidemiology 30,000 new cases per year in UK Half under 65 - Half of these need mastectomy So at least 7500 breast reconstructions per year + prophylactic Most common cancer in after skin cancer. 1 in 9 who reach 85 will get breast ca. 1 in 8-10-12 over lifetime, Second leading cause of cancer after lung cancer. incidence with screening programme Survival @ 5 yrs but no change in Improved mortality by 15% in last 10 yrs due to breast services. quality, standards. Breast = 25% of gen surgery referrals 90% of breast clinic refs are discharged after assessment 90% of all breast surgery is cancer related, majority elective, none routine. Surgery alone cures 70% of breast cancer. We do not need more breast surgeons we need more nurse practitioners, breast physicians (and reconstructive surgeons?)

Benign Breast Lumps ANDI Abnormalities of Normal Development & Involution new term for Fibrocystic disease covers most benign conditions: o fibro adenomas, cysts, nodularity of the breasts and overgrowth of the breast duct lining Aetiology and Risk Multifactorial Exogenous and endogenous factors Gender, 1% of all breast ca in Age next most important risk of getting ca with age, most post menopausal Family history = 15-20% have a family member with breast ca Mother with breast ca = 2x risk relatives = risk Magnitude of risk with no of relatives and proximity Menstrual status Age at diagnosis Presence of bilateral cancer. Links with early menarche, late menopause and late first pregnancy The total duration of menstrual cycles before full-term pregnancy is cancer risk Premalignant histology on biopsy risk Unilateral ca = risk of contralateral but the development of this does not

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Carcinoma of the male breast (Benedetto PRS 1998) 1% all breast cancers, ~1% bilat, Aggressive tumours Delayed diagnosis but symptoms and signs as for breast ca. Mean age at diagnosis = 60yrs Path types etc as for except invasive lobular only seen in assoc with Klinefelters Neoplastic cells are hormone dependent aetiology related to hyper oestrogen states incidence of +ve IM nodes compared with disease Reconstruction depends on stage. (Stage IV may need chest wall recon) Almost impossible to close the margins after radical or modified mastectomy need thoraco-epigastric flap or distant LD. Pathology Ductal and Non-ductal WHO classify breast cancer into 2 groups Non-invasive and invasive. Non-invasive = DCIS and LCIS Malignant transformation process. 80% are adenocarcinoma 50% in upper half of breast Risk of mets with number of +ve nodes Mets to lung, liver and bone. Ductal - Most cancers are from ductal element of the breast and are invasive Stages: Normal Hyperplasia Atypical hyperplasia DCIS Invasive Ca - Takes 10-20yrs not always through all stages Ductal Carcinoma in Situ o Also called Intraductal Carcinoma (Cancer but not yet learnt to be invasive yet.) is cancer confined by the basement membrane of ducts. o Subtypes Comedo and Non-comedo o 10% bilateral, 20% multicentric, 30% become invasive o Microcalcification on mammogram Invasive ductal. o 75% of all breast ca. Grey white, irregular, spiculated, hard and gritty. o = Adenocarcinoma of the ductal elements Medullary Carcinoma o (= 6% of all invasive ca <5 of all) o soft and fleshy, grows big and well circumscribed. o Good prognosis even with mets (numerous lymphocytes) Tubular Ca o (2%)(well differentiated adenocarcinoma) o small and found on mammogram o High differentiated good prognosis. Mucinous/Colloid. o <5% (bulky mucin forming tumour) o Soft gel mass. o Well diff, excellent prognosis

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Non ductal = from the epithelium of breast lobules Lobular Carcinoma in Situ o no special signs o traditionally NOT regarded as malignant o usually an incidental finding o LCIS = MARKER for risk of getting ca in either breast. o no mammogram changes o a marker of invasive disease rather than a precursor. o Tends to be bilateral (40%) and multifocal (60%). o Affected pts estimated to have 1% chance per yr of getting invasive cancer. Invasive Lobular o 5-10% of invasive ca. o Extensively infiltrative without distinct tumour mass. o Similar prognosis to invasive ductal. o NO MICROCALCIFICATION. Phyllodes o (mixed connective tissue and epithelial tumour o fern-like cellular pattern) o Local Recurrence (De Roos BJS 1999) - Uncommon, 20% of local recurrence o 90% 5 yr survival, low to high grade tumours, low recurrence after radical surgery, o higher recurrence if margins involved, o Size and grade of tumour were prognostic for metastatic . Breast Cancer Genes o 4-5% of all breast ca is inherited with high penetrance autosomal dominant cancer predisposing genes. o Over 25% of all under 30yr with breast cancer are genetic (80% BRCA or TF53) o Less than 1% of over 70s are genetic o All women possess the BRCA 1 and 2 genes. Mutation of these genes inhibits tumour suppression and risk of breast ca. Between 1 in 200-400 are carriers of mutations in the BRCA 1 gene. AD inheritance. o BRCA1 and BRCA2 genes for breast cancer account for 2-3% of breast cancer cases. o Significant family history is strongest risk factor o More than 4 cases under 60yrs age in one family likely to be genetic. o 2-3 cases likely to be chance o Carriers more likely to get ca before 50 and lifetime risk = BRCA 1 = 85%, BRCA 2 is less. o But not cumulative i.e. if dont have cancer by certain age not more likely that you will get it in the next few years each year is the same risk. o The genetic risk of breast cancer decreases with age and the remaining risk of breast cancer if the is older (>40) is lower than the lifetime risk. BRCA 1 carrier only has a 50% risk if she is tumour free at 50. o 25 yr old with BRCA 1 = greater risk of ca in next 10 yrs than age 70 without BRCA. o BRCA1 = usually grade 3, Oestrogen Receptor Neg (ER-ve) likely to be medullary type. o Likely early onset, bilateral (BRCA assoc with ovary ca, TP53 with sarcoma) o BRCA 1 65% chance of ovarian cancer by 70yrs. Other genes may also exist and contribute.

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Ashkenazi Jews = 2% of pop with BRCA 1 or 2 with only 3 mutations (usually lots) Genetic screening not good. Easier if they are in a family where the actual mutation type is know so can be looked for. Detection rates for mutations in isolated breast cancer even at very young age is considerable less than 10%. Even with 4 or more family Breast ca cases the risk of an unaffected inheriting the mutation in a predisposing gene is still only 50%. Carriers may wish to have subcut mastectomy and reconstruction. Only effective form of risk reduction at this time is risk reducing mastectomy (RRM). But only 90% effective Can try Tamoxifen but only works for Oestrogen Receptor Positive (ER+ve) tumours and most BRCA tumours are Oestrogen Receptor Neg (ER-ve).

Assessment of the breast lump Risk Assessment - Age/FHx/Endogenous oestrogen Triple Assessment - Examination/Radiology/Pathology - allows 90% women to be discharged - weekly lump lists are now a rarity MDT Discussion Screening Identifies 6 cancers per 1000 screened. Premenopausal dense breast mammogram not god so only offer mammogram to over 50s MRI good for premenopausal and is done for BRCA families. USS if have lump see between cystic and solid High Res US can pick up some cancers and can monitor tumour response to chemo/radio MRI imaging of implants linguine sign where the implant has pulled away from the capsule leaving multiple parallel lines (stepladder sign), need MRI with silicone or water suppressed sequences. Snowstorm appearance of ruptured implant on USS. Mammography UK screening program = Mammogram every 2 3 yrs between 50 and 65. American Cancer Soc annual mammogram over 40yrs o Benefit of screen between 40 and 50 controversial Strong FH early screening Young pts not good mammogram, US better to see lump/cyst Signs on mammogram = microcalcification, density changes, asymmetry, architectural distortion. Swedish trials demonstrated 44% in mortality from breast Ca with regular mammogram. Follow up Radiology Annual mammography for 6 yrs then Under 50s annual mammogram to 50 then routine screening o - routine screening only 70+ - eligible for voluntary screening 3 yearly on request.

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Stage I and II = early breast cancer, good prognosis Stage III = Locally advanced breast cancer, poor prognosis Inflammatory breast cancer (always Stage III) = warm, erythema and oedema, dermal lymphatic invasion (orange peel skin).

Locoregional Treatment Goals : Optimum local control Adequate disease staging Long term survival Preserve or restore body form

Historical (Halsted - 1894) Mechanistic theory of cancer dissemination (local disease with lymph pathway spread only) Total mastectomy (radical) and axillary clearance. Now we know blood spread also important so more conservative local Rx + systemic Rx He removed pec major and minor during the procedure Breast Conservation Surgery (BCS) For most Stage I/II (6 RCT with 4,300=similar survival rates) Contraindicated if multiple lesions, diffuse microcalcification, steroid dependent collagen vascular disease. Relative contraindication if Small breast with large ca, radiation induced, ongoing pregnancy. Oncoplastic surgical principles allows bigger tumours to have Breast Conservation Surgery.

Lumpectomy Removal of tumour with negative margins + Radiotherapy + Node sampling or clearance. Based on results of NSABP B-06 trial: o Total mastectomy vs. Lumpectomy vs. Lumpectomy & Radiotherapy o No difference in survival between any of the groups o But 40% local recurrence for lumpectomy alone, reduced to 8% if radiotherapy added o Radiofrequency thermal ablation - studies ongoing in breast Sardinia (Milan 14Dec07). Already established for liver etc. Quadrantectomy Young pts + with extensive DCIS around invasive ca are risk of local recurrence. DCIS also spreads towards the nipple quadrantectomy proposed. = better local recurrence rates cosmesis but no survival. Local recurrence total mastectomy Primarily used to treat T2 (2-5cm)tumours. A significant deformity may result if the defect is not reconstructed. May be Rx with circumareolar- orientated mobilisation of the breast mound and direct closure of the overlying skin.

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Concept of mirror surgery to achieve symmetry Thoraco-epigastric flaps (based on the superior superficial epigastric A and V ) may be used for skin following lower quadrant resection. Axillary tail transposition flap used for the upper outer quadrant, also inverted T breast reduction.

Follow-Up Invasive Disease and all conserved breasts followed up at 3/12 to check arm mobility then 6/12 for 2 yrs, annual for 4 yrs, consider discharge at 6yrs. Mastectomy

Subcutaneous Mastectomy 90-95% of the breast tissue is removed The NAC is preserved When used prophylactically is breast cancer reducing not preventing as some breast tissue remains. There are reports of cancer occurring after this. Can perform immediate reconstruction with implant or expander under muscle or de-epithelialised flap. Skin sparing mastectomy for extensive DCIS Skin Sparing Mastectomy (Kroll Surg Gyn Obs 1991, Carlson Ann Surg 1997, Slavin PRS 1998, Hidalgo PRS 1998) o Removes breast, nipple/areolar complex and biopsy scar. o Superior aesthetic result o Preserves native breast skin (except skin over Ca) o Keeps IMF o Less need to change the other breast o Improves response to mastectomy All forms of mastectomy leave SOME breast tissue behind Local recurrence rate is proportional to the STAGE of disease and tumour biology rather than the type of surgery. SSM used safely in the treatment of invasive Ca without compromising local control Average time to recurrence ~2-4 years (30% in yr1, 50% by end yr2) Most recurrence in skin Local recurrence is a marker for disseminated disease: (All pts of mets) Incidence of skin flap necrosis same as for non-SSM Indications = o Prophylaxis, DCIS, Stage 1 or 2 Invasive Ca, Phyllodes, Immediate recon o For DCIS Treat with Mastectomy and 6 node sample so if there is only a small focus of invasive ca they may not need further

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surgery. However if any of the 6 nodes are +ve they may need formal axillary clearance. Follow up 3/12, then annually for 6yrs then discharge.

Classification (Carlson?) o Type 1 NAC only (prophylactic) o Type 2 NAC + separate scar excision o Type 3 NAC + in-continuity scar excision o Type 4 NAC within a breast reduction ( large breast unsuited for tram with contralateral BR planned) May need separate incision for axillary sampling/clearance and/or microsurgery Nipple reconstruction after 3 months remove the obvious patch.

Simple (Total) mastectomy Remove entire breast, NAC and skin overlying tumour. Stage 3 or 4 disease, or stage 2 with small breasts. Common treatment. Done if pt prefers or if breast conservation has been contraindicated.

Modified radical mastectomy Simple mastectomy and Level 1 & 2 clearance Leaves Pec Major (unlike traditional radical) Normal for Stage II and IV assoc with systemic Rx

Risk Reducing Mastectomy (RRM) In high risk women = life time risk 25% or greater Carriers BRCA1-2 (?TF53) 2 relatives including x1 1st degree below 50yrs 3 relatives under 60yrs Reduces risk of ca by 90% (Hartmann N Eng J Med 1999, Maiijers-Heijboer N Eng J Med 2001) Contralateral RRM o Use the reference malignancy to assess prognosis pattern o i.e. do not do in someone who has poor prognosis from her original breast ca. Manchester Protocol (E J Surg Oncol 2000) o FH Clinics since 1987 MDT.
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RRM degrees of risk reduction depending on what is removed /left behind. Most have SSM leaving areolar but taking nipple. Objectives of RRM incidence of breast ca, anxiety, mortality. Balance risk with cosmetic outcome Highest risk area = upper outer quadrant

35%

15%

5% NAC 25% 20%

Breast Cancer Site (% of total breast cancers)

The Axilla May be treated by axillary clearance or biopsy followed by post-op radiotherapy if +ve nodes. Sampling = remove at least 5 nodes from level I. Sentinel node believed to accurately stage the axilla and morbidity. Remove nodes get staging + locoregional control +ve LN most important prognostic indicator (x1 positive node reduces 5 year survival 90% 60%) Clinic exam axilla poor (25% clinically normal have micromets) Levels of dissection relate to pec minor, I = lateral, II = under, III = medial Level I + II =10-15 LNs adequate staging in clinically uninvolved axilla Skip mets to III is rare (if none in I + II) Level III clinically involved nodes but risk lymphoedema If no LNs get risk of local recurrence but is OK in older pts with ER +ve small tumours

Treatment of DCIS Degree of malignant potential not clear If not treated some but not all will become invasive ductal ca. Local recurrence after surgical excision only = 30% depending of tumour size and hist type. 50% of these of local recurrence will be invasive Radiotherapy risk of local recurrence (NSABP B-17 trial Fisher 1993, 818 with DCIS, lump +/- Radiotherapy, Lump only = 16% local recurrence, lump + Radiotherapy = 7% local recurrence.) Extensive DCIS = SSM

SYSTEMIC THERAPY Adjuvant chemo and hormonal Rx used to eliminate occult mets responsible for later recurrences. Can reduce odds by 30%. Effect on disease free interval is than overall survival. risk of local recurrence or risk = benefit of Rx Post Op Chemotherapy prolongs disease free survival in pre-menopausal Not clear benefit in post menopausal
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Chemo regimes include: o CMF (Cyclophosphamide, methotrexate, 5 FU) o FAC (5 FU, Doxorubicin, cyclophosphamide) o AC (Doxorubicin, cyclophosphamide) Tamoxifen (oestrogen antagonist) for 5 years esp. good in post menopausal , may also have beneficial effect on survival in premenopausal . YES for all Oestrogen Receptor Positives (ER+ve).

Receptors - positivity indicates more aggressive behaviour, but can be targeted with specific receptor blockers ER - Oestrogen receptor and/or PR - Progesterone receptor Tamoxifen blocks here (Femara (letrozole) for post-menopausal after tamoxifen) HER2 (Human epidermal growth factor 2) Herceptin (trastuzumab) blocks the receptor Triple Negative None of the above 3 receptors present Neo-adjuvant therapy Neo-adjuvant chemo Rx downstages tumour size and treats systemic disease. Downstaging tumour size may chances of breast conservation Neo-adjuvant radiotherapy may also be used except where local tissues are required for flap closure. Overall response rate to neo-adjuvant chemo ~ (80%) with complete response in ~30%, but no evidence of a survival advantage. But there is significant morbidity rate assoc with chemotherapy Radiotherapy usually used post op. Radiotherapy High energy x-rays to treat cancer Damage cells limit tumour growth, then the normal cells recover better time between cycles is critical so that the normal cells recover while the tumour cells dont.

Treatments Radiotherapy considered post-surgery for early ca aim to eradicate the remaining ca cells in the treatment area minimise risk of regrowth of the ca. Lumpectomy followed by radiotherapy to rest of breast Mastectomy followed by RT to chest wall or LNs Occasionally preop to size of tumour to avoid mastectomy. If chemo + radio timing not established so trials happening. If ALL LNs surgically removed then AVOID radio to axilla to avoid lymphoedema. Side Effects Common o Skin reactions (red, pigment, tender, itchy10-14/t, flake, peel, moist, weepy) o Aches/twinges and shooting pains (? years after treatment, in time.) o Dont usually feel unwell just tired. Less Common

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o o o Rare o o o o o

Lung tissue inflammation dry cough, SOB appetite and nausea Axillary hardening and fibrosis lymphoedema Fibrosis, breast size telangiectasia, #, paraesthesia

Breast Cancer Drugs Oestrogen-Receptor Antagonists o Tamoxifen (Nolvadex) = Adjuvant hormonal treatment of choice in all women with oestrogen-receptor positive breast cancer. Delays the growth of mets and increases survival. If tolerated should be continued for 5 years. Also risk of developing cancer in the other breast. o Prophylaxis can reduce breast ca in high risk , but adverse effects may preclude its use. o Fulvestrant (Faslodex) o Toremifene (Fareston) Aromatase Inhibitors o Act predominantly by blocking the conversion of androgens to oestrogens in the peripheral tissues. They do not inhibit ovarian oestrogen synthesis so should NOT be used in premenopausal women. Better for mets than tamoxifen. o Anastrozole (Arimidex) o Letrozole (Femara) o Exemestane (Aromasin) o Aminoglutethimide (problems with adrenal hypofunction) Gonadorelin Analogues o Goserelin (Zoladex) licensed for the management of advanced breast cancer in premenopausal and ER positive early breast cancer. They cause initial stimulation the depression of luteinising hormone release by the pituitary. (Used to produce a chemical orchidectomy in prostate cancer) Side effects are menopausal symptoms. (Implant type s/c injection every 28 days). Cytotoxic chemotherapy o Preferred for pre and post menopausal with ER neg cancer and for aggressive disease esp. with visceral mets, or when disease free interval after treatment is short. o Most common adjuvant and for mets was cyclophosphamide, methotrexate and fluorouracil. Now anthracycline containing regimes are better (but contra-indicated in cardiac disease) Trastuzumab (Herceptin) o Licensed for metastatic breast cancer in patients with tumours overexpressing the human epidermal growth factor receptor 2 (HER2) who have not received chemotherapy for mets and in whom anthracycline treatment is inappropriate. Is also licensed as monotherapy for mets ca in HER2 +ve ca where 2 chemo regimes have not worked and have also tried hormonal treatment.
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o o

Cardiotoxicity possible so need monitoring and resus facility. Addendum May 2006 licensed for early cancer by NICE

Progestogens o Medroxyprogesterone acetate. Role in postmenopausal with advanced Ca. As good as tamoxifen but less well tolerated, less good than aromatase inhibitors. Retinoids and Rexinoids E.g. Fenretinide Studies for BrCA positives and ER neg under way. Promising results so far according to Bonanni at Milan meeting 13dec07 But ?teratogenic, so contraception is mandatory Breast Psychology (Penny Hopwood, Manchester BAPS 31Mar06) Burgess - BMJ 2005 o Interview based study of depression/anxiety o Anxiety levels back to normal at 1yr (15%) o Depression back to normal at 5yrs (15%) o Both are predictors for low body image and sexual dysfunction o Younger at higher risk Pre-Op Predictors of dissatisfaction o Low self esteem o High self conscious o Emotional investment in appearance e.g. fashion/fitness industry Living with Genetic Risk o Associated with poor QoL?

BCT - G. Querci della Rovere - Marsden look up notes from Milan Thu 13dec07 look up grisotti advancement rotation flap and this guys e3 modification of it. Consider superior or inferior pedicle, comma mastoplasty, grisotti, benelli etc.. Imaging post recon Mammography in combination with USS MRI coming in.

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