Locally advanced breast cancer

LABC -SURGERY AND TREATMENT

1. Locally advanced breast cancer DR.I.DAVID THANKA EDISON MS PG ,MADURAI

2. LOCALLY ADVANCED BREAST CANCER DEFINITION: Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but have no clinically detected distant metastases. LABC includes stage III A and III B of TNM staging – AJCC 2010

3. TNM STAGING OF LABC T N M STAGE III A T3 N1 M0 T0-3 N2 M0 STAGE III B ANY T4 N0-2 M0 STAGE III C ANY T N3 M0

4. CLINICAL PRESENTATION Skin edema- peau’d orange Satellite skin nodules Skin ulceration Tumor fixation to the chest wall Fixed axillary nodes   • I nfraclavicular , internal mammary, and supraclavicular adenopathy  

5. TRIPLE ASSESSMENT. CORE NEEDLE BIOPSY - histology and receptor status studies MAMMOGRAPHY to the contralateral breast METASTATIC WORK UP - Chest X Ray USG abdomen pelvis, Liver function tests CT chest, Skeletal survey by Bone scan or X-rays CT brain - only if symptoms suggestive . ROUTINE EVALUATION INVESTIGATIONS

6. Why no FNAC? Histological type, grade and receptor status is must for all LABC Receptor status helps in selecting chemotherapeutic agents Triple negative tumors – Adriamycin based chemotherapy Her 2 positive tumors- Herceptin can be added Tumor may completely disappear after anterior or neo adjuvant chemotherapy

7. SKELETAL SURVEY A routine X-ray will pick up metastatic lesion only when 60% of the bone is demineralized. Bone scanning will pick up metastases even <30% demineralization in about 20–30% of cases of stage III breast cancer

8. MANAGEMENT OF LABC Options available: Chemotherapy Surgery Radiotherapy Hormone Therapy Multi-pronged approach adopted Single approach ineffectual 8

9. OPERABLE SUBSETS OF LABC Mobile axillary node No chest wall fixity Small skin involvement T 3 N 1 M

10. T 3 N 1 M T any N 2 M “ Can achieve negative pathology margins ” III B & III C Management Operable Non-operable Multidisciplinary N CCN 2013 Surgery Then adjuvant Chemotheraphy & Radiotheraphy According to guidelines Neoadjuvant Systemic therapy

11. CHEMOTHERAPY APPROACH Types; Neoadjuvant Chemotherapy (Anterior or upfront ) Administration of Cytotoxics in large operable tumours before surgery Reduce loco-regional tumour burden – downstage Amenable to surgical resection after 3 doses Adjuvant Chemotherapy Administration of Cytotoxics after surgery Eliminate clinically undetectable distant spread Palliative Chemotherapy Advanced Ca Breast Metastatic Ca Breast 12

12. CHEMOTHERAPY REGIMES CAF and CMF – commonly used, monthly/3 weeks cycles for 6 months Taxanes Eg: PACLITAXEL and DOCETAXEL G2/M phase arrestors 4 AC  4 T 1 st line : CMF > CAF > MMM 2 nd line : Taxanes 3 rd line : Gemcitabine SR_Ca_Breast_Rx 13

13. NACT REGIMENS (HER2 NEGATIVE) Dosage day cycle CMF Cyclophosphamide 600 mg/ m 2 i.v Day 1 Every 21 days Methotrexate 40 mg/ m 2 i.v Days 1 & 8 5-Fluro Uracil 600 mg/ m 2 i.v Days 1 & 8 CAF Cyclophosphamide 600 mg/ m 2 i.v Day 1 Every 21 days Adriamyci n (Doxorubicin) 60 mg/ m 2 i.v Days 1 & 8 5-Fluro Uracil 600 mg/ m 2 i.v Days 1 & 8 4AC  4T 4 cycles of AC Day 1 Every 21 days Followed by 4 cycles of Taxanes Paclitaxel 175mg/ m 2 i.v Day 1 Docetaxel mg/ m 2 i.v

14. CLASS GENERIC NAMES COMMON/SEVERE SIDE EFFECT Anthracycline Doxorubicin,Epirubicin Cardiomyopathy, secondary AML Alkalyting agents Cyclophosphamide Hamorrhagic cystitis, pulmonary fibrosis Antimetabolites Methotrexate Alopecia, Renal tubular damage Fluropyrimidines 5-Flurouracil Mucositis , Hand foot syndrome,Myelosuppression Taxanes Paclitaxel Peripheral neuropathy,arrhythmia Antimetabolites Gemcitabine Myelosuppression , Pulmonary fibrosis Vinca alkaloids Vin cristin Myelosuppression , Paralytic ileus Platinums Carboplatin, Cisplatin Electrolytic distrubance , SIADH

15. ROLE OF HERCEPTIN(TRASTUZUMAB) IN NACT Monoclonal Ab. Blocks Her-2/ Neu receptors (Tyrosine kinase receptor) Useful only in Her-2/ Neu +’ve cases NACT regimen (Her2 positive) 4AC followed by Taxane and Trastuzumab Taxane for 12 weeks Trastuzumab 4mg/kg loading dose With 2mg/kg maintanence dose i.v weekly Or 6mg/kg i.v every 21 days For one year

16. RESPONSE TO CHEMOTHERAPY Complete responders – 100% Partial responders – 50-99% Poor/non responders - <50% decrease or upto 25 % increase Progressive disease - >25% increase or appearance of new lesions

17. Locally Advanced Breast Cancer Duration of neoadjuvant chemotherapy Optimal duration of treatment is not known. Rule of thumb: “treat until maximal response.” May require from 2-8 treatments, depending on rapidity of response. Patients should be assessed by multidisciplinary team after every 2 cycles of chemotherapy to determine optimal timing of surgery.

18. SURGERY – TYPES OF MASTECTOMY

19. INCISIONS FOR MRM CLASSIC STEWART ELLIPTICAL SKIN INCISION FOR CENTRAL AND SUBAREOLAR BREAST CANCERS. MODIFIED STEWART OBLIQUE ELLIPTICAL SKIN INCISION FOR INNER QUADRANT BREAST CANCERS.

20. VARIATION OF THE ORR OBLIQUE ELLIPTICAL INCISION FOR LOWER INNER QUADRANT AND LOWER MIDLINE (6 O'CLOCK) BREAST CANCERS. ORR INCISION FOR UPPER OUTER QUADRANT

21. GRAY INCISION FOR MASTECTOMY IN CARCINOMA BREAST WHICH EXTENDS TO OPPOSITE SIDE. RODMAN INCISION FOR MASTECTOMY.

22. GREENOUGH INCISION FOR MASTECTOMY.

23. FLAP RAISING Skin flap thickness varies with body habitus Ideally skin flap is 7 to 8 mm in thickness , inclusive of the skin and telasubcutanea

24. ANATOMIC BOUNDARIES OF MRM Lateral - anterior margin of latissimus dorsi muscle Medial - midline of the sternum Superior - subclavius muscle Inferior - caudal extension of the breast 2 to 3 cm inferior to the inframammary fold

25. BOUNDARIES OF AXILLARY DISSECTION Superior - Axillary vein Inferior - Angular vein Medial – costo clavicular ligament Lateral – Anterior border of latissimus dorsi Anterior - Pectoralis major Posterior - Subscapularis

26. COMPLICATIONS OF M.R.M Injury/thrombosis of axillary vein Seroma —50-70% Shoulder dysfunction 10% Pain (30%) and numbness (70%) Flap necrosis/infection Lymphoedema (15%) and its problems Axillary hyperaesthesia (0.5-1%) Winged scapula Pectoral muscles atrophy if medial and lateral pectoral nerves are injured Weakening of internal rotation and abduction of shoulder occurs due to injury to thoracodorsal nerve 33

27. LYMPHANGIOSARCOMA (Stewart-Treve’s Syndrome) In ipsilateral upper limb Develops in people with Lymphoedema after Mastectomy with Axillary clearance. 3-5 years after development of Lymphoedema Presentation: Multiple subcutaneous nodules Requires Forequarter Amputation Poor prognosis 34

28. POST OP MANAGEMENT Adjuvant Chemotherpy Adjuvant Radiotherpy Hormonal therapy

29. INDICATIONS FOR ADJUVANT CHEMOTHERAPY All node positive patients Primary tumour >1cm in size Tumor 0.6 to 1 cm with high risk factors All locally Advanced Ca Breast Inflammatory Ca Breast 36

30. INDICATIONS FOR ADJUVANT RADIO THERAPY Chest Wall Axilla T3 tumour>5cm Residual disease LABC Positive margin/close surgical margin <2cm Inflammatory Carcinoma 4 or more nodes +’ve in post menopausal females 1 or more nodes in pre menopausal females Extra-nodal spread Axillary status unknown/ not assessed

31. EXTERNAL RADIOTHERAPY Over Breast area, axilla, Internal mammary and Supra-clavicular area Total dosage: 5000 cGy units 200-cGy units daily 5 days a week for 6 weeks Internal Radiotherapy 38

32. HORMONE-THERAPY APPROACH Principles; Used in ER/PR +’ve patients only All age groups included now Relatively safe Easy to administer Adequate prophylaxis against Ca of opposite breast Useful in Metastatic Carcinoma Reduces recurrence – improves quality of life and longevity 39

33. LOCALLY ADVANCED BREAST CANCER Hormonal Management, continued:LIMITIONS Rate of pathologic complete response is greatly diminished. Rate of breast-conserving treatment is greatly diminished. Response to treatment is much slower, e.g. 3-9 months.

34. HORMONAL THERPY Medical Oestrogen Receptor Antagonists – Tamoxifen 20 mg Progesterone receptor Antagonist Oral Aromatase Inhibitors – Letrozole 2.5 mg OD, Anastrozole , Exemestane ; Aminoglutethimide [ Medical Adrenalectomy ] Androgens – inj.Testosterone propionate 100mg IM three times a week, Fluoxymestrone 30 mg daily LHRH Agonists – Goserelin (Zoladex) [ Medical Oophorectomy ] Progestogens – Medroxypregesterone acetate 400 mg Surgical Ovarian Ablation by Surgery (Bilateral Oophorectomy) Radiation Adrenalectomy Pituitary ablation 41

35. Tamoxifen SERM ( Selective Estrogen Receptor Modulator ) Blocks cytosolic ER in breast tissue Dose: 10 mg BD or 20 mg OD for 5 days T1/2: 7 days . Shows effects after 4 weeks Cheap, easily available, effective Indications: Carcinoma Breast Fibroadenosis Male infertility Desmoid tumours Side-effects: ‘ Tamoxifen Flare ’: Flushing, tachycardia, sweating, pruritis vulva, vaginal atrophy and dryness (pre-menopausal), vaginal discharge (post-menopausal), fluid retention, weight gain Agonistic action: Endometrium (Ca), Bone (Osteoporosis, pathological #), Coagulation system (DVT, TIA, CVA, MI) 42

36. Letrozole Non-steroidal competitive inhibitor of Aromatase Reduces Oestrogen levels by 98% More expensive, more effective, fewer side-effects Indications: Adjuvant Endocrine therapy in Post-menopausal women with hormone sensitive breast cancer Metastatic disease Recurrent disease Dosage: 2.5 mg OD for 5 years or for 3 years after Tamoxifen Side-effects: Vaginal atrophy, bleeding p.v, CVS problems and osteoporosis. 43

37. Novel drugs - Biologicals TRANSTUZUMAB (Herceptin ) Monoclonal Ab. Blocks Her-2/Neu receptors (Tyrosine kinase receptor) Useful only in Her-2/Neu +’ve cases Metastatic d/s Intravenous infusion 4mg/kg loading, 2mg/kg maintenance dose for 1 year BEVACIZUMAB Vascular Growth Factor receptor inhibitor LAPITINAB Combined Growth Factor receptor inhibitor 44

38. Inflammatory Ca Breast ‘ Mastitis carcinomatosis’/ ‘Lactating Ca of Breast ’ 2% incidence Younger age T4d LABC (Stage IIIB) FNAC or incision biopsy Neoadjuvant ChemoT and RT Surgery (if downstaged) + Axillary clearance Five years survival 25-30% 45

39. Inflammatory Vs Noninflammatory Breast Cancer Inflammatory Noninflammatory Dermal lymph vessel invasion is present with or without inlflammatory changes Inflammatory changes are present without dermal invasion Cancer is not not sharply delineated Cancer is better delineated Erythema and Edema frequently involve >33% of the skin over breast Erythema is confined to the lesion , and Edema is less extensive Lymph node involvement is >75% of cases Lymph nodes are involved in approximately 50% of the cases Distant metastases are present in 25% of the cases Distant metastases are less common at presentation Distant metastases are more common at initial presentation

40. BCS in LABC Following neoadjuvant therapy , down staging of breast cancer allow for breast conservation sugery . SELECTION CRETIRIA Complete resolution of skin edema Residual tumour diameter <5cm Absence of known multicentric disease/extensive lymphatic invasion

41. Follow-up Clinical examination in detail @ regular intervals Yearly/2-yearly Mammography of the treated and contralateral breast is a must Bone-scan, CT Chest/abdomen, tumour markers are done only if there is clinical suspicion. Not a regular routine follow-up at present SR_Ca_Breast_Rx 48

42. THANK YOU