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Locally advanced diseaseSpecific recommendations in systemic therapy (ESO-ESMO ABC Guidelines and more…) Alexandru ENIU, MD, PhD Medical Oncologist Department of Breast Tumors Head, Day Hospital Unit Cancer Institute Ion Chiricuţă Cluj-Napoca, Romania Heterogeneity of candidates for neoadjuvant therapy Stage StageIIIB IIIA Locally Advanced- goal is to convert to operability N0 N1 T4 N1 T3 StageN1IIB N1 T4 Operable : goal is to conserve the breast Stage IIIC N0 N3 T2 +T3 N2 For the purpose of this N2 talk, LABC means INOPERABLE, N2 T4 NON-METASTATICT1-3 LOCALLY ADVANCED BC Locally advanced Breast Cancer Heterogeneity at presentation: neglected versus rapidly progressive disease BREAST CANCER EPIDEMIOLOGY: Stage at diagnosis: United States vs. India DISTRIBUTION USA INDIA STAGE EXTENT 5 year SURVIVAL 0 Noninvasiv e 100% 16% ---- I Early stage disease 100% 40% 1% II Early stage disease 86% 34% 23% III Locally advanced 57% 6% 52% IV Metastatic disease 20% 4% 24% USA: 90% DCIS or early staged invasive disease at diagnosis INDIA: 76% locally advanced or metastatic at diagnosis Sources: SEER Survival Monograph (NCI), 2007; Chopra, Cancer Institute Chennai, India, 2001 Neoadjuvant therapy Paradigm shift: from LABC to “all tumors” • Initially used to shrink inoperable cancers… • Offers similar DFS and OS, vs. the same regimen given as adjuvant treatment, same toxicity Benefit seen in operable , large tumors (downstaging) Predictive: size, high grade, ductal, ERCollateral benefit: pCR patients survived longer! Excellent in vivo experimental setting –FDA.. Few studies specifically in LABC ! ! The MD Anderson experience- LABC pCR Kuerer 12% Predictive ER-, G3 4 x FAC n=372 Green (n=258) 4x q3wP + 4 x FAC 15,7% 12 x wP + 4 x FAC 28,2% ER-, PR- Kuerer, J Clin Oncol,1999; Green, J Clin Oncol 2005; Hennessy, J Clin Oncol 2005 Evaluation prior to primary systemic therapy Clinical examination: – Clinical size of tumor – Skin changes: erythema, edema, ulceration, and dimpling – Lymph node status Photo documentation (inflammatory, T4’s…) Elicitation of symptoms suggestive for distant metastasis Natural history of the disease (rapid growing <6 months versus neglected tumor to differentiate T4d from T4b) Evaluation prior to primary systemic therapy (2) BEFORE starting any therapy, a core biopsy providing histology and Pathology: CORE BIOPSY ! biomarker (ER, PR, HER-2, proliferation/grade) expression is – Full assessment of grade,decisions. RE, RP and (ki67) indispensable to guide treatment (LoE:Her2 I B) (97%) Adequate breast imaging: extent of disease – Mammography – Ultrasound for T and N (FNA of suspicious nodes) – MRI- if available for response assesment – Clip placement dg (for surgery &risk pathology!) Since LABC patientsathave a significant of metastatic disease, a full staging workup, including a complete history, physical examination, lab tests and imaging of chest and abdomen (preferably CT) and bone, prior to initiation of systemic therapy is highly recommended. (LoE: I B) (100%) PET-CT, if available, may be used (instead of and not on top of CTs & bone scan). (LoE: II B) (100%) LOCALLY ADVANCED INOPERABLE BC (LABC) Systemic therapy (not surgery or RT) should be the initial treatment. If LABC remains inoperable after systemic therapy and eventual radiation, “palliative” mastectomy should not be done, unless the surgery is likely to result in an overall improvement in quality of life. (LoE: Expert opinion) (100%) A combined treatment modality based on a multidisciplinary approach (systemic therapy, surgery and radiotherapy) is strongly indicated in the vast majority of cases. (LoE: I A) (100%) Triple Negative Breast Cancer (ER-, PR-. Her2-, grade 3, high ki-67) HETEROGENEITY Basal - like ER, PR, Her2 Negative “3-” Infiltrating ductal carcinoma Non Basal - like Other histologies (medullary, squamous, apocrine Used as a surrogate to represent the basal-like category ( ~80% of “3-” are basal-like) Carboplatin in TNBC subgroup of GEPARSIXTO centrally confirmed TNBC (RH<1%) R T>1 cm (US) or T>2cm PM 100% Correlate germline BRCA alterations and 80% family history for breast and ovarian 60% cancer with pCR in patients with TNBC 40% 20% 0% Surgery N=315 PMCb Paclitaxel 80 mg/m² q1w 36 % 53 % PM PMCb Non-pegylated liposomal doxorubicin (M) 20 mg/m² q1w Carboplatin AUC 1.5-2 q1w Bevacizumab 15 mg/kg q3w Primary aim :pCR rates (ypT0 ypN0) rates between PM and PMC von Minckwitz et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 1005) and Lancet Oncology, May 2014 pCR (ypT0 ypN0) in all Patients with TNBC Family history for BC/OC gBRCA/RAD alteration no yes (N=250) (N=44) 40.4% 45.5% (N=193) (69/171) (10/22) yes 44.3% 63.6% (N=101) (35/79) (14/22) no von Minckwitz et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 1005) Tumor-infiltrating lymphocytes are linked to chemotherapy response and prognosis in breast cancer 40 Lymphocyte-predominant breast cancer (LPBC) = more that 60% TILs pCR rate (%) 40 30 20 15.4 7.2 10 0 no focal Lymphocyte lymphocytes lymphocytes predominant breast Denkert et al, JCO, 2010 cancer non-LPBC Loi et al, JCO, 2013 – BIG2-98 Denkert et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 510) Metastasis-free survival • • • • Overall survival 278 TNBC patients 48% stage III ( LABC) 54% Node positive after neoadjuvant chemo 45% Anthra plus taxanesMetastasis-free regimen survival, Metastasis-free survival, pN0, ypT<2 cm pN+, ypT>2 cm What have we learned? Carboplatin increases pCR in TNBC Best incremental benefit in patients with alteration and family history( pCR rate 64%) Little gain from Carbo if no risk factors We are (almost) ready to incorporate Carbo in neoadjuvant setting for TNBC (…adjuvant for TNBC? Not yet…) 15% of TNBC carry a BRCA alteration Immunological factors in breast cancer are linked to response to neoadjuvant chemotherapy LOCALLY ADVANCED INOPERABLE TNBC Anthracycline- and-taxane-based chemotherapy is recommended as initial treatment. (LoE: I A) (85%) Response assessment Clinical exam at each cycle (T, N)-> to identify progression Post therapy: 2 weeks after last cycle of chemo – Clinical exam: notoriously inaccurate! – Mammography / ultrasound ( Chagpar, Ann Surg, 2006) MRI if performed at dg Clinical utility? better anatomic staging limitations: false +, false - ! Functional Imaging (Dynamic Contrast Enhanced MRI, PET)- still investigational GEPARTRIO Individualized therapy “Her2 positive cc.” Her2 positive, ER - or +, PR – or +, High grade ( 3) High Ki-67 Gianni et al. Lancet 375(9714) , 2010 Can we improve the pCR? Dual HER2 Blockade with Taxanes:NeoAltto and NeoSphere LOCALLY ADVANCED INOPERABLE HER-2+ Concurrent taxane and anti-HER-2 therapy is recommended since it increases the rate of pCR. (LoE: I A) (92%) Anthracycline-based chemotherapy should be incorporated in the treatment regimen. (LoE: I A) (72%) When an anthracycline is given, it should be administered sequentially with the anti-HER-2 therapy. (LoE: I A) (87%) LOCALLY ADVANCED INOPERABLE HR+ Options for HR+ LABC include an anthracycline- and taxane-based chemotherapy regimen, or endocrine therapy. (LoE: I A) (85%) The choice of CT versus ET, as initial treatment, will depend on tumor (grade, biomarker expression) and patient (menopausal status, performance status, comorbidities, preference) considerations. (85%) Primary hormonal therapy: luminal A (ER +++, PR +++, Her2 -, Low Grade. Low ki-67) Chemotheraphy versus Hormone Therapy as Neoadjuvant Treatment in Luminal Breast Cancer: GEICAM 2006-03 In luminal phenotypes, chemotherapy induces more pCR than hormonal therapy in the neoadjuvant setting • • Chemotherapy appears to be more effective than hormonal therapy in patients with Ki67 >10%, pre-menopausal and with high Allred score Hormonal therapy appears to have similar efficacy to chemotherapy in patients with Ki67 ≤10% and post-menopausal Alba et al. ASCO 2010 Impact of pCR for luminal A tumors pCR rate: 5,5% ! Preoperative Endocrine Therapy: Conclusions Aromatase inhibitors more effective than TAM 30-50% clinical response…but <5% pCR Breast conserv. in >40% initially proposed MRM Optimal duration: at least 4-6 mth (…12-18mths?) Not a substitute for surgery on the long term How to select? – Postmenopausal patients ( no neoadj endocrine for premenopausal patients) – “true” Luminal A – Ki-67 <10%?? Inflammatory breast cancer (IBC): introduction 5-year survival: 40% Diagnosis is based on clinical presentation: Erythema >30-50% of the breast, oedema, induration of the breast, rapidly progressing disease ( history < 6 months) Pathology findings: Dermal lymphatic invasion, increased angiogenesis, 30–40% ErbB2+ Staging: Imaging of thorax and abdomen recommended Bone scan for patients with symptoms/elevated alkaline phosphatase Newer imaging modalities (FDG-PET) may be useful By definition, inoperable at presentation Mainstay of treatment: neoadjuvant chemotherapy (≥6 cycles) with anthracyclines ± taxanes FDG-PET; [18F]-fluorodeoxyglucose positron emission tomography NOAH study results: pathological complete response in ErbB2+ IBC Pathological complete response (%) (n=62) 80 p=0.004 55 60 40 20 0 19 Without T Gianni et al. SABCS 2008;Abstract 31 and presentation With T INFLAMMATORY LABC For inflammatory LABC, overall treatment recommendations are similar to those for non-inflammatory LABC, with systemic therapy as first treatment. (LoE: I B) (93%) Mastectomy with axillary dissection is recommended in almost all cases, even when there is good response to primary systemic therapy. (LoE: I B) (95%) Immediate reconstruction is generally not recommended in patients with inflammatory LABC (LoE: Expert opinion) (95%) Loco-regional radiotherapy (chest wall and lymph nodes) is required, even when a pCR is achieved with systemic therapy. (LoE: I B) (98%) LOCALLY ADVANCED INOPERABLE BC (LABC) Following effective neoadjuvant systemic therapy with or without radiotherapy, surgery will be possible in many patients. This will consist of mastectomy with axillary dissection in the vast majority of cases, but in selected patients with a good response, breast conserving surgery may be possible. (LoE: II B) (98%) Role of conservative surgery after Neoadjuvant treatment? • NeoALTTO: predictive factor: planned surgery • Education of patients? Surgeons? • Type of surgery – Breast conserving surgery if appropriate – MRM for all LABC ?! – No“palliative” surgery if unresectable • Criteria for breast conservation ( Singletary, Cancer Treat Res 1997) – – – – – Resolution of skin edema Residual tumor size <5 cm Absence of extensive breast lymphatic invasion Absence of extensive suspicious microcalcifications No evidence of multicentricity Postoperative pathology report: what do we need? pT ( number, location, diameter) ER pN ( number of positives/excised, dim, extent of mets) Her2 Histologic type Grade Margin status (mm) Symmans, J Clin Oncol 2007, 25:4414 PR Proliferation (Ki-67) Systemic treatment after surgery Hormone receptor positive -> hormone therapy Her2 positive -> adjuvant trastuzumab Further chemotherapy ? Would more chemotherapy be better? Many (all?) patients had anthra+alkylator and taxanes Yes, tumor is really sensitive to chemo No data to suggest further chemo No, benefit prognosisfrom is already very good In the absence of trial data, in general further chemotherapy should not be administered if anthra and taxanes have been already used Would more chemotherapy be better? Yes, high risk imposes further treatment No, tumor does not respond to chemo IBCSG Trial 22-00 (CM Maintenance) Presented By Marco Colleoni at 2015 ASCO Annual Meeting Slide 14 • 1 year CM maintenance is feasible with acceptable toxicity • Alternative ( ..to nothing…) to be discusses with high risk triple-negative patients willing to “invest” Presented By Marco Colleoni at 2015 ASCO Annual Meeting NEOADJUVANT SYSTEMIC THERAPY: UNSOLVED QUESTIONS How to select CT versus HT in luminal tumors? Optimal strategy for TNBC (platinum, PARPs) Her2+ : who needs double blockade, and which one? Predictive markers for antiHer2 agents (PI3K ??) Do pCR patients need adjuvant anti-Her2 therapy? Non-pCR patients: how to improve outcome? Conclusions Anthra plus taxanes= standard backbone pCR is prognostic Endocrine neoadjuvant: for postm, “true”luminal A Anti-Her2 primary therapy: use trastuzumab! Recent approved indication for pertuzumab (limited availability in Europe) Double anti-Her2 blockade: for ER-? PIK3CA wild? TNBC: anthra plus taxanes, discuss platinum(BRCA mut. or family history): Immunological factors in breast cancer are important- stay tuned!