Breast Cancer Earlier Disease Stefan Aebi Luzerner Kantonsspital stefan.aebi@onkologie.ch
Switzerland
Breast Cancer Earlier Disease Diagnosis and Prognosis Local Therapy Surgery Radiation therapy Adjuvant systemic therapy DCIS Staging Surgical and radiation techniques including accelerated partial breast irradiation Neoadjuvant therapy, specific chemotherapy regimens, bisphosphonates Fertility Pregnancy
Diagnosis Clinical examination Radiology Mammogram, ultrasound (to include axilla) MRI is not routinely needed How can you know? Core biopsy of primary and of suspicious axillary lymph nodes Definition: Earlier Disease = no distant metastases Interdisziplinäre S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms Langversion 3.0, Aktualisierung 2012 AWMF-Register-Nummer: 032 045OL NCCN Guidelines 2013. www.nccn.org
Risk of Relapse and Death Anatomic stage: N > T Histological grade, proliferation Estrogen receptors: weak prognostic factors but predict response to endocrine therapy HER2: poor prognostic factor but predicts response to trastuzumab
Luminal, basal-like, etc. Subtypes Approximation Therapy? Intrinsic Subtype Approximation Therapy Luminal A Luminal B or HER2 (erbb2) ER+ and/or PR+, HER2 not amplified or IHC, Ki67 low* ER+ and/or PR+, HER2, Ki67 high* ER+ and/or PR+, HER2 amplified or IHC+++ HER2 amplified or IHC+++, ER and PR negative Endocrine therapy Chemotherapy + endocrine therapy Chemotherapy + endocrine therapy + trastuzumab Chemotherapy + trastuzumab Basal-like dƌŝɖůğŷğőăɵǀ Ğΐ Chemotherapy *SG Consensus 2011 recommends 14% threshold ΏŽƌŽƚŚĞƌŵĞĂƐƵƌĞŵĞŶƚŽĨƉƌŽůŝĨĞƌĂƟŽŶ 80% concordance with basal-like adapted from Goldhirsch 2011 Ann Oncol 2011 22 1736
Subtypes Breast cancer ER/PR+ «Luminal» ER/PR+, high proliferation, «luminal B» «Basal-like» «Triple negative» ER/PR HER-2 +++
Risk of Relapse and Death «Molecular Prognostic Scores» Oncotype Dx Recurrence Score predicts response to some types of chemotherapy Mammaprint PAM 50 ROR Gene Expression Grade Index (GGI) Endopredict Common denominators: Proliferation, ER. These test are correlated and identify similar populations of «high risk» patients.
Staging MRI = Preoperative MRI Will detect multifocal, multicentric and contralateral disease Does not improve the complete resection rate or improve long-term prognosis Does delay resection and increase the mastectomy rate
Preoperative Magnetic Resonance Imaging in Breast Cancer Meta-Analysis of Surgical Outcomes 2 RCTs, 7 comparative cohorts Random-effects logistic meta-regression modeling, estimation of the proportion of women with each outcome in the MRI versus no-mri groups, odds ratio (OR) and adjusted OR (adjusted for study-level median age, and, where appropriate, for temporal effect) for each model. Houssami Ann Surg 2013 257 249
Surgery Prognosis with regarding disease-free and overall survival: lumpectomy + radiation therapy = segmentectomy + RT = quantrantectomy + RT = mastectomy Clear surgical margins lower local recurrence rates Negative sentinel lymph nodes obviate axillary surgery
Breast Conserving Therapy «Must Read»: NSABP B-06 Local recurrence Survival Years after randomization Fisher NEJM 2002 347 1233
Breast Conserving Therapy Jatoi Am J Clin Oncol 2005 28 289
Breast Conserving Therapy «Must Read»: Holland 282 invasive ductal cancers No additional foci 37% Foci 2 cm: 20% >2 cm: 43% (16% invasive) Resection with «clear margins» will leave residual foci in the breast Holland Cancer 1985 56 979
BCT Radiation Therapy «Must Read»: EBCCTG 2005 Meta-analysis comparing breast conserving surgery ±radiation therapy Local recurrence risk ratio 0.52 0.48/0.08 = 6:1, Death risk ratio 0.92 Compare to 4:1 ratio EBCCTG Lancet 2005 366 2087 and Lancet 2011 378 1707
BCT Radiation Therapy: Boost In breast recurrence Age < 40 Age 40-49 Age 50-59 Age 60+ Bartelink JCO 2007 25 3259
Postmastectomy Radiation Therapy Δ 5 year 15 year Local Breast Recurrence Cancer Mortality N0 4%* 3.6% N+ 17.1%* 5.4%* *p<0.05 Overall: Avoid 4 recurrences @ 5 years avoid 1 death at 15 years EBCCTG Lancet 2005 366 2087
Systemic adjuvant therapy Endocrine therapy for ER+ breast cancer Premenopause: Tamoxifen ± GnRH analog Postmenopause: Aromatase inhibitors, tamoxifen Chemotherapy for certain ER+ breast cancers for ER breast cancers for HER2-positive breast cancers Trastuzumab
What is ER+ breast cancer? CAP/ASCO Guideline 2010 It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. Hammond JCO 2010 28 2784
Tamoxifen Recurrence Breast cancer mortality Mortality x Age Similar proportional reduction of risk of recurrence in N0 and N+ Absolute DFS benefit @ 15 years: N, 9.1%; N+, 16.1% EBCTCG. Lancet 2005 365 1687
Tamoxifen: Duration of Therapy 1 year 2 years 5 years Lancet 1998 351 1451
Tamoxifen 5 vs. 10 years ATLAS-Trial Recurrences Breast Cancer Mortality Δ nach 15 Jahren: 2.8% P = 0.01 Davies ATLAS Lancet 2013 381 805
ATLAS-Trial Gray SABCS 2012
Aromatase Inhibitors To date pending SOFT and TEXT results aromatase inhibitors + GnRH analogs are not indicated before menopause In terms of overall survival, sequences of tamoxifen followed by aromatase inhibitors and monotherapy with letrozole are superior to tamoxifen monotherapy.
Aromatase Inhibitors Monotherapies prolong DFS compared with tamoxifen Letrozol prolongs survival Tamoxifen AI «Switch» prolongs survival Dowsett JCO 2010 28 509
Endocrine Therapy «Must Read» Tamoxifen: «Oxford overview» Lancet 2011 378 771; ATLAS Lancet 2013 381 805 GnRH analogs: Cuzick Lancet 2007 369 1711 Aromatase inhibitors: Dowsett JCO 2010 28 509; BIG 1-98 Regan Lancet Oncol 2011 12 1101 Regan Lancet Oncol 2011 12 1101
Subtypes Clinical Implications Breast cancer «Basal «Basal--like like»» ER/PR+ «Luminal» «Triple negative» ER/PR+, high proliferation, «luminal B» Chemotherapy probably effective ER/PR ER/PR HER HER--2 +++
Adjuvant Chemotherapies CMF-like, e.g. cyclophosphamide + methotrexate + fluorouracil Anthracycline-based, e.g. doxorubicin + cyclophosphamide (AC), fluorouracil + epirubicin + cyclophosphamide (FEC) Taxane-based, e.g. docetaxel + cyclophosphamide (TC), docetaxel + doxorubicin + cyclophosphamide (TAC) Sequential anthracycline/taxane regimens, e.g. AC Paclitaxel Gianni Bonadonna
Adjuvant Chemotherapies Overall Survival No Chemotherapy vs. Anthracycline CMF EBCCTG Lancet 2012 379 432
Adjuvant Chemotherapies Overall Survival CMF vs. Anthracycline Doxorubicin > 240 mg/m2 Epirubicin > 360 mg/m2 Doxorubicin 240 mg/m2 Epirubicin 360 mg/m2 EBCCTG Lancet 2012 379 432
Adjuvant Chemotherapies: Age Overall Survival Control (CMF + no Chemotherapy) vs Anthracycline Age < 55 Age 55 to 69 EBCCTG Lancet 2012 379 432
Adjuvant Chemotherapies Overall Survival Anthracycline vs. Anthracycline+Taxane Same dose anthracycline in control and experimental arms More anthracycline in control than in experimental arms EBCCTG Lancet 2012 379 432
Who Profits from More/More Intense Chemotherapy? «More» chemotherapy = Higher dose intensity Higher dose density Additional drugs Patients with luminal B breast cancers Patients with HER2-positive breast cancers Patients with ER-negative breast cancers Maybe patients with (extensive?) lymph node metastases
What is «HER2-Positive»? FISH = Detection of HER2 gene and centromere 17, fluorescent in situ hybridization Non-amplified = negative Amplified = positive HER2:CEP17 ratio <2 2 Response to trastuzumab, pertuzumab, T-DM1 0 or + ++ +++ Negative Inconclusive Positive IHC = Immunhistochemistry, detection of the protein Tan Clin Cancer Res 2008 14 461
Adjuvant Trastuzumab HERA CTx T NSABP B31 AC P+T T N9831 AC P±T T BCIRG 006 AC D+T T D+CBDCA+T T others: FinHER, PACS04 NO TRIAL WITHOUT CHEMOTHERAPY! Prolong disease-free survival Prolong overall survival Low risk of heart failure 0.5% to 3%, frequently reversible HERA: Gianni Lancet Oncol 2011 12 236 NSABP B-31/N9831 Perez JCO 2011 29 3366 BCIRG006 Slamon NEJM 2011 365 1273 FinHER Joensuu JCO 2009 27 5685 Spielmann PACS04 JCO 2009 27 6129
Adjuvant Trastuzumab Duration = 1 year HERA: 2 years not superior to 1 year PHARE: ½ year not non-inferior to 1 year (but not inferior either!) Pivot Lancet Oncol 2013 14 741 Small HER2-positive cancers (T1a, T1b) No randomized clinical trials, but observational studies document poorer prognosis than HER2negative tumors potential benefit of standard therapy for small cancers Rodrigues JCO 2010 29 e541; Banerjee Lancet Oncol 2010 11 1193
Neoadjuvant Chemotherapy Aims = Aims of adjuvant therapy + shrinking of primary to allow breast conserving surgery (+ assessment of chemotherapy effect to allow adaptation of therapy?) Same regimen as adjuvant therapy HER2 positive: Consider adding pertuzumab or lapatinib
Adjuvant Systemic therapy Consider comorbidity and patient preferences Select the target ER or PgR positive: Endocrine therapy HER2 amplified: Trastuzumab Use chemotherapy for HER2 positive breast cancer ER negative breast cancer Luminal B breast cancer Consider chemotherapy for patients with (advanced) lymph node metastases