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N. El Saghir - Breast cancer - State of the art for early breast cancer
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  • ReferenceGianni L, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomized controlled trial. Lancet Oncology Epub 25 Feb, 2011. DOI: 10.1016/S1470-2045(11)70033-X.
  • Table
  • Small significant reductions of mortality seen

N. El Saghir - Breast cancer - State of the art for early breast cancer N. El Saghir - Breast cancer - State of the art for early breast cancer Presentation Transcript

  • State of the art for Early Breast Cancer EASO Masterclass October 27-29, 2011Nagi S. El Saghir, MD, FACP Professor & Director, Breast Center of Excellence NK Basile Cancer Institute American University of Beirut, Beirut, Lebanon
  • Breast cancer incidence and mortality• Breast Cancer is most common in women, except for skin cancers, worldwide, including most Arab countries• Breast cancer is the second leading cause of cancer death in women (1st: lung cancer): Arab countries have no reliable mortality statistics• Death rates declining since 1990s as a result of: - earlier detection, screening, increased awareness, & improved treatment.
  • Breast cancer in Arab countries• National & Regional Registries: Increasing• Frequency data: 14-42% of all women’s cancers• ASR Incidence Rates: 9.5- 46 (up to 69/ 100.000)• Young Age at presentation: Median: 48-52 yrs: 50% of cases < age 50 (USA & Europe: 25% are < 50; 50% are >age 63)• High proportion of Locally advanced and metastatic disease at presentation: 60-80%: (LABC is decreasing because of increased awareness!)• High rates of Mastectomy: 88-60% (…Decreasing)• Low percentages of in-situ: <5% (… Increasing!) Adapted from El Saghir et al, Intl J Surg. 2007 Aug;5(4):225-33 View slide
  • Heterogeneity of Breast Cancer• Breast Cancer is not an only one disease: Breast Cancer is a heterogeneous disease• Different histologies and Receptors• Different biological behaviors• Different invasive potentials, different Stages: Local / Regional / Metastatic• Different Host characteristics View slide
  • TNM staging of Breast Cancer• Early Breast Cancer: I & II• Locally Advanced Breast Cancer: III• Metastatic Breast Cancer: IV… & use of new receptor and molecular classification
  • Molecular Subtyping of breast cancerHeterogeneity of Breast Cancer is evident by different receptors expression - Estrogen Receptors (ER) - Progesterone Receptors (PR) - HER2/neu Receptors (HER2 aka ErbB2)• New Molecular Classification incorporates - Receptors - Tumor Grade - Prediction of biological behavior of disease  Gene expression profiles validated by clinical follow-ups of patients
  • Molecular Classification of Breast Cancer: Phenotype-expression and Gene-profiling• ER positive, HER2 negative: Luminal A Group (mostly grade 1)• ER positive, grade 3, or HER2-pos: Luminal B Group (mostly grade 3)• ER negative, HER2-pos HER2/neu-Overexpressive Group (mostly grade 3)• ER negative, PR negative, HER2-neg: Triple Negative Breast Cancer (Express breast epithelial cell markers CK5/6 and HER1: Basal-like tumors: Sorlie, et al. PNAS 2001 (mostly grade 3) Sorlie et al. NEJM 2004
  • Gene microarrays, subtypes, and probability ofmetastasis and of survival in early breast cancer Time to Distant Metastasis Of 4 subtypes of Breast cancer  Overall Survival Of 4 subtypes of breast cancer  Luminal A & B: Patients do BETTER HER2/neu overexpressors & TNBC: Patients do WORSE Sorlie, et al. PNAS 2001
  • Breast Cancer managemnt: Diagnosis  Workup  TreatmentAbnormality discovered by Screening, or Accidental or Symptomatic:1- Clinical Examination: Breast & Axilla, systemic exam2- Mammography (+/- Breast Ultrasound)3- Diagnosis by Fine Needle Aspiration or Core Biopsy(Frozen Section followed by Mastectomy one-time procedure is not acceptable!)4- Metastatic work-up: Staging5- Discuss treatment options: Amongst physicians, and with patient (& family)
  • Assessment of patient with breast mass• After imaging: Proceed with a Biopsy: FNA or Core BiopsyThere is rarely ever need to take the patient immediately for surgery the same day or next day!Excisional biopsy or frozen section may be needed only at rare times, when diagnosis could not be made by biopsy!
  • • Spiculated irregular mass, highly suspect mass :Diagnosis is to be made before any treatment is applied
  • Diagnosis: When to do an FNA?• If you plan Primary Surgery, then FNA might be enough to reach a diagnosis• If the Tumor is clinically & radiologically suspect• FNA is easier, less discomfort to patient and cheaper• FNA is not for used for microcalcifications because it does not differentiate DCIS from Cancer• FNA cytology needs training and expertise
  • When to do a Core Biopsy?1. If you plan Neo-adjuvant therapy2. If you need to know receptors before any treatment3. Cases of microcalcifications only4. Nonpalpable lesions5. Less suspicious lesions6. Non-diagnostic FNA, …
  • FNA or Core Biopsy• Histological development:Normal duct  In-Situ Cancer  Cancer (Invasive)
  • Clinical Case: FNA or Biopsy ?M.O.: 40 y-o-w-fLarge mass; nippleretraction and oozing forseveral months • Nipple retraction and oozing, massLocally Advanced Br CaThis patient needs pre-optherapy: a core biopsy forPathology & Receptors
  • Heterogeneity, hormone receptors, and definitions of positivityNew guidelines for Receptor positivity: >1% of cells
  • HER2-positive breast cancer• Up to 25% of women with Early Breast Cancer have HER2-positive disease• Aggressive form of the disease: Early progression and poor prognosis (recurrence within 2-3 years)• HER 2 positivity is an independent risk factor• HER2-positive means: HER2 +++, or HER++ with FISH+ Slamon et al 1987, 1989, 2001; Goldhirsch et al 2005; Marty et al 2005
  • HER2 receptors’ expression: IHC and FISH testing: Definitions and guidelines3+: Positive 2+ Equal: Equivocal Needs FISH Test1+: Negative 0: Negative
  • Testing for ErbB2/HER2: Quality, Volume, Experience & Relability! Cell surface Protein expression ++ is Equivocal then do  FISH testing  Gene amplification: FISH +) (if no amplification: FISH -)What is +++: >.30% of cells complete membrane staining Remember: Clinical trials used >10% criteriaWhat is exactly ++ ? How does your pathologist choses cells for FISH testing?!
  • Surgery for Early Breast Cancer1. Breast Conserving Therapy (Surgery + RT): Partial Mastectomy, Lumpectomy, Quadrantecto my2. Mastectomy3. Mastectomy + Reconstruction4. Sentinel Lymph Node Biopsy (SLNB)5. Axillary Lymph Node Dissection (ALND) Veronesi U; Fisher B, Giuliano A, Krag D; and others,
  • BCT vr MRM +/-RT BCT vs MRM in TNBC Abdulkarim, et al. J Clin Oncol 2011;29:2852-2858
  • B-32 OS NSABP Protocol B-32 100 80 Overall Survival for Sentinel Node Negative Patients % Surviving 40 60 Trt N Deaths 20 SNR+AD 1975 140 SNR 2011 169 HR=1.20 p=0.117 0 Data as of December 31, 2009 0 2 4 6 8 Years After Entry* 300 deaths triggered the definitive analysis* 309 reported as of 12/31/2009 Krag et al, ASCO 2010
  • ACOSOG Z 0011 in patients with positive SLNB DFS and OS: Completion ALND or not Disease Free Survival Overall Survival 100 100 90 90 80 80 70 70% Recurrence-Free and Alive 60 60 % Alive 50 50 40 40 30 30 ALND 20 ALND 20 No ALND No ALND P-value = 0.14 P-value = 0.25 10 10 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Time (Years) Time (Years) Giuliano AE et al, ASCO 2010, JAMA 2011 23
  • ACOSOG Z 0011 Survival Curves Disease Free Survival Overall Survival 100 100 90 90 80 80 70 70% Recurrence-Free and Alive 60 60 % Alive 50 50 40 40 30 30 ALND 20 ALND 20 No ALND No ALND P-value = 0.14 P-value = 0.25 10 10 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Time (Years) Time (Years) 24
  • Breast and Axilla Conservation!• Breast Conserving Therapy (+ RT) is at least as good as Total Mastectomy• New data is emerging that BCT (+RT) may be even superior to Mastectomy in TNBC!• Sentinel Lymph Node Biopsy has become standard of care for EBC with clinically negative axilla• SLNB negative: Stop there• SLNB positive: Select cases for completion ALND• Every surgeon and every hospital that treats breast cancer should be equipped and gain expertise in SLNB for Early Breast Cancer
  • Radiation Therapy (RT) in EBC• BCT = Partial breast surgery + RT• Post-mastectomy Irradiation:• BCT: partial breast surgery + RT• Post-Mastectomy RT: T >5cm; N2 and above: Always N1: More & more patients are being offeredthe option of post-mastectomy RT.Reminder: For every 1 local recurrence prevented at 5years, there is one life saved at 15 year! EBCTGoverview
  • Adjuvant Post-operative SystemicTherapy for Early Breast Cancer• Eliminates micrometastases• Reduces recurrences• Improves survival• It is traditionally based on TNM stage, and known prognostic and predictive factors
  • Factors used to choose type of adjuvant therapy• Patient-related factors: Age, Menopausal status, known risk factors, hereditary factors, comorbidities• Tumor-related factors: - Disease history - Anatomical stage: TNM - Biological characteristics: Grade, Differentiation, LVI, Receptors,• Predictive factors of response to certain therapies• Known toxicities of therapy
  • Benefit from adjuvant chemo, CMF or AADJUVANT Therapy & BREAST CANCER MORTALITY (Peto R, SABCS 2007)•CMF chemo vs no chemo Anthracycline-based chemo vs CMF chemo
  • Common regimens for adj. chemo in EBC• Non-anthracyline regimens: CMF: Cyclophosphamide, Methotrexate, 5-FU - Classical CMF q4w: Oral C 100/m2x14d, M 40/m2 F 600/m2 days 1 & 8) - IV CMF q3w: C (600/m2) M (40/m2; 30/m2 if >60) F (500/m2)• CAF not > CMF in INT0102 trial (Hutchins JCO 2006)• CMF = EC (Belgian Trial, follow-up 15 years E 100 > E60)• Metaanalysis of 4 phase III trials and Oxford overviews: Anthracycline-regimens > CMF• CMF remains most useful in luminal cancers, low bulk tumors, patients who refuse hair loss, less toxic regimen, older patients.
  • Common Adj. chemo regimens in EBC• Anthracycline regimens, without taxanes: AC: A (60mg/m2), C (600mg/m2): Q3w x 4 cycles fornode-negative patients CAF or FAC: F (500mg/m2), A (50/m2), F (500mg/m2) x 6 cyclesused for node-positive patientsEpirubicin may be used instead of Adriamycin(Example: E (90/m2) C (600/m2) instead of AC (60,600/m2)• Higher dose Epirubicin: C E (100) F > CAF• A (75m/m2) q3w x 4 followed by CMF x8 (Bonnadona, et al)
  • Common Adj. chemo regimens in EBC• Anthracycline regimens, with taxanes: Sequential administration (preferred):• AC-T: AC-Paclitaxel or AC-Docetaxel: A (60mg/m2), C (600mg/m2): Q3w x 4 cycles followed by Paclitaxel or Docetaxel:• AC-Paclitaxel: 175/m2 IVD over 3 hours q3w x 4 cycles: (Example CALGB 9344 study) Curently, preferred use of Paclitaxel is weekly dosing: Paclitaxel 80mg/m2 qweek x 12 weeks (P q1w = D q3w & > to q P 3w or D qw :Sparano 2008).• AC-Docetaxel: (D100mg/m2 q3w x 4 cycles)• FECx3 – D x3 (PASC01 study)• Sequencing: Superior efficacy and less cardiotoxicity
  • Common Adj. chemo regimens in EBC• Anthracycline regimens, with taxanes:Concurrent: TAC (T 75/m2, A 50/m2, C 600/m2), plus g-csfBCIRG 001, updated:TAC > FACUseful in certain younger patientsmore aggressive diseaseMore toxic regimen, requires g-csf
  • Common Adj. chemo regimens in EBC• Anthracycline regimens, with taxanes:Sequential Dose Dense Regimens:AC-T: q 2 weeks , with g-csf support (Citron, et al. CALGBstudy 9741: JCO): Benefit mostly for ER-, HER2+ ptsT-CEF (MD Anderson Cancer Center)Paclitaxel (80mg/m2) qw x 12 weeks followed byCEF (500/m2, 75/m2, 500mg/m2) q 3w x 4 cycles
  • Common Adj. chemo regimens in EBC• Taxanes, without anthracyclines:• TC > AC: (Jones S, et al JCO 2010) useful in more aggressive cases, useful when contra-indication for anthracyclines)• T-CMF• TCH (Docetaxel + Carboplatin + Trastuzumab) in HER2 positive patients: see following slides)
  • Adjuvant targeted therapy trastuzumab in HER2 positive EBCMajor Trials in the Adjuvant Setting: (Presentations in2005 and updates in 2011):• HERA (positive, 1 year trastuzumab)• NSABP-B31 (Positive, 1 year trastuzumab)• NCCTG N9831 (Positive, 1 year trastuzumab)• BCIRG 006 (Positive, has arm without anthracyclines)• FinHer (Smaller trial, short duration Trastuzumab)• PACS-04 (Smaller trial, negative)
  • Adjuvant Therapy for patients with ERB2-positive breast cancer• Anti-HER2 Benefit is established for patients with HER2 +++ or HER2 ++ with FISH positive• Patients are given Adjuvant Chemotherapy + Trastuzumab +/- Hormonal therapy Recurrence: is cut by 50%; Risk of Death: is cut by 30% Slamon et al 1987, 1989, 2001; Goldhirsch et al 2005; Marty et al 2005
  • Design & 2005 Results of 4 major positive Adjuvant Trastuzumab in EBC •HERA •BCIRG 006 •Observation •IHC / FISH •FISH •1 year (n=5090) (n=3222) •1 year •2 years •1 year •NCCTG N9831 •NSABP B-31•IHC / FISH •IHC / FISH •1 year (n=3505) (n=2030) •1 year •1 year •Doxorubicin + •Docetaxel + •Standard CTx cyclophosphamide •Docetaxel carboplatin •Herceptin® •Paclitaxel Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006
  • Summary of Benefit of adjuvant Trastuzumab therapy in EBC• Trastuzumab improves DFS benefits across 5 out of 6 major trials• Trastuzumab reduces the risk of death by one- third in 4 trials• Trastuzumab provides DFS benefit, irrespective of LN status (T1 N0 M0 Patients) Joensuu et al 2006; Slamon et al 2006; Perez et al 2007; Smith et al 2007; Spielmann et al 2007
  • HERA study Update: New 4-years F-Up Results on Treatment & Observation Arms •HER2-positive early breast cancer (IHC 3+ and / or FISH+) n=5102 •Surgery + (neo)adjuvant chemotherapy + radiotherapy •Herceptin •Herceptin •Observation •q3w x 1 year •q3w x 2 years •Option to cross over to Herceptin • 50% pts crossed to treatment arm •(after IA, 2005)•IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation Piccart; Smith; Gianni
  • DFS benefits of 1-year adjuvant trastuzumab persist at 4-year 100 follow-up (ITT) 1-year trastuzumab Alive and disease free (%) 80 Observation 6.4% 60 40 4-year Events DFS HR 95% CI P-value 20 458 72.2 0.76 0.66–0.87 <0.0001 369 78.6 0 0 6 12 18 24 30 36 42 48 Months from randomisation No. 1698 1564 1440 1363 1297 1240 1180 992 712 at risk 1703 1619 1552 1485 1414 1352 1280 1020 854CI, confidence interval; HR, hazard ratio; ITT, intent to treat Gianni, et al. 2011
  • HERA 4-year Follow-up: Summary• 1 year of adjuvant trastuzumab following chemotherapy provides significant and long- lasting DFS benefits(Crossover confounded the OS analysis in the ITT population)• Patients crossed over from observation arm to Trastuzumab had fewer DFS events (HR 0.68)• The overall incidence of cardiac dysfunction remained low with longer follow-upGianni, et al. Lancet Oncology. Epub 25 Feb, 2011
  • St Gallen guidelines for HER2-positive Early Br Ca (Since 2007) •Herceptin® •Chemoth •Hormonal therapy •Endocrine responsive •HER2-positive •Endocrine non-responsive• HER2 positivity alone confers either intermediate- or high-risk status – 1-year adjuvant trastuzumab is current standard – Role of 2-year adjuvant Trastuzumab is unknown – Shorter durations: 6 months vs 12 months: Ongoing French & Italian Trials• Patients should also receive – Chemotherapy (prior, or concurrent); Hormonal therapy, as indicated •Adapted and modified from Goldhirsch et al 2007
  • Adjuvant Trastuzumab for T < 1cm ?! There is some evidence that HER2 positivity carries an adverse prognostic significance even in patients with tumors <1 cm• MD Anderson retrospective review: HER2- positive small tumors: worse prognosis Chia S, et al. J Clin Oncol 2008; 26: 5697–5704, Curigliano G, et al. J Clin Oncol 2009, Smith IE. Breast 2009; 18 (Suppl 1): S17 (Abstr S41).
  • What about smaller tumors & negative LN? (DFS benefit for (For T1 N0 M0 Patients ; T >1cm) •HERA •N- •1-3+ nodes •>4+ nodes •Not assessed•N9831 / B31 •N- •1-3+ nodes •4-9+ nodes •>10+ nodes•BCIRG 006 •N-•ACDH •N+ •N-•DCarboH •N+ •0 •0.5 •1.0 •1.5 •2.0 •2.5 •Favours Herceptin® •Favours no Herceptin® •Hazard ratio •Size of square represents sample size; horizontal bars indicate 95% confidence intervals •Perez et al 2007;•N, node Slamon et al 2006; Smith et al 2007
  • St Gallen 2011 Experts’ votes onAdjuvant Therapy for HER2-positive Early BC (including small tumors)Trastuzumab (+chemo) for 1yr Yes No Do not knowChemotherapy Duration x 1yr 100% - -Trastuzumab for T1b (5-10mm) 79% 15% 6%Trastuzumab for T1a 24% 61% 15%Trastuzumab +/- adj. endocrine if 67% 23% 9%chemo is contraindicatedTrastuzumab for < 1 year 26% 63% 11%according to resources (low)(OK : Better than nothing) Personal notes and Goldhirsch et al. Ann Oncol. 2011 Aug;22(8):1736-47
  • St Gallen 2011: treatmentrecommendations for subtypes
  • Hormonal Therapy for Breast Cancer• Blockade of Estrogen Receptors – Selective Estrogen Receptor Modulators: - Tamoxifen 20 mg / day: Useful for treatment and chemoprevention - Toremifene: cross-resistant with tamoxifen; little usage - Raloxifene: used for osteoporosis and chemoprevention – Pure Antiestrogen Receptor /Estrogen Receptor Down-regulator: - Fulvestrant• Suppression of Estrogen Synthesis – Ovarian Ablation - Surgical (Laparoscopic) Oophorectomy - Irradiation of ovaries - Chemo-induced amenorrhea --- Ovarian Suppresion : LHRHa (GnRHa) – Aromatase Inhibitors (in Post-menopausal women): Anastrozole, Letrozole, Exemestane
  • Landmark study: NSABP B-14Adjuvant 5-yr Tamoxifen vs Placebo Tumors ER > 10 fmol/mg Node Negative Stratification: age,T size, quantitative ER, type of surgery 5 YEARS PLACEBO TAMOXIFEN
  • NSABP B-14Effects of TAM on Disease-Free Survival 100 T 90 T T T % 80 T P = <0.000005 70 PLACEBO 60 T TAM 0 1 2 3 4 5 YEAR NSABP
  • Early Breast Cancer Trialists Cooperative Group Peto, et al. Lancet 1998; 351: 1451-67 Five Years of Tamoxifen
  • Benefits (reduced Recurrence) from Tam Therapy: ~5 years Tam vs no Tam (Peto R, SABCS 2007) •ER-poor disease •ER+ disease •ER+ disease
  • Benefits (reduced Mortality) from hormonal tx:~5 years tamoxifen vs no Tamoxifen (Peto R, SABCS 2007)•~5 years tamoxifen vs. Not, ER+ only BREAST CANCER MORTALITY
  • ABCSG-12 Trial in Premenopausal pts (Gnant, et al, ASCO 2008- ECCO 2011)• Accrual 1999-2006• 1,803 premenopausal breast cancer patients• Endocrine-responsive (ER and/or PR positive)• Stage I&II, <10 positive nodes• No chemotherapy except neoadjuvant• Treatment duration: 3 years Tamoxifen 20 mg/d Tamoxifen 20 mg/d Surgery Goserelin Randomize + Zoledronic acid 4 mg q6m (+RT) 3.6 mg q28d 1 : 1 : 1: 1 Anastrozole 1 mg/d Anastrozole 1 mg/d + Zoledronic acid 4 mg q6m 54
  • If you are still hesitant, you may follow ABCSG-12 Tam + LHRHa + Zoledronic Acid (Gnant et al ASCO 2008) Primary Endpoint: Disease-Free Survival 100 90 80 Disease-free survival, % 70 60 50 40 30 No. of Hazard ratio (95% CI) events vs No ZOL P value 20 ZOL 54 0.643 (0.46 to 0.91) .011 10 No ZOL 83 0 0 12 24 36 48 60 72 84 Time since randomization, months Number at risk No ZOL 904 838 735 565 441 265 161 6055 ZOL 899 851 744 573 434 270 131 59
  • Choices of Adjuvant hormonal therapy in premenopausal women with EBC• Tamoxifen: 5 years is standard (ATLAS study 5 vs 10 years: ongoing, earlier reportis promising positive: Peto et al, SABCS 2009)• Tamoxifen + LHRHa + Zoledronic Acid: supported by ABCSG-12 trial• Tamoxifen + switch to AI when patient becomes menopaused (after 2-3 years or more)• Importance of Chemo-induced amenorrhea• Tamoxifen + LHRHa: Role of Ovarian Ablation/Ovarian Suppression: No final word yet!
  • Adjuvant hormonal therapy in post-menopausal women• How to improve on adjuvant tamoxifen?! Add or replace by AI:• This was the start of a very long chapter in hormonal therapy of breast cancer:• AI are more effective in Metastatic Breast Cancer:  AI were moved into the Adjuvant (and Neo=Adjuvant)settingsATAC, MA-17, 1-98, IES, …, …
  • ADJUVANT TRIALS of Tamoxifen & AITamoxifen x 5y Upfront, head to head comparaison ATAC (A vs T), BIG 1-98 (T vsA.I. x 5y L), TEAM (T vs E)Tamoxifen x 5y Sequential: IES (Exem) ,1-98 (T vs L)Tamoxifen A.I. ARNO (A vs T), ABCSG-8 AvsT, ITA (A vs T) Placebo x 5y MA-17: ExtendedTamoxifen x 5y A.I. x 5y L vs PlaceboTamoxifen x 5y “Reverse” SequentialA.I. Tamoxifen Big 1-98 arm
  • ATAC: Disease-Free Survival 100 % patients event free 90 80 70 60 HR 0.59 [95% CI 0.48-0.74] p<0.0001 0 0 1 2 3 4 5 6 7 Time to DFS event (years)At risk:Anastrozole 2009 1522 1161 792 509 256 99 9Tamoxifen 1997 1492 1109 764 460 241 78 9Jonat W, et al. SABCS. 2005. Abstract #18.
  • MA.17 Post-Unblinding: (DFS at 4yr: 93% vs 87%) Median F/U 30 Months 54 (16 –86) Months Letrozole n= 2593 Letrozole (LET) n = 2457 Tamoxifen n = 5187 Placebo n= 2594 No Letrozole (PLAC) n = 613 5 years 5 years Letrozole (PLAC-LET) n = 1655 1998 2003 2005 Unblinding Benefit for switching Ingle et al Goss et al: & for late switching! Goss PE, et al. SABCS. 2005. Abstract #16.
  • Intergroup Exemestane Study T then T vs Exem. Disease-Free Survival Patients Surviving Free of Disease (%) 100 Exemestane 75 Tamoxifen 50 HR 0.68 25 p<0.001 0 0 1 2 3 4 Years after RandomizationNo. of Events/No. at RiskExemestane 0 / 2362 52 / 2168 60 / 1696 44 / 757 20 / 201Tamoxifen 0 / 2380 78 / 2173 90 / 1682 76 / 730 18 / 185
  • UPFRONT AI TRIALS: Summaries & Combined Analysis Ratio, annual event rates Upfront AI studies: (Al:Tam) 2P Any recurrence 0.77 (SE 0.05) <0.00001 ATAC Isolated local* 0.70 (SE 0.10) 0.003 & Isolated 0.59 (SE 0.12) 0.0009 BIG 1-98 contralateral* Distant* 0.84 (SE 0.06) 0.009 Any distant 0.82 (SE 0.06) 0.002 * As first event, heterogeneity, p = 0.08 Dowsett M et al JCO 2009No significant reduction of mortality, yet!
  • SWITCHING TRIALS:Combined Analysis and summaries Ratio, annual event rates (Al:Tam) 2PSwitching Trials: Any recurrence 0.71 (SE 0.06) <0.00001IES Isolated local* 0.60 (SE 0.13) 0.002ABCSG 8 Isolated 0.65 (SE 0.17) 0.03ARNO contralateral* Distant* 0.76 (SE 0.07) 0.001ITA Any distant 0.77 (SE 0.06) 0.0009 * As first event, heterogeneity, p = 0.4 Dowsett M et al JCO 2009Switching favored!
  • Switching is favored!
  • Reverse Switching is OK!
  • SABCS 2009 Updates on switching adjuvant endocrine therapy trials Median Trial Nr. Pts Design F.up Results Tam 7.5 y • E remains superior IES 4724 Tam 2-3y R DFS HR 0.82 (0.73- Exem 0.92) OS HR 0.86 (0.75-0.99) • E seems to ↓ bone mets • E seems to ↓ non breast 2d cancersNCIC-CTG 5168 Tam 5y Letrozole • Larger absolute benefit R MA17 (n = 889 Placebo in pre compared to postmen. (≈ 10%) in premen.) delayed let both N+ and N- disease observ.Bliss, Goss, SABCS 2009
  • Conclusions and take home messages for adjuvant AI and TamoxifenPremenopausal women, derive a large benefit fromthe switching strategy, whether LN+ or LN-: Patientwho is started on Tam as premenopaused, switch toAI when becomes “definitely” meno-pausedPatients at higher risk of recurrence (more positivenodes, etc) benefit more from upfront AINode-negative patients: In general, switch strategy isfineIf patients have poor tolerance to AI, reverseswitching to Tamoxifen seems fine
  • Adjuvant Chemo based on Anatomy only!• Larger T size & Higher N stage: Yes for using chemotherapy (& targeted therapy if HER2-positive)• What to do in patients with Smaller Tumors?! May not need chemotherapy! May get help from Genomics & Microarray studies: - RS-21: Recurrence Score 21 (Oncotype DX) - Amsterdam 70-gene signature (Mammaprint)
  • Role of Genomics in adjuvant therapy• Retrospective Validation: of multigene assays (Amsterdam 70-gene, RS-21) using paraffin blocks of tumors: NSABP: B-14 (Tam vs placebo) NSABP: B-20 (Tam vs Chemo + Tam) SWOG 8814 (Tam vs CAF + Tam)• Prospective Randomized definitive trials:- MINDACT (Study BIG / EORTC): Validation of the 70-gene Amsterdam signature score- TAILORx (Study in the USA): Validation of the 21-gene Recurrence Score
  • Established Rates of Distant Recurrence: vs Ranges of RS-21 score Paik, et al. NEJM 2004, 351;27
  • B-20 & RS-21: Distant Recurrences for Tam + Chemo vs Tam alone . (A: All Patients, B: Low Risk, C: Intermediate, D: High Risk) Paik S et al. JCO 2006;24:3726-3734 Only High group benefits from chemo©2006 by American Society of Clinical Oncology
  • TAILORx DesignDetermine Oncotype RS For NN ER+ Patients Low Risk (RS-21 <11) < 6 % Risk of Metastasis Endocrine Therapy Only Intermediate Risk Endocrine Therapy 6-16% Risk of Mets Randomized Chemo + Endo Tx High Risk (RS-21 >25) > 16% Risk of Metastasis Tx= Chemo + Endo
  • MINDACT: Use of Amsterdam 70-genesignature
  • Adjuvant therapy for small tumors:• Anatomo-pathology remains important• Biology is gaining more and more importance Hormone receptor negative require chemotherapy Trastuzumab is indicated in most patients with HER2positive tumors, but probably not all of them! Not everybody benefits from addition of chemotherapy Many patients can be treated with hormonal therapy alone, especially well differentiated, grade 1, with strongly positive hormone receptors:TNM, histology, IHC, receptors, biology, genomics: Helps usto better tailor adjuvant therapy!
  • State of the art in Early Breast Cancer• Most areas covered!• Thank you for your attention-----------------------------------------------------Back-up slides: 2 Cases• Locally Advanced Breast Cancer• and relatively large Early Breast Cancer with positive Lymph Nodes) Breast Cancer• (HER2+ and HER2-)
  • HER2-negative Locally Advanced Br Ca (& relatively Large Early Breast Cancer)• NM: 52 y-o-f, diagnosed in 2008• cT2 (3.2x2.6cm) cN1 (FNA+) M0;• IDC; ER++, PR+, HER-• Neo-Adjuvant chemo: AC – D (NSABP B-27 protocol) cCR• Partial Mastectomy + ALND yT0 yN0 Mo• Radiation Therapy• Tamoxifen, with plans to switch to AI once definitely menopaused• 2011: No Evidence of Disease; already switched to AI
  • HER2-positive LABC (& relatively large Early Breast Cancer)• NH: 56 y-o-f, diagnosed in 2009• cT3 (7x8cm) cN1 M0; IDC; ER-, PR+, HER+++• Neo-Adjuvant chemo: T(H)- CEF(H) [MDACC regimen] Paclitaxel 80/m2 qw x 12 - CEF x4  cCR• MRM + ALND yT0 N1 (1/33, treatment effects, DCIS) Mo• Radiation Therapy• Letrozole• Trastuzumab x1 yr• 2011: Remains with No Evidence of Disease
  • Multi-Disciplinary Management of cancer338 Physicians surveyed: 72% hold TUMOR BOARDS52% only: Hold it weekly57% attend Tumor Boards at Neighboring Hospitals60% attend it for group opinion and discussion93% agree it should become mandatory100% agree to have at least a MINI-TUMOR BOARD with whoever is available (Ex: Surg +Radiol +/- Oncol +/- Path