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  • This is the schema of the TAILORx trial. The eligible patients for this trial are N–, ER+ and are candidates for chemotherapy (ie, patients who do not have comorbid conditions that would preclude them from receiving chemotherapy and who are willing to take it if recommended).The fact that the Breast Cancer Intergroup is stratifying patients for the TAILORx trial by the Oncotype DX™ assay demonstrates that this assay is widely accepted and validated in the study population. Treatment will be based on the results of the assay.Patients will be stratified as follows:Patients with a Recurrence Score below 11 will receive hormonal therapy alone. Patients with a Recurrence Score between 11 and 25 will be randomized to either hormonal therapy alone or hormonal therapy + chemotherapy. This is the primary study group. This corresponds approximately to a risk of recurrence at 10 years of 10%-20%. Patients with a Recurrence Score greater than 25 will receive chemotherapy + hormonal therapy.Since this trial has a dealer’s choice–type design, individual investigators can select the type of hormonal therapy and chemotherapy from a list included in the protocol.The groups in this trial do not correspond to the low-, intermediate-, and high-risk cutoffs found on the Oncotype DX™ report. However, the cutoffs for the TAILORx trialwere picked for different reasons from those involved with the selection of cutoffs for the validation trial and the Oncotype DX™ report. The cutoffs in the study were selected to correspond with specific risk levels. For instance, it was felt that it was not ethical to deprive a women of chemotherapy if she had a risk level above 20%.
  • Ongoing trials exploring 10 years of AI Extension of MA-17Bias obviously is that you’re selecting for patients who have already tolerated 10 years of endocrine therapy and have not yet recurred
  • When to use it?When to use CMF?What are the anthracycline-based regimens?What is the role of taxanes?What is dose-dense chemotherapy?What are the available standard adjuvant chemotherapy regimens?
  • Unselected populationBenefits appear greater in women <50 yo and for those with LN-positive diseaseProbably speaks to the biology of the cancerBetter survival BUT also risks…
  • In general, anthracycline and taxane containing regimens appear superior to non- A and –T containing regimensCan we better determine which women will benefit from adj chemotherapyAre there certain subgroups of patients who have greater benefit1990s The TaxanesBuilding upon the backbone of anthracyclines, the taxanescontinued to improveupon adjuvant breast cancer treatmentoutcomesFrom CMF:BCIRG 001: Docetaxel replaced 5FU. TAC x6 > FAC x6 in DFS and OSFROM AC:Adding Taxol to ACCALGB 9344 showed addition of Taxol 175 q3 to AC improved DFS and OSNSABP B28 confirmedimproved DFS when Tq3 added to AC. No OS difference, but thismightbe due to concurrent tam use and the lowerrisk nature of this trials’ participantsCALGB 9741 concept of dose density: q2w issuperior to q3w in terms of DFS and OSECOG 1199 lookedatschedule as well as drug; ACq3x4 weekly/q3, taxol or doce. Weekly Taxol superior in terms of DFS/OS. Doce q3 superior to q3 Taxol in terms of DFS.Continuing the trend, PACS01 showed the addition of Doce x3 to FEC3 wasbetterthan FEC6 in DFS and OSGEICAM 9906 compared FECx6 vs FECx4 weekly taxol. DFS wasimprovedwithweekly Taxol.Eliminating AnthracyclineTC vs. ACx4  N=1000, 50% LN+  TC>AC in terms of DFS and OSLet’s look atsome of theseregimens more closelyAnd reviewsome of the unanswered questions!
  • In the 2005 update of the overview, there is a ~5% mortality benefit to the addition of anthracyclines in unselected patients with LN+ breast cancer.
  • Are the benefits from taxanes enough to be able to abandon use of anthracyclines given risk of cardiac toxicity and leukemia?
  • BRCAness about TNBC and BSBC

Breast cancer overview Breast cancer overview Presentation Transcript

  • Breast Cancer 101: an overview of therapy Tiffany A. Traina, MD Breast Cancer Medicine Service April 2011The following material is intended for MSKCC internal medicine housestaff teaching purposes only. Theslides are courtesy of Dr. Tiffany Traina and were updated for the LibGuide in 2011-2012 .
  • New Invasive Breast Cancer Cases United States 2010 Estimates 207,090 invasive ca 54,010 in situ ca
  • Breast cancer mortality is declining
  • Treatment of Early Stage Disease Curative intent! Local therapy Risk assessment Systemic therapies
  • What do we need to know from pathology to estimate risk? • T • Don’t sweat the • N staging! • ER/PR – LN- – LN+ • HER2 – MBC – IHC – FISH • Margins • LVI, Grade
  • History of Risk Assessment• Traditional prognostic factors – Limited predictive power (T 10% N 5% rule) – Poor reproducibility – Lack standardization, validation – Limited insight into relative benefits of chemotherapy for different individuals Bundred. Cancer Treat Rev. 2001;27:137-142.
  • Risk Assessment www.adjuvantonline.com60yo healthy woman with: T1 (0.1-1cm), N0 Grade 2 IDC ER(+)
  • Risk Assessment www.adjuvantonline.com40yo healthy woman with: T2 (2.1-3cm), N1, Grade 3 IDC ER(-)
  • Why we need better risk assessment tools?• Only 15% of LN(-) patients recur BUT – 50% of these patients receive chemotherapy!• Rationale for predictive/prognostic technologies: – Avoid Over-treatment – Avoid Under-treatment• Potential economic benefits
  • Oncotype DX™• 21 gene RT-PCR assay on FFPE tumor• Prognostic: – Estimates risk of breast cancer recurrence• Predictive: – What added benefit from chemotherapy• ER(+), Lymph node (-) cancers• “Recurrence score”= risk of recurrence in 10yrs• Some data for its use in LN(+), but too early to change practice (Albain SABCS 2007) Paik et al, NEJM 2004 Dec 30;351(27):2817-26.
  • What is this patient’s risk of recurrence?
  • Low Recurrence Score: 4Rate of Distant Recurrence at 10 Yrs: 5%
  • TAILORx closed to accrual N=11,000+ patients
  • Early Stage Breast Cancer Systemic Therapy• Endocrine therapy – Tamoxifen – Aromatase Inhibitors• Chemotherapy – Anthracycline-based – Anthracycline- & Taxane-based• Biologic therapy – Trastuzumab
  • Endocrine Therapy: The oldest targeted therapySERMs E Aromatase(ie, tamoxifen) Steroid inhibitors precursors (ie, letrozole, anastrozole) ER ER ER antagonist (ie, fulvestrant)
  • Tamoxifen Improves DFS & OS Recurrence Breast Cancer Mortality EBCTCG, Lancet 365:1665, 2005
  • Aromatase Inhibitors ↓ Estrogen SynthesisCholesterol CortisolPregnenoloneProgesterone Androstenedione Testosterone AromataseAldosterone Enzyme Complex Estrone Estradiol
  • AI Trial DesignsDIRECT COMPARISON SUPPORTING TRIALS • ATAC • BIG FEMTASWITCHING SUPPORTING TRIALS • IES • ITA * • ARNO/ABCSGEXTENDED ADJUVANT SUPPORTING TRIALS • MA-17 • ABCSG-6A * • NSABP B33SEQUENCING SUPPORTING TRIALS • No reported trials • BIG FEMTA • TEAM
  • AIs improve DFS over Tam Med. f/u N (mo) DFS (HR, p) OS (HR, p) ATAC 6241 SABCS 2007 100 0.85 (0.003) 0.97 (0.7) Up-Front BIG-1-98 4922 JCO 2007 51 0.82 (0.007) 0.91 (>0.05) ITA-1 380 JCO 2001 61 NR NR Ann Oncol ITA-2 448 64 0.57 (0.005) 0.56 (0.1) 2006 “Early” Switch IES 4742 Lancet 2007 56 0.76 (0.0001) 0.85 (0.08) ABCSG8/ARNO 3224 Lancet 2005 28 0.60 (0.0009) NR MA.17 5157 JNCI 2005 30 0.58 (0.001) 0.82 (0.3)“Extended” ABCSG 6a 856 ASCO 2005 60 0.64 (0.047) NR Switch NSABP B-33 1598 SABCS 2006 30 0.68 (0.07) 1.20 (0.64)
  • Safety of Anastrozole vs. Tamoxifen On Treatment Off TreatmentSerious Adverse Anastrozole Tamoxifen Anastrozole TamoxifenEventsTreatment Related 153 284 49 57Endometrial 4 12 1 12CancerMyocardial 34 33 26 28InfarctionCerebrovascular 20 34 22 20AccidentFracture Episode 375 234 146 143• Relative risk of fracture episode at 5 years = 1.55; P < .0001• Relative risk of fracture episode at 9 years = 1.03; P = 0.79• No excess fracture episodes or new morbidities after completion of anastrozole Forbes et al. Breast Cancer Res Treat 2007; 106 (suppl 1): S12 (abstract 41) Howell et al. Lancet Oncol. 9: 45-53, 2008
  • Adjuvant AI Trials: ToxicityTamoxifen AI– Genitourinary bleeding – Bone loss/Osteoporosis– Endometrial cancer – Bone fracture– DVT/CVA etc – Arthralgia/myalgia • More or less similar – Hot flashes / night sweats – Headache / dizziness – GI side effects – Compliance
  • Chemotherapy
  • Adjuvant Chemotherapy: What We Know• Chemotherapy improves DFS and OS• Polychemotherapy x3-6 months• Anthracycline-containing regimens > CMF• Anthracycline and Taxane-containing regimens > anthracycline-containing regimens• Chemotherapy and hormonal therapy benefits are independent
  • History of Adjuvant Chemotherapy1970’s • Improvement in disease free survival for LN+ BC • Single agent vs. various drug combinations • Sequencing of single agents & drug combinations • Evaluation of dose intensity • Improvement in DFS for LN- BC1980’s • Greater use of anthracyclines • Introduction of taxanes1990’s • Dose intensive regimens +/- stem cell support • “dose-dense” plus colony stimulating factors • Role of prognostic factors in choosing therapy2000’s • Biologic therapies – trastuzumab • Oncotype/Mammaprint
  • Improved Survival with Polychemotherapy 15 Years of Follow-Up 10% gain 12% gainEBCTCG Lancet „05
  • Evolution of Adjuvant Chemotherapy CMF = AC = FEC 50 (Milan) (B-15) (ICCG) CEF FAC TC AC-P FEC 100 (MA-5) (GEICAM) (US 9735) (C 9344;B-28) (FASG 05) AC-T AC2w- FEC-T TAC (E 1199 AC-Pw P2w (PACS 01 FEC-Pw (BCIRG 001, 005) BCIRG 005 (E 1199) (C 9741) EC-T (G 9906) B-30) WSG)Walshe et al, 2006; Ellis, 2006; Fumoleau et al, 2003; Roche et al, 2006; Eiermann et al, 2008; Mamounas, 2005; Joensuu et al, 2009.
  • Acute Toxicities of Chemotherapy• Myelosuppression• Gastrointestinal (mucositis, nausea, vomiting, diarrhea)• Alopecia• Fatigue• Infections (febrile neutropenia)• Cystitis• Sterility/Chemical Menopause• Cardiomyopathy (with anthracyclines)• Neuropathy
  • Long-term complications of chemo CHF TAC ACWouters et al, 2005.
  • Long-term complications of chemo Hematologic malignancyAnthracyclines:2-4 yearsAlkylators:5-10 years
  • CMF
  • What is CMF?• Cyclophosphamide, Methotrexate, 5FU• 1st regimen to show improved DFS and OS in adjuvant treatment of breast cancer• Well-tolerated: – fatigue, mild nausea or diarrhea• Use has diminished with data showing benefit of anthracycline-based therapy EBCTCG. Lancet 352:930-942, 1998 EBCTCG Lancet 2005
  • When we consider CMF?• Low-risk breast cancer – Lymph node (-) – ER/PR (+) – HER2/neu “normal”• Elderly patients• Cardiac dysfunction• Prior anthracycline
  • Anthracyclines
  • Anthracyclines Add Benefit in Unselected, Node-Positive Disease 4.6% 3.7%EBCTCG, Lancet 2005
  • Anthracycline-Based Regimens ↑DFS and OS • Doxorubicin-based regimens: – AC x 4 – CAF/FAC – A CMF • Epirubicin-based regimens: – CEF/FEC – E  CMF
  • What is Role of Taxanes in the Adjuvant Setting?
  • Taxane Benefit in Unselected Patients • Taxane vs. no taxane: Breast cancer death – 5.1% ↓ over no taxane • Built upon anthracycline backbonePeto et al, 2007.
  • CALGB 9344 5-yr DFS N >3,000 pts 65% vs 70% P=0.0023 A: 60 = 75 = 90 mg/m2 P 175 mg/m2 (3 h) C: 600 mg/m2 5-yr OS 77% vs 80% P=0.0064Henderson et al. JCO 2003
  • Dose-Dense Chemotherapy
  • The Norton-Simon Hypothesis Standard Regimen Dose-Dense Regimen 1012 1012Cell Number 108 108 Cell Number 104 104 100 100 0 20 40 60 0 20 40 60 Weeks Weeks
  • CALGB 9741 - INT C97412X2 Factorial Design q 2 wk +Filgrastim q 3 wkSEQUENTIAL 24 weeks 36 weeks SEQ Q2 SEQ Q3CONCURRENT 16 weeks 24 weeks CON Q2 CON Q3 doxorubicin 60 mg/m2 cyclophosphamide 600 mg/m2 paclitaxel 175 mg/m2 over 3 hours Citron JCO 2003
  • Overall Survival by Density Overall Survival By Density 1.0 q2 0.8 q3Proportion Surviving 0.6 31% reduction in mortality 0.4 P=0.013 0.2 0.0 0 1 2 3 4 Years From Study Entry q 2 wks N= 988 Events= 75 q 3 wks N= 985 Events= 107
  • E1199: Paclitaxel vs Docetaxel Weekly vs Q 3 Week dose/cycle total dose (mg/m2) (mg/m2) Paclitaxel (q3w vs. q1w) 175 700 80 960 100 400 35 420 Docetaxel (q3w vs. q1w) N=4950Primary Endpt=DFS Sparano, NEJM 358:1663-1671. April 17, 2008
  • ECOG 1199: DFS Comparison HR 95% CI p Value Paclitaxel vs. docetaxel 1.032 0.91, 1.17 .61 q 3 wks vs. wkly 1.062 0.94, 1.20 .33 1.0  No significant 0.9 difference by taxane or schedule 0.8 DFS (%) 0.7 5-year DFS rates (No. Events)  Hint that best ------------------------------------------------------------ outcome in wkly 0.6 P3: 76.9% P1: 81.5% D3: 81.2% D1: 77.6% paclitaxel or q 3 wks docetaxel 0.5 0m 20 m 40 m 60 m 80 mSparano et al, 2008.
  • Making the Decision Based on Toxicity: ECOG 1199 (Grade 3–4) P3 (%) P1 (%) D3 (%) D1 (%) Neutrophils 4 2 47 3 Febrile neutropenia < 0.5 1 16 1 Infection 3 3 13 4 Stomatitis < 0.5 0 5 2 Fatigue 2 3 9 11 Myalgia 7 2 6 1 Arthralgia 6 2 6 1 Tearing < 0.5 0 < 0.5 5 Grade 3–4 neuropathy 5 8 4 6 Grade 2–4 neuropathy 20 27 16 16Sparano et al, 2008.
  • Do we need anthracyclines?
  • USO 9735: AC vs. TC Doxorubicin 60 mg/m2 + Stage I–III operable R cyclophosphamide 600 mg/m2 breast cancer AC q 3 wks A N = 1,016 N n = 510 20% stage I, 70% stage II D 70% HR+ O 50% N+ (40% 1–3, 10% 4+) M I Docetaxel 75 mg/m2 + Z TC cyclophosphamide 600 mg/m2 E n = 506 Primary objectives: DFS and OS at 7-year F/UJones et al, 2006, 2009.
  • TC > AC 26% improvement in DFS TC > AC 31% improvement in OSJones et al, 2009.
  • Do We Need Polychemotherapy in Older Patients? CALGB 49907 Age > 65 (~ 60% > 70) Randomize Oral CMF x 6 Capecitabine (X) x 6 AC x 4 cycles  Both arms tolerated but more toxicity in AC/CMF arm than X armSOG, 2010.
  • CALGB 49907: RFS  Polychemotherapy still relevant even in older populations!  Difference particularly marked in ER-  Median F/u: 2-4 yearsMuss et al, 2009.
  • Trastuzumab in the Treatment of Her2(+) Breast Cancer
  • Trastuzumab: humanized monoclonal Ab to HER2Hudis CA. NEJM2007;357:39-51
  • Pivotal Combination Trial of First-Line Chemotherapy Trastuzumab in MBC: Overall Survival 1.0 Trastuzumab + CT (n=235) CT (n=234) 0.8 Proportion alive 0.6 25.1 mo (median) 0.4 20.3 mo (median) 0.2 RR=0.80 P=0.046 0 5 15 25 35 45 MonthsSlamon et al. N Engl J Med. 2001;344:783.
  • Adjuvant Trastuzumab Trials Anthracyclines and Adjuvant Trastuzumab NSABP B-31 BCIRG 006 Doxorubicin Cyclophosphamide Paclitaxel H…x 52 Docetaxel H…x 52 Carboplatin H…x 52 Epirubicin NCCTG 9831 HERA Vinorelbine No therapy Fluorouracil H…x 52 Standard H Trastuzumab ChemoRx H… x 1 year H… x 2 years H…x 52 FinHer PACS 04 H…x 52 H…x9 No therapy H…x9Romond et al, 2005; Slamon et al, 2006; Joensuu et al, 2009; Smith et al, 2007; Spielmann et al, 2007.Courtesy of Clifford Hudis
  • 4-Year DFS Adjuvant Trastuzumab Trials DFS Duration of Median Study HR p Value therapy F/U T + CT CT alone NSABP B-31/ 1 year 4 years 86% 73% 0.49 < .0001 NCCTG N9831 84%: AC-TH 0.64 < .0001 BCIRG 006 1 year 65 mos 75% 81%: TCarboH 0.75 .004 HERA 1 year 4 years 79% 73% 0.76 < .0001Perez et al, 2007; Slamon et al, 2009.
  • Adjuvant Trastuzumab Regimens: Cardiotoxicity % NYHA Class III-IV CHF Study Control arm Trastuzumab arm NSABP B-31 0.8 4.1 N9831 0 2.9 HERA 0 0.6* BCIRG 006** .95† 1.33‡ / 2.34§ FinHer¶ 0 0*1-yr trastuzumab arm; **Includes: Grade 3 or 4 arrythmias, Grade 3 or 4 cardiacischemia / infarction; †AC T; ‡TCH; §AC TH; ¶Small sample size.
  • Adjuvant Trastuzumab: Cardiac Toxicity and DFS Improvement NonanthracyclineBird et al, 2008.
  • Risk Factors for Trastuzumab- related Cardiotoxicity•Prior use of anthracycline• Age• Baseline LVEF• Hypertension medication use
  • Metastatic Breast Cancer Lots of drugs work,but we haven’t cured breast cancer yet
  • Chemo that “works” in breast cancer • Taxanes • Irinotecan – paclitaxel, docetaxel, nab- • Etoposide paclitaxel • Continuous infusion 5FU • Anthracyclines • Cis- or Carboplatin – doxorubicin, epirubicin, lip osomal dox Biologics plus Chemo: • Capecitabine – HER2+ • Ixabepilone • Trastuzumab • Lapatinib • Vinorelbine – AntiVEGF • Gemcitabine • Bevacizumab • Eribulin
  • Basic concepts for MBC• Goals are palliative so minimize toxicity while improving response & survival• For ER/PR+ MBC  start with and use hormones as long as possible – Tam, letrozole, anastrozole, exemestane, fulvestrant… – Exception is rapidly progressing visceral mets• Single, sequential agent therapy over combinations – Combinations = better response, more toxicity, not necessarily longer survival than using same drugs in sequence
  • Triple Negative and Basal-like Breast Cancer
  • Triple-Negative Breast Cancer  Defined as negative on clinical assays for – ER – PR – HER2 (c-erbB2, neu) Approximately 25,000–30,000 cases per year in U.S. but responsible for a disproportionate number of deathsCleatore et al, 2007; ACS, 2009.
  • Intrinsic Breast Cancer Subtypes “Unsupervised” gene expression array analysis of unselected breast cancers = intrinsic subtypes Intrinsic gene clusters identify distinct subtypes – Hormone receptor (luminal) cluster Subtypes – HER2 “enriched” cluster with low – Basal cluster expression – Proliferative cluster of luminal ER-negative and HER2 subtypes clusters = When luminal and HER2 mostly clusters low = usually ER- basal-like , PR-, and HER2- on clinical assays  “triple-negative”Image coutesy of Chuck Perou, MD.Seal et al, 2010.
  • Basal-Like Breast Cancer and BRCA1 Basal-like BRCA2 BRCA1 = BRCA1+T et = BRCA2+ Sorlie al. PNAS 03 • Most BRCA1 carriers get basal-like breast cancer but • Most basal-like breast cancers are not in BRCA1 carriers Is BRCA1 pathway abnormal in sporadic (noninherited) basal-like breast cancers?Sorlie et al, 2003. Courtesy Lisa Carey
  • Jury is still out on platinums…Byrski et al, 2010 Silver et al, 2010• Neoadjuvant cisplatin pCR • Prospective trial of cisplatin 83% in BRCA1+ patients in 28 pts with (n=12) BRCA1+/TNBC• Retrospectively compared to • pCR 22% historic standard • pCR 14% if non-BRCA1 neoadjuvant regimens (pCR • Unclear if this is platinum 7-22%) sensitivity or just• Cisplatin arm has smaller chemotherapy sensitivity tumors, more LN-negative
  • Targets for Triple-Negative Breast Cancer Target Rationale TreatmentDNA DNA aberrations suggestive Chemotherapy-double of defective DNA repair; strand DNA breaks, selective chemosensitivity such as platinumsPARP1 DNA aberrations suggestive PARP inhibitors of defective DNA repairEGFR Overexpression of EGFR Cetuximab, erlotinibSrc Sensitivity to dasatinib DasatinibAndrogen Expression in 15% of triple- Bicalutamidereceptor negative tumors Adapted from Cleator S et al. Lancet Oncology 8:235-244, 2007
  • Poly(ADP-Ribose) Polymerase (PARP) • A key role in the repair of DNA single-strand breaks • Through the base excision repair pathway (BER) • Binds directly to sites of DNA damage • Once activated, it uses NAD as a substrate, and generates large, branched chains of poly (ADP-ribose) polymers on multiple target proteins • Recruits other DNA repair enzymes • PARP-inhibition prevents recruitment of DNA repair enzymes  failure of single strand break repair  accumulation of ssDNA breaks • During S-phase, this leads to arrest of the replication fork at site of ssDNA break and degeneration to dsDNA breaks. Normal cells can then repair dsDNA break using homologous recombination Helleday T et al. Cell Cycle 2005; 4: 1176-1178.
  • Randomized Phase II Trial of Gemcitabine and Carboplatin BSI-201 in TNBC Gemcitabine (1000 mg/m2 IV d1, 8) Eligibility Carboplatin (AUC 2 IV d 1, 8) q21 days• Metastatic TNBC with measurable disease• 0-2 prior chemotherapy R BSI-201 (5.6 mg/kg IV D1, 4, 8, 11) regimens for metastatic disease Gemcitabine (1000 mg/m2 IV d1, 8) N = 123 Carboplatin (AUC 2 IV d 1, 8) q21 days Primary Endpoint: Clinical benefit rate (CR + PR + SD 6 mo) O’Shaughnessy J et al. J Clin Oncol 2009;27(18S):793s (abstr 3)
  • 2009 SABCS Update: Overall SurvivalO’Shaughnessy J et al. SABCS 2009;(abstr 3122)
  • TNBC Treatment• No defined standard of care for metastatic or adjuvant treatment of TNBC• Subset analyses suggest TNBC benefits from antiangiogenic therapy• Current trials determining the role of PARP inhibition and platinum agents in this subtype of breast cancer