Evolving Insights into Adjuvant Chemotherapy. Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology US Oncology

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1 Evolving Insights into Adjuvant Chemotherapy Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology US Oncology

2 Dilemmas in Adjuvant Chemotherapy Is adjuvant chemotherapy effective in ER+ disease? If adjuvant chemotherapy will be administered Clinical utility of treatment options Duration of adjuvant chemotherapy Sequential vs concurrent chemotherapy

3 Pathological CR by ER status: Chemo # Pts pcr ER neg ER pos FAC x % 1% FAC x % 6% Pac x % 6% Pac (q 3 w) FAC x % 6% Pac (q 1 w) FAC x % 14% (A + Doc) x % 7% Total % 5% Buzdar, et al. SABCS 2003

4 Advances in Chemotherapy Have Dramatically Improved Outcomes in ER-Negative Breast Cancer Reduction in Relative Risk of Recurrence Corresponds to an absolute improvement in 5 year DFS of 23%, and to an absolute improvement in 5 year OS of 17% in ER negative subset 55% 26% ER- ER+ 0 CALGB Trial Overall Optimizing Adding taxane Optimizing anthracycline taxane Berry et al, JAMA 295: , 2006

5 Tam vs CMF/Tam: NSABP Node neg, ER+ pre 46%: post 53% 49 years: 45% years: 27% 60 years: 28% Tam [5] CMF [6,oral] +Tam [5] Fisher et al Lancet 364:858, 2004

6 NSABP B20: 12 yr Overall Survival 87% 83% P=0.063 Fisher, et al, Lancet 364: , 2004

7 B-20: Hazard Ratios CMFT vs T 49 yrs yrs 60 yrs DFS RFS OS DFS, DDFS, RFS, OS benefits with CMF in ages < 49 and 50-59, but not in > 60

8 Randomized trials of OA+/- Tam vs. Chemo no difference Colozza, M. et al. Oncologist 2006;11:

9 Tam vs CMF/Tam: IBCSG VIII LHRH [24] 1063 Node neg, premenopausal ER+ 68%; ER neg 30% CMF [6] CMF [6] LHRH [24] IBCSG JNCI;24:1833, 2003

10 IBCSG Trial VIII STEPP Analysis n = 1,063 IBCSG, J Natl Cancer Inst 2003;95:1833

11 IBCSG Trial VIII STEPP Analysis n = 1,063 IBCSG, J Natl Cancer Inst 2003;95:1833

12 Most Important Paradigm Shift: Breast Cancer is not one disease ER % A B Breast Cancer HER % Basal 15% Triple Negative

13 21-Gene Recurrence Score Technology: Final Gene Set: The Usual Suspects PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 GSTM1 CD68 BAG1 ESTROGEN ER PGR Bcl2 SCUBE2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC

14 NSABP B-20 Distant RFS by Recurrence Score 651 All pts, p=.02 Low risk, p= Inter risk, p=.39 High risk, p< Paik, S. et al. J Clin Oncol; 24: Copyright American Society of Clinical Oncology

15 CAF Benefit Greatest in Higher RS for Both Nodal Subsets, with No Benefit in Lower RS Five-Year Probability of Death or Disease Recurrence Linear model for Recurrence Score and interactions with treatment Five Year Probability of an Event Tam, 4+ nodes (n=54) CAF-T, 4+ nodes (n=86) Tam, 1-3 nodes (n=94) CAF-T, 1-3 nodes (n=133) Chemo benefit 4+ nodes Chemo benefit 1-3 nodes Recurrence Score Albain, et al. Lancet Oncology 11:55-65, 2010

16 TransATAC: 21-gene recurrence score to predict risk of distant recurrence in postmenopausal patients treated with an AI Results Node- (N=872) Node+ (N=306) % pts 9-year DR rate % pts 9-year DR rate Low RS <18 59% 4% 52% 17% Int RS % 12% 31% 28% High RS 30 15% 25% 17% 49% High vs. Low RS: HR 5.2 Int vs. Low RS: HR 2.5 High vs. Low RS: HR 2.7 Int vs. Low RS: HR 1.8 P<.001 for RS in predicting time to distant recurrence (DR) in N+ and N- patients Dowsett et al. J Clin Oncol 2010; 28:

17 COMPARISON OF TAILORX AND MINDACT TRIALS TAILORx MINDACT Groups TBCI BIG Population Node neg, ER+ Node neg, ER+/ Assay 21 gene RS 70 gene Prognostic Signature Utility Scale & Level of Evidence + or ++ II + or ++ III Tissue FPET Fresh or frozen Accrual Goal ~10,500 ~6,000 Randomized group RS (40%) Discordant risk (32%) Randomization Non randomized groups Treat with hormones +/ chemotherapy RS < 11: Hormones RS > 25: Chemo + hormones Treat by clinical vs. genomic risk Both low risk (13%):Hormones Both high risk (55%): Chemo hormones

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19 St. Gallen 2011: Shorthand Determination of Breast Cancer Subtypes Intrinsic Subtype Surrogate Definition Luminal A Luminal B1 Luminal B2 HER2 over-expression Basal-like ER and/or PgR(+), HER2(-) Ki-67 low (<14%)* ER and/or PgR(+), HER2(-) Ki-67 high ER and/or PgR(+), HER2(+) Any Ki-67 ER and PgR absent, HER2(+) Triple negative ductal (not medullary, adenoid cystic, apocrine) * Using PAM5O cutpoint from Cheang et al. JNCI 2009 Goldhirsch, A, et al, Annals Oncol 22:1736, 2011

20 Subtype Type of therapy Notes Luminal A Luminal B (HER2 negative) Luminal B (HER2 positive) HER2 positive (non luminal) Endocrine therapy alone Cytotoxics + endocrine therapy Cytotoxics + anti-her2 + endocrine therapy Cytotoxics + anti-her2 Few require cytotoxics (e.g. high nodal status). Inclusion and type of cytotoxics may depend on level of endocrine expression, perceived risk and patient preference. No data are available to support the omission of cytotoxics in this group. Patients at very low risk may be observed without treatment Triple negative (ductal) Cytotoxics Special histological types * A. Endocrine responsive B. Endocrine non responsive Endocrine therapy Cytotoxics Goldhirsch, A, et al, Annals Oncol 22:1736, 2011 Medullary and apocrine carcinomas may not require any adjuvant cytotoxics (if node negative).

21 Theoretical Spectrum of Sensitivity to Adjuvant Systemic Therapy by Intrinsic Subtypes Hayes DF. J Clin Oncol 30:1264, 2012

22 Dilemmas in Adjuvant Chemotherapy Is adjuvant chemotherapy effective in ER+ disease? If adjuvant chemotherapy will be administered Clinical utility of treatment options Duration of adjuvant chemotherapy Sequential vs concurrent chemotherapy

23 EBCTCG 2007 Update Unselected for HER2 status

24 EBCTCG 2011 Chemotherapy Meta-analysis Summary: Breast Cancer Mortality Trial Grouping ER+ and ER poor RR SE 2p CMF vs no chemo 0.76 (0.05) < CAF vs no chemo 0.64 (0.09) < AC/EC vs no chemo 0.78 (0.09) AC vs CMF 0.98 (0.05) 0.67 CAF/CEF vs 4AC 0.78 (0.06) Anthra then T vs shorter anthra 0.86 (0.04) Anthra + taxane vs expanded anthracycline alone 0.94 (0.06) 0.33 EBCTCG, Lancet 379:432-44, 2012

25 ER+ Anthra/CMF plus ET vs ET Control Age < 55 Age EBCTCG, Lancet 379:432-44, 2012

26 Anthracyclines vs No Chemotherapy by Subsets of ER+ EBCTCG, Lancet 379:432-44, 2012

27 What We Learn from the New EBCTCG 2011 Chemotherapy Overview in ER+ Disease Major benefit overall to anthracyclines and taxanes, reducing breast cancer mortality by about 1/3 (the same as in ER-poor disease) No apparent heterogeneity by age, grade, T size, nodes, presence of tamoxifen - when factors generally considered one at a time Even in strongly ER+ disease, chemotherapy impacted outcome, though not to the same extent as in less strongly ER+ disease in the largest trial S8814 which had heterogeneity K Albain, SABCS 2011 Webcast 12/6

28 SWOG 8814 CAF-Tam vs Tamoxifen Recurrences Only ER fm/mg ER100+ Interaction p = 0.04 Peto R, Personal Communication, 2011

29 Adjuvant Chemotherapy Regimens CMF = AC CAF/FAC DAC(Tac) CEF/FEC FEC P/D DC AC P/D AC > wkly P ddac P Differential Benefits by Subtype?

30 OS Gennari, A, et al. J Natl Cancer Inst 100:14-20, 2008

31 Women aged 66 to 70 years: freedom from congestive heart failure by adjuvant chemotherapy type Pinder, M. C. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

32 US Oncology 06090/NSABP B49 TC X 6 HER-2 Negative Operable Early-Stage Breast Cancer (N=5900) R TAC or AC then T Principal Investigator: Joanne Blum, MD, PhD

33 Meta analysis: Adjuvant taxane vs no taxane: DFS De Laurentiis, M. et al. J Clin Oncol; 26: De Laurentiis, M. et al. J Clin Oncol; 26: Copyright American Society of Clinical Oncology

34 Meta analysis: Adjuvant taxane vs no taxane: OS Copyright American Society of Clinical Oncology De Laurentiis, M. et al. J Clin Oncol; 26: De Laurentiis, M. et al. J Clin Oncol; 26:

35 Disease-free Survival among Patients Treated with or without Paclitaxel According to Estrogen-Receptor Status and HER2 Expression Hayes DF et al. N Engl J Med 2007;357:

36 BCIRG001 Study Median follow-up: 4.6 years n=746 N = 1491 Node + R FAC q 3 wk x6 TAC q 3 wk x 6 Eligibility: Stage II disease n=745 (Docetaxel 75 mg/m 2 ) Tamoxifen for all ER+ or PR+ patients after chemotherapy Martin M et al. N Engl J Med, 2005;352:2302

37 BCIRG 001 FAC vs. TAC by biologic subtype TNBC HER2+ LUM B LUM A Copyright American Society Hugh, of Clinical J. Oncology et al. J Clin Oncol; 27:

38 DFS according to treatment and Ki67 Arm B: FEC - DOC Arm A: FEC Luminal A Luminal B Penault-Llorca, F. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

39 E1199: Adjuvant AC T q3w vs. q1w AC TAXANE Endocrine/RT A: 60 mg/m2 C: 600 mg/m2 q3w Paclitaxel (q3w vs. q1w) dose/cycle (mg/m 2 ) total dose (mg/m 2 ) Stratification: ER/PR Status # Nodes Tumor size Surgery Type Docetaxel (q3w vs. q1w) Sparano, ASCO 2007, Abstract 516

40 E1199: Best Taxane for Luminal BC? Primary Comparisons: Paclitaxel vs. Docetaxel: HR: 1.032; P = 0.61 q3w vs. q1w: HR: 1.062; P = 0.33 Docetaxel Paclitaxel Secondary Comparisons: q3w q1w q3w q1w 5-Year DFS 81.2% 77.6% 76.9% 81.5% compared to paclitaxel q3w HR: 1.23 P = 0.02 HR: 1.09 NS HR: 1.0 NS HR: 1.27 P = Hormone Receptor Positive* HR: 1.28 P = 0.03 HR: 1.15 NS HR: 1.0 NS HR: 1.20 NS Hormone Receptor Negative* HR: 1.08 NS HR: 0.96 NS HR: 1.0 NS HR: 1.40 P = Year OS 87.3% 86.2% 86.5% 89.7% compared to paclitaxel q3w HR: 1.13 NS HR: 1.02 NS HR: 1.0 NS HR: 1.32 P = 0.01 * Exploratory analysis Sparano et al. NEJM, 2008; 358:16

41 Weekly paclitaxel in adjuvant treatment and HR status Sparano et al. NEJM, 2008; 358:16

42 Does Dose Density Matter in Luminal Breast Cancer? Conventional Schedule Dose Dense Schedule 1,000,000,000,000 Cell number 10,000,000, ,000,000 1,000,000 10, Weeks

43 Advances in Chemotherapy Have Dramatically Improved Outcomes in ER-Negative Breast Cancer Reduction in Relative Risk of Recurrence Corresponds to an absolute improvement in 5 year DFS of 23%, and to an absolute improvement in 5 year OS of 17% in ER negative subset 55% 26% ER- ER+ 0 CALGB Trial Overall Optimizing Adding taxane Optimizing anthracycline taxane Berry et al, JAMA 295: , 2006

44 USON 9735 TC vs AC: DFS and OS N= % ER+ 48% N From: Jones, S. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

45 Summary of unplanned, exploratory analyses of disease-free survival hazard ratios (HR) and CI Docetaxel/cyclophosphamide (TC) is favored left of 1. Jones S et al. JCO 2009;27: by American Society of Clinical Oncology

46 Meta analysis of disease free survival (DFS) according to ER status for Taxanes Copyright American Society of Clinical Oncology De Laurentiis, M. et al. J Clin Oncol; 26:

47 Meta analysis of disease free survival (DFS) according to HER 2 status De Laurentiis, M. et al. J Clin Oncol; 26: Copyright American Society of Clinical Oncology

48 Do Adjuvant Antimetabolites Add Benefit? NO NSABP B38 and tango adjuvant gemcitabine studies -- negative FINXX and USON adjuvant capecitabine studies-- non-significant trends towards improved DFS Joensuu, et al. J Clin Oncol 30:11-18, 2012 Pippen et al. Proc ASCO, 2011

49 Adjuvant CMF or AC vs Capecitabine in women >65 Capecitabine Alone for Selected Luminals? Muss et al, NEJM 360: , 2009 Muss et al, NEJM 2009

50 Cisplatin (not much data..)

51 Phase II Neoadjuvant Cisplatin 28 women Tumor 1.5 cm Triple Negative CDDP x4 3-weekly S U R G E R Y 5/22 (23%) achieved a pathologic complete response (pcr) The 2 pts with known BRCA1 mutations had pcr Silver D, et al J Clin Oncol 28: , 2010

52 Neoadjuvant Cisplatin in BRCA1-deficient and Triple Negative Breast Cancer Patient Population Stage Regimen Pathological Complete Response, n (%) BRCA1 mutation 1 (n = 25) I III* Cisplatin 75 mg/m 2 q3w X4 18 (72%) Triple negative 2 (n = 28) II - III Cisplatin 75 mg/m 2 q3w X4 6 (22%)** Triple negative 3 (n = 51) II - III Cisplatin 75 mg/m 2 q3w X4 + bevacizumab 15 mg/kg X3 8 (16%) Triple negative 4 (n = 78) II - III Multiple cisplatin - based*** *Includes T1 (n = 10) and N0 (n = 18) **Including both patients with identified BRCA1 mutations ***Retrospective study subgroup analysis NA (32%) 1 Gronwald et al. J Clin Oncol 2009; 27(suppl):7s (abstract 502) 2 Garber et al. Breast Cancer Res Treat 2006; 105(suppl1):S149 (abstract 3074) 3 Ryan et al. J Clin Oncol 2009; 27(suppl):18s (abstract 551) Leone et al. J Clin Oncol 2009; 27(suppl):37s (abstract 625)

53 Neoadjuvant Chemotherapy and Pathologic Complete Response (pcr) Study N TN Treatment pcr Le Tourneau FAC x4 or FEC x4 28.6% TN ; HR 6.2, p= % Luminal 16.7% HER2pos 36% TN p<.0001 Marty EC x4 Docetaxel x % Luminal 14% HER2pos Allada Anthra + Taxane + H 23% TN 19% non-basal Sikov 54 Carbo (AUC6) x 4 Paclitaxel x 16 wkly +H 67% HER2neg/ERneg 12% HER2neg/ERpos 76% HER2pos Sikov W. J Clin Oncol SABCS Abstracts 4010, 5058, 5076, 5063.

54 Triple-Negative BC: Response to Neoadjuvant Platinum Small numbers Large confidence intervals

55 Alliance Randomized Phase II Trial William Sikov, MD PI wpaclitaxel then DD AC TNBC Clinical Stage II/III Increase pcr from 35% to > 55% R wpaclitaxel + Bev then DD AC + Bev wpaclitaxel + Carbo AUC 6 then DD AC wpaclitaxel + Carbo AUC 6 + Bev then DD AC + Bev

56 Duration of Adjuvant Chemotherapy

57 CALGB 40101: 4 Versus 6 Cycles of AC Versus Paclitaxel as Adjuvant Therapy Stratification factors: Prepostmenopausal ER/PgR HER2 R A N D O M I Z E Doxorubicin/ cyclophosphamide (AC) Paclitaxel 4 cycles 6 cycles 4 cycles 6 cycles Tam or AI if HR+; Trastuzumab is HER2+ after 2005 Protocol Changes Years Trial design Pts enrolled AC q3w 4 or 6 cycles T wkly for 12 or 18 wks AC q2w 4 or 6 cycles Tq2w 4 or 6 cycles AC q3w 4 Tq2w Originally for node-neg only; pts with 1-3+ nodes allowed in 2005 Shulman L, et al. J Clin Oncol Epub, July, 2012.

58 CALGB 40101: Efficacy of 4 Versus 6 Cycles of AC Versus Paclitaxel as Adjuvant Therapy N All patients year RFS 4-year OS 6 cycles 4 cycles 6 cycles 4 cycles 92% 92% 95% 96% HR 1.10; P =.42 HR 1.31; P =.097 ER % 94% 98% 98% ER % 88% 91% 93% 10 patients had cardiac toxicity; 1 grade 5 LV systolic dysfunction and 1 grade 5 other cardiac toxicity 5 patients with AML and 1 with MDS All in AC arms (5 in AC 6 arm and 1 in AC 4 arm) 5 have died, including patient with MDS Shulman L, et al. J Clin Oncol Epub, July,

59 CALGB 40101: Toxicity Grade 3/4 adverse AC Paclitaxel events (%) 4 cycles 6 cycles 4 cycles 6 cycles Hemoglobin 2/0 6/0 0/0 1/0 Neutropenia 9/17 11/23 2/1 2/1 Neutropenia and fever 5/1 6/0 0/0 0/0 Neuropathy (sensory + motor) 0/0 0/0 6/0 13/0 Cardiac 0/0 0/0 0/0 0/0 10 patients experienced cardiac toxicity, including 1 grade 5 LV systolic dysfunction and 1 grade 5 other cardiac toxicity 5 patients with AML and 1 with MDS All in AC arms (5 in AC 6 arm and 1 in AC 4 arm) 5 have died, including patient with MDS Shulman L, et al. J Clin Oncol Epub, July, 2012.

60 NSABP B-30: Combinations of doxorubicin, cyclophosphamide and docetaxel for earlystage node-positive breast cancer Stage II or IIIA BC Node Positive HR+ or HR- No metastatic disease Stratification: # Nodes Radiotherapy Surgery Tamoxifen R a n d o m i z e N=5351 AC T: A (60 mg/m2) + C (600 mg/m2) q3w x 4 T (100 mg/m2) q3w x 4 AT: A (50 mg/m2) + T (75 mg/m22) q3w x 4 TAC: A (50 mg/m2) + C (500 mg/m2) + T (75 mg/m2) q3w x 4 Primary aims: - Concurrent vs. sequential: effect on DFS, OS - Utility of cyclophosphamide Swain S, et al. NEJM 363:2268, 2010

61 NSABP B-30: Combinations of doxorubicin, cyclophosphamide and docetaxel for earlystage node-positive BC: Efficacy Efficacy: Median follow-up 73 months AC T (N=1753) AT (N=1753) ACT (N=1758) DFS 388 events 468 events 457 events OS 240 events 285 events 278 events Hazard Ratios 0.83 (AC T vs TAC) 0.80 (AC T vs AT) 0.96 (TAC vs AT) 0.86 (AC T vs TAC) 0.83 (AC T vs AT) 0.96 (TAC vs AT) P- Value AC T : DFS events by 17% (vs. TAC) and 20% (vs. AT) : OS events by 14% (vs. TAC, n.s.) and 17% (vs. AT) No difference between TAC and AT Swain S, et al. NEJM 363:2268, 2010

62 NSABP B-30 % Surviving N # Events HR p-value AC T 1, vs. TAC vs. AT AT 1, TAC 1, vs. AT Overall Survival (Intention-To-Treat) Years After Randomization Swain S, et al. NEJM 363:2268, 2010

63 % Disease-Free NSABP B-30 Disease-Free Survival (Intention-To-Treat) N # Events HR p-value AC T 1, vs.tac vs. AT AT 1, TAC 1, vs. AT Years After Randomization Swain S, et al. NEJM 363:2268, 2010

64 NSABP B-30: Combinations of doxorubicin, cyclophosphamide and docetaxel for earlystage node-positive BC: Safety Select Grade 3/4 Adverse Events AC T (N=1749) AT (N=1750) TAC (N=1749) P-Value Febrile Neutropenia 22% 13% 16% <.0001 Vomiting 8% 5% 7%.003 Infection 8% 6% 6%.0036 Diarrhea 5% 4% 6%.0012 Stomatitis 5% 1% 2% <.0001 Treatment Deaths 5 (0.3%) 7 (0.4%) 12 (0.7%) - Cardiotoxicity observed in 1% of patients across all arms Swain S, et al. NEJM 363:2268, 2010

65 NSABP B-30: Summary AC T superior to TAC and AT for DFS AC T superior to AT, and marginally better than TAC for OS No treatment interactions between outcome and nodal, ER or menopausal status Significantly improved OS and DFS across all arms in patients with amenorrhea 6 months Swain S, et al. NEJM 363:2268, 2010

66 BCIRG005: Phase III trial evaluating adjuvant Docetaxel given concurrently (TAC) versus sequentially (AC T) following anthracyclines for LN+ breast cancer Eligibility: - LN+ breast cancer - HER2-negative - HR pos or neg Stratification: # of + nodes (1-3 vs. 4+) HR status R a n d o m i z e N=3298 TAC (75/50/500 mg/m2) q3w x 6 AC (60/600 mg/m2) q3w x 4 T (100 mg/m2) q3w x 4 Primary endpoint: DFS Secondary endpoints: OS, safety Eiermann, W, et al. J Clin Oncol 29:3877, 2011

67 BCIRG005: TAC versus AC T: Efficacy TAC (N=1649) AC T (N=1649) HR P-Value 5-year DFS 78.9% 78.6% year OS 88.1% 88.9% Efficacy of treatment arms not significantly different in all subgroups analyzed: # nodes, HR status Eiermann, W, et al. J Clin Oncol 29:3877, 2011

68 BCIRG 005 TAC vs AC then Docetaxel Disease-free Survival 1.0 Disease free probability Patients Events TAC AC T Total Logrank p= % 78.6% HR = (95% CI, ) Months Eiermann, W, et al. J Clin Oncol 29:3877, 2011

69 1.0 BCIRG 005 Overall Survival Primary Analysis Survival probability Patients Events TAC AC T Total Logrank p= % 88.1% HR = 0.91 (95% CI, ) Months Eiermann, W, et al. J Clin Oncol 29:3877, 2011

70 BCIRG005: TAC versus AC T: Safety Select Adverse Events TAC (N=1635) AC T (N=1634) P-Value All Grades Febrile Neutropenia 18% 8% <.0001 Sensory Neuropathy 27.5% 43% <.0001 Myalgia 36% 51% <.0001 Grade 3/4 Anemia 3% 2%.07 Thrombocytopenia 2.5% 1%.01 Sensory Neuropathy <1% 1.5%.0004 Arthralgia < 1% 2%.001 Hand Foot Syndrome 0 2% <.0001 Eiermann, W, et al. J Clin Oncol 29:3877, 2011

71 Conclusions CMF benefits ER-poor and high RS ER+ node negative Anthracyclines improve survival in ER+ and ER-poor disease (advantage over non-a confined to HER2+?) Taxanes are effective regardless of ER and HER2 status and improve OS Dose dense and weekly paclitaxel are superior to q 3w BUT, does luminal A EBC benefit from adjuvant chemotherapy beyond OFS? TailoRx; MINDACT, RxPonder trials ongoing Cisplatin no data yet Antimetabolites - No

72 Conclusions 6 cycles = 4 cycles AC or paclitaxel in node negative pts but 6 has more toxicity 6TAC and AC/T superior to 4-cycle regimens in node positive pts (duration matters in node +) Is 4 cycles TC enough in chemotherapy-sensitive node + breast cancer? (B49 6 TC vs 6TAC) Give most effective chemotherapy for biologically aggressive disease regardless of age AC/T is standard of care