Recomendados
Recomendados
Mais conteúdo relacionado
Mais procurados
Mais procurados (20)
Destaque
Destaque (8)
Semelhante a Early breast updates
Semelhante a Early breast updates (20)
Mais de Ahmed Allam
Mais de Ahmed Allam (10)
Último
Último (20)
Early breast updates
- 1. Early Breast Cancer Updates
- 2. Why Effect of adjuvant therapy : adjuvant hormonal with Tam. (ER +ve) • 40% decrease in risk of recurrence by 5 years. • 34% decrease in br. cancer mortality by 5 years. adjuvant polychemotherapy . • < 50 years old: 10% decrease in br. cancer mortality by 15 years. • 50-69 years old: 3% decrease in risk of br. cancer mortality by 15 years Meta-analyses of adjuvant therapies for women with early breast cancer: the Early Breast Cancer Trialists’ Collaborative Group overview Annals of Oncology 17 (Supplement 10): x59–x62, 2006.
- 3. Outline • Molecular Classification. • Adjuvant Chemotherapy. • Adjuvant Hormonal. • Adjuvant Targeted Therapy. • Neoadjuvant therapy.
- 4. Molecular Classification: • Early EBC was 2 groups only • Now we reached to more recent approach utilizing both TNM staging Plus ER/PR status and Her2 status. Dividing EBC into 4 main groups Node –ve Node +ve Luminal A ER ++ Luminal B ER + Her 2 +ve Triple –ve Basal like virulent
- 5. Disease outcome in subgroups
- 6. What are the lessons we achieved from molecular classification • Lumina A: more benefit in hormonal and less in chemo. • Luminal B: grey zone: chemo, hormonal and/or Her 2 blockade (Luminal B2) • Her 2 +ve: benefit from single and more recently dual Her 2 blockade + chemo • Triple negative: the hidden mystery, rapid response to chemo, but still survive poor.
- 7. Prognostic and Predictive markers: are we there yet? • In the last decade, advances in gene expression profiling dramatically changed our understanding of genomic and transcriptomic landscape of breast cancer, with improved our ability to prognosticate behavior and response to treatment. • Traditional prognostic factors: Tumor size, Nodal status, Histological grade ER/PR status , Her 2 status and age. Multiparametric tools have been developed to improve the predictive value of those factors TNM staging Nottingham Prognostic index Adjuvant online ( http://www.adjuvantonline.com)
- 8. • Prognostic multigene classifiers in routine clinical practice: among the them, the top 3 assays in current clinical decision making are Oncotype Dx, the 21 gene assay. Mammaprint the 70 gene signature of Van’t veer. PAM50 clinically updated version of intrinsic subtypes. →Why Oncotype Dx in EBC: • Use paraffin embaded fixed materials • Prognostic • Predictive value for the value of chemo in those of HR+ve. Her 2- ve, -ve Node • Validated in randomized trail : NSABP B14, B20
- 9. The Oncotype DX • 16 BREAST CANCER RELATED GENES Estrogen ER PR Bcl2 SCUBE2 Proliferation Ki-67 STK15 Survivin Cyclin B1 MYBL2 HER2 GRB7 HER2 Invasion Stromelysin 3 Cathepsin L2 Others CD68 GSTM1 BAG1 • 5 REFERENCE GENES Beta-actin GAPDH RPLPO GUS TFRC Paik S, et al. N Engl J Med. 2004;351:2817-2826.
- 10. • The Oncotype DX Recurrence Score is correlated with distant recurrence rate at 10 years, hormone therapy benefit, and chemotherapy benefit. ▫ Low risk is up to 17 ▫ Intermediate risk 18-30 ▫ High risk > 30 • Validation: a study was performed to clinically validate the prespecified 21-gene RT-PCR assay and Recurrence Score algorithm as a predictor of the prospectively defined primary endpoint of distant recurrence-free survival in node-negative, estrogen receptor–positive patients treated with tamoxifen from the large multicenter study NSABP - B14.
- 11. Distant recurrence over time 10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% 0 2 4 6 8 10 12 14 16 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Proportionwithoutdistantrecurrence RS < 18, n = 338 RS 18-30, n = 149 RS ≥ 31, n = 181 All Patients, n = 668 P < 0.001 10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% Oncotype DX Clinical Validation: NSABP B-14, Distant Recurrence Paik S, et al. N Engl J Med. 2004;351:2817-2826.
- 12. Oncotype DX Clinical Validation: NSABP B-20 • Objective: Prospectively determine the relationship between Recurrence Score result and chemotherapy benefit in node-negative, ER+ patients Randomized Tam + MF Tam + CMF Tam Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
- 13. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 4.4% absolute benefit from tamoxifen + chemotherapy N Events All patients Tamoxifen + chemotherapy Tamoxifen 424 227 33 31 P = 0.02 RS 18-30 Tamoxifen + chemotherapy Tamoxifen 89 45 9 4 P = 0.39 RS < 18 Tamoxifen + chemotherapy Tamoxifen 218 135 8 4 P = 0.61 N Events RS 18-30 Tamoxifen + chemotherapy Tamoxifen 89 45 9 4 P = 0.39 PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy RS ≥ 31 Tamoxifen + chemotherapy Tamoxifen 117 47 13 18 P < 0.001 2 4 6 8 10 12 Years Proportionwithoutdistantrecurrence Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
- 15. The Oxford Overview Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) • The most comprehensive analysis of the adjuvant settings • 1984, 1990, 1995, 2000, 2005/6, 2010 • 2010: cover more than 100,000 patients among 123 randomised trails, published 2012, postulating 3 questions to be answered in meta-analysis ▫ Benefit of polychemotherapy Vs non. ▫ Benefit of anthracycline (A) vs CMF. ▫ Benefit of Taxane + (A) vs (A) alone.
- 16. Polychemotherapy versus No chemotherapy 10y results in 23500 women
- 17. • RRs were 0·69 (SE 0·04) for distant recurrence • RRs were 0·73 (SE 0·03, χ²1=70·3) for any recurrence. • RRs 0·79 (SE 0·04, χ²1=33·7) for breast cancer mortality. • the proportional effects of anthracycline based regimens on breast cancer outcomes did not depend much on age, nodal status, ER status, or, if ER-positive, on endocrine therapy, age, nodal status, tumor differentiation, or ER level
- 18. Anthracycline regimens vs standard CMF 10y results in 22000 women
- 19. • Almost equal 4 AC, vs CMF.
- 20. • shows results from the trials with anthracycline dose per cycle at least 60 mg/m2 doxorubicin or 90 mg/m2 epirubicin and with cumulative anthracycline dosage more than 240 mg/m2 doxorubicin or 360 mg/m2 epirubicin. • RRs were 0·89 for recurrence. • RRs were 0·80 for breast cancer mortality A N T H R A C Y C L I N E M O R E
- 21. Taxane + Anthracycline regimens vs Anthracycline regimens 5y results in 44000 women
- 22. • Recurrence RRs were 0.85. • Mortality RRs were 0.87. T + A Vs s a m e A 5 y results
- 23. 5 years results • Recurrence RRs were 0.83. • Mortality RRs were 0.86. T + A Vs m o r e A
- 26. Estrogen and Breast Cancer Estrogen Cell Growth and Division Estrogen Receptor SERMS, SERDSAromatase inhibitors, ovarian suppression
- 27. Endocrine Therapy in Breast Cancer • Selective Estrogen Receptor Modulators ▫ tamoxifen ▫ toremifene ▫ raloxifene • Aromatase inhibitors (postmenopausal) ▫ anastrozole ▫ letrozole ▫ exemestane • Medical or surgical oophorectomy (premenopausal) • Selective Estrogen Receptor Downregulators ▫ fulvestrant • Others: Progestins, Estrogens, Androgens
- 29. Selective Estrogen Receptor Modulators EBCTCG 2000 (Oxford Overview) Tamoxifen vs. Nil: Disease-free Survival ER Negative ER Positive 5 years of adjuvant tamoxifen became standard in ER+ patients tamoxifen nil ER status matters!! 5 yrs 15 yrs
- 30. Aromatase Inhibitors Adrenal Hormones Cortisol Androstenedione Aldosterone Estradiol TestosteroneEstrone Aromatase inhibitors block post-menopausal estrogen production Anastrozole Letrozole Exemestane
- 31. Adjuvant Aromatase Inhibitors AIs as Initial Therapy AIs After 2-3 Yrs of TAM AIs After 5 Years of TAM TAM X 5 Yrs AI X 5 Yrs TAM X 2-3 AI X 2-3 TAM X 5 Yrs TAM X 5 Yrs PLAC X 5 Yrs AI X 5 Yrs Three Strategies Survival benefit for AI arm ATAC and BIG1-98 studies Reduction in recurrences
- 32. Upfront Use of Aromatase Inhibitors vs. Tamoxifen ATAC Trial: Anastrozole vs. Tamoxifen Howell A et al, Lancet 365:60-62, 2005 BIG 1-98 Trial: Letrozole vs. Tamoxifen Thurlimann B et al, NEJM 353: 2747-57, 2005 68 months follow-up: 17% relative reduction in events for A vs T (3% absolute difference) 26 months follow-up: 19% relative reduction in events for L vs. T (3% absolute difference)
- 33. Extended Adjuvant Hormonal Therapy Trials MA17 Trial: Letrozole vs. Placebo After Completing 5 Years of Tamoxifen Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005 30 months of follow-up: 42% decrease in breast cancer events Node positive patients show statistically significant improvement in survival
- 34. Letrozole + Zoledronic Acid 4 mg q6m Letrozole + Delayed* Zoledronic Acid 4 mg q6m Stage I-IIIa breast cancer Postmenopausal or amenorrheic due to cancer treatment ER+ and/or PgR+ T-score ≥ -2 SD N = 1065 Treatment duration 5 yrs De Boer R, et al. SABCS 2011. Abstract S1-3. ZO-FAST: 5-Yr Final Analysis Treatment duration 5 yrs
- 35. ZO-FAST: Conclusions • Immediate initiation of ZOL at start of letrozole significantly prolonged DFS vs delayed initiation of ZOL in postmenopausal women with endocrine-responsive EBC ▫ Continued to improve BMD after 5 yrs of follow- up ▫ 34% improvement in DFS
- 37. 37 HER-2 as a Target for Therapy cell division HER-2 nucleus cancer cell Trastuzumab (Herceptin) Anti-HER-2 Antibody HER-2 Oncogene: amplified and overexpressed in 20-25% of breast cancer Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor
- 38. Adjuvant trastuzumab trials: >13,000 patients NCCTG N9831 (USA) HERA (ex-USA) BCIRG 006 (global) NSABP B-31 (USA) Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006 IHC or FISH (n=5090) 2 years Herceptin Observation Standard chemotherapy 1 year Herceptin IHC or FISH (n=2030) Herceptin 1 year IHC or FISH (n=3505) Herceptin 1 year FISH (n=3222) Herceptin 1 year IHC or FISH (n=5090) Docetaxel Docetaxel + carboplatin Doxorubicin + cyclophosphamide Paclitaxel FISH (n=3222) IHC or FISH (n=3505) IHC or FISH (n=2030) Herceptin 1 yr Herceptin 1 yr Herceptin 1 yr Herceptin 1 yr Herceptin 2 yr Observation
- 39. aBased on small subgroups of patients with HER2-positive breast cancer; brelapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil DFS benefit across 5 out of 6 trials 4 2 3 4 Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007 Spielmann et al 2007 3 3 Median follow-up, years 0 1 2Favours Herceptin Favours no Herceptin HR DFS benefit B-31 / N9831 ACPH HERA CTxH 1 year FinHera VH / DHCEFb PACS-04a CTxH 1 year BCIRG 006 ACDH BCIRG 006 DCarboH
- 40. 0 1 2 Favours Herceptin Favours no Herceptin HR Adjuvant Trastuzumab trials: proven OS benefit B-31 / N9831 ACPH BCIRG 006 ACDH HERA H 1 year BCIRG 006 DCarboH FinHer VH / DHa 4 3 2 Median follow-up, years 3 Joensuu et al 2006; Perez et al 2007; Slamon et al 2006; Smith et al 2006 3
- 41. Cumulative incidence of cardiac events: N9831/NSABP B31 updated analysis • Longer follow-up showed no additional concerns regarding the cardiac safety profile Cardiac events occurred early No evidence of increased toxicity or late toxicity • In NSABP B 31 the following factors were shown to be predictive for CHF: Age (p=0.03) Hypertensive medications (p=0.02) Baseline LVEF (p=0.0003) • The incidence of cardiac events reach a plateau at around 1 year • Cardiac effects of trastuzumab were largely reversible Perez et al Abs 512 ASCO 2007 Perez et al Abs 512 ASCO 2007
- 42. Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008 Incidence of trastuzumab-related cardiac events in EBC trials 3.0 NR NR 18.0 8.6 Asymptomatic LVEF decline, %a H 1 year ACPH ACPH ACDH DCarboH Arm HERA NSABP B-31 NCCTG N9831 BCIRG 006 1,678 947 570 1,068 1,056 n Severe CHF, % 0.6 3.8cum (5 yr) 3.3cum (3 yr) 1.9 0.4 Cardiac death, n 0 0 0 0 0
- 43. Surgery & Chemo Complete Randomize Trastuzumab 1 Lapatinib 2 Lapatinib + Trastuzumab 4 Lapatinib 3Trastuzumab Taxane Taxane Taxane Taxane Wash out 52 Weeks All Patients: Radiotherapy, if indicated Hormone receptor-positive patients: Endocrine therapy for at least 5 yrs 34 Weeks6 Weeks 12 Weeks Consent & Send Blocks for Central Path Review
- 45. Goals of Neoadjuvant Theapy in Early Breast Cancer • Make tumours more operable, increase the rate of breast conserving surgeries • Improve prognosis of certain disease subtypes (i.e. HER2+) • Have a better idea of prognosis based on response to neoadjuvant treatment • Allow patients to start treatment earlier • Reduce the extent of surgery required in breast and axilla • Improve DFS and OS using pathological response rate for selection of subsequent treatment in individual patients
- 46. Definition of pCR Different definition of pCR are in use: - Absence of invasive cancer in the breast - Absence of invasive cancer in the breast and in the axillary lymph nodes. - Absence of invasive and in situ cancer cells in the breast and in the axillary nodes There is high degree of concordance between the different definition With very definition pCR identifies cases with favorable disease Marchiò C. & Sapino A. JNCI Monogr 2011;43:86–90
- 48. There was no significant difference in overall survival (OS) between the treatment arms (data not shown). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR 0.33; P .0001). Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027. Disease free- survival Overall Survival pCR to Neoadjuvant Chemotherapy is correlated with improved DFS & OS (NSABP B-27)
- 49. Intrinsic sub-types have different prognosis and different response to Neoadjuvant therapy.
- 50. Impact of treatment characteristics on the pCR Untch M. et al J Nat Cancer Inst Monogr 2011.
- 51. Pre and Post-operative Chemotherapy plus Trastuzumab Improve DSF
- 52. Women with operable or locally advanced breast cancer (N = 2072) TAC-NX* (4 cycles NX) (n = 301) TAC x 6 (4 additional cycles TAC) (n = 321) TAC x 6 (4 additional cycles TAC) (n = 704) TAC x 8 (6 additional cycles TAC) (n = 686) TAC* (2 cycles) Assess response† Minimal response‡ (n = 622) CR or PR (n = 1390) *TAC regimen: docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 all on Day 1 q21d. NX regimen: vinorelbine 25 mg/m2 on Days 1 and 8, capecitabine 1000 mg/m2 on Days 1-14 q21d. †Response assessed by ultrasound/palpation. ‡< 50% tumor reduction. Von Minckwitz G, et al. SABCS 2011. Abstract S3-2. GeparTrio Trial: Study Design Not working? Try another type of chemotherapy Working? Give more of the same chemotherapy
- 53. GeparTrio Trial: DFS and OS • Median follow-up: 62 mos • DFS benefit in early responding and nonresponding patients who received response-guided vs conventional chemotherapy Von Minckwitz G, et al. SABCS 2011. Abstract S3-2. Endpoint HR for Response-Guided vs Conventional Chemotherapy (95% CI) P Value DFS 0.71 (0.60-0.85) < .001 OS 0.79 (0.63-0.99) .048 Patient Subgroup Treatment Comparison HR for DFS (95% CI) P Value Responders TAC x 8 vs TAC x 6 0.78 (0.62-0.97) .026 Nonresponders TAC-NX vs TAC x 6 0.59 (0.49-0.82) .001
- 54. GeparTrio Trial: DFS by Patient Subgroup Response-guided treatments better Conventional treatments better 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Subgroup Overall Age (yrs) <40 ≥ 40 cT-stage cT1-3 cT4 cT-size < 40 mm ≥ 40 mm cN status Negative Positive Histological type Ductal or other Lobular Grade 1 or 2 3 Hormone receptor status Negative Positive HER2 status Negative Positive Breast cancer phenotype Luminal A Luminal B (HER2-) Luminal B (HER2+) HER2+ (nonluminal) Triple negative N patients 2012 353 1659 1737 267 775 1212 894 NR 1571 270 1176 725 717 1295 1145 486 572 211 281 178 362 Test for Interaction 0.67 0.66 0.22 0.19 0.71 0.25 0.008 0.54 0.12-0.01 HR (95% CI) 0.74 (0.60-0.85) 0.66 (0.42-1.03) 0.73 (0.60-0.88) 0.70 (0.56-0.85) 0.79 (0.54-1.17) 0.62 (0.44-0.85) 0.79 (0.63-0.98) 0.84 (0.61-1.14) 0.66 (0.53-0.82) 0.73 (0.60-0.88) 0.61 (0.37-1.03) 0.79 (0.61-1.01) 0.65 (0.49-0.85) 0.94 (0.73-1.22) 0.56 (0.44-0.73) 0.63 (0.49-0.81) 0.72 (0.51-1.04) 0.55 (0.37-0.82) 0.40 (0.20-0.79) 0.56 (0.33-0.96) 1.01 (0.61-1.67) 0.87 (0.61-1.25) Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
- 55. GeparTrio Trial: pCR by Breast Cancer Subtype Von Minckwitz G, et al. SABCS 2011. Abstract S3-2. pCR(%) 40 35 30 25 20 15 10 5 0 Luminal A (n = 572) Luminal B (HER2-) (n = 211) Luminal B (HER2+) (n = 281) HER2+ (Nonluminal) (n = 178) Triple Negative (n = 362)
- 56. GeparTrio Trial: Conclusions • Adapting neoadjuvant chemotherapy based on early response significantly improved DFS and OS vs conventional chemotherapy • Response-guided chemotherapy most effective in patients with luminal A or luminal B tumors ▫ Low pCR rates in these tumors ▫ pCR not prognostic • No DFS benefit with response-guided chemotherapy in patients with HER2-positive or triple-negative tumors Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
- 57. Baselga J et al. Lancet 2012
- 58. • pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1—59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4—37·5]; difference 21·1%, 9·1—34·2, p=0·0001). •no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1—32·3]) and the trastuzumab (difference −4·8%, −17·6 to 8·2, p=0·34) groups. Baselga J et al. Lancet 2012
Notas do Editor
- *Early breast cancer Trialists’ Collaborative Group in 2005 metanalysis for the effect of tamthe effect in women whose tumors were foundto be ER-positive is clear and definite. For the trials of 1 or2 years of tamoxifen, both recurrence (ratio of annualrecurrence rates: 0.74 SE 0.02) and deaths due to breast cancer(ratio of annual death rates: 0.82 SE 0.03) were significantlyreduced among the 14 000 ER-positive women randomized.The effects were even larger among the 8000 ER-positive womenin the trials of five years of the drug. Comparing womenallocated to take five years of tamoxifen with those allocatednot to receive tamoxifen after their surgery, the annual rate ofrecurrence was reduced by about 40% (ratio of annualrecurrence rates: 0.59 SE 0.03). Deaths due to breast cancerwere 34% lower (ratio of annual death rates: 0.66 SE 0.04). By15 years after initial treatment for breast cancer, these benefitstranslate into average absolute reductions in recurrence of11.8% (SE 1.3, logrank 2p< 0.00001) and in breast cancermortality of 9.2% (SE 1.2, logrank 2p< 0.00001). Thus, for every11 women allocated to 5 years of tamoxifen there was one fewerdeath from breast cancer by year 15, because of tamoxifen.* Among women under 50 years of age when diagnosed withbreast cancer, the use of prolonged polychemotherapy wasshown to change the average proportion of women who hada recurrence by 15 years in these trials from 53.5% in the controlgroup to 41.1% in the chemotherapy group. The effect onbreast cancer mortality was such that the absolute risk by15 years was reduced by 10.0% (SE 1.6, logrank 2p< 0.00001).The effect in women aged 50–69 years was smaller but stillstatistically significant. By year 15, the reduction in recurrencewas 4.1% (SE 1.2, logrank 2p< 0.00001) and the reduction inbreast cancer mortality was 3.0% (SE 1.3, logrank 2p< 0.00001)
- Our data evolved in risk classfication of br cancer from staging ( node +ve/ -ve) into more new approach utlizing the TNM + ER/PR status + Her2
- Main point: The final gene set used for the Oncotype DX® assay includes the 16 cancer genes identified in the clinical trials.5 genes are in the proliferation group, 2 in the HER2 group, 4 in the estrogen-receptor group, 2 in the invasion group, and 3 are unaligned. Some of the genes are well known in the breast cancer literature; others are relatively new.The 5 reference genes are used for normalizing the expression of the cancer-related genes., it is important to note that there are other genes linked to breast cancer (eg, the 250 candidate genes from which the 16 genes were selected). The 16 genes presented in this slide were selected for the Oncotype DX assay based on the 3 clinical trials, which demonstrated a consistent statistical link between these genes and distant breast cancer recurrence and the most robust predictive power across the 3 studies.Additional information on some of the 16 cancer related genes:MYBL2: The protein encoded by this gene, a member of the MYB family of transcription factor genes, is a nuclear protein involved in cell cycle progression. The encoded protein is phosphorylated by cyclin A/cyclin-dependent kinase 2 during the S-phase of the cell cycle and possesses both activator and repressor activities. It has been shown to activate the cell division cycle 2, cyclin D1, and insulin-like growth factor-binding protein 5 genes. Transcript variants may exist for this gene, but their full-length natures have not been determined.STK15: The protein encoded by this gene is a cell cycle-regulated kinase that appears to be involved in microtubule formation and/or stabilization at the spindle pole during chromosome segregation. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. This gene may play a role in tumor development and progression. A processed pseudogene of this gene has been found on chromosome 1, and an unprocessed pseudogene has been found on chromosome 10. Multiple transcript variants encoding the same protein have been found for this gene.Scube2 can modulate the long-range action of Bmp-dependent Hedgehog signaling in the neural tube and somites.STMY3 (MMP11): Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is activated intracellularly by furin within the constitutive secretory pathway. Also in contrast to other MMP's, this enzyme cleaves alpha 1-proteinase inhibitor but weakly degrades structural proteins of the extracellular matrix CL2: The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomalcysteineproteinase that may play an important role in corneal physiology. This gene is expressed in colorectal and breast carcinomas but not in normal colon, mammary gland, or peritumoral tissues, suggesting a possible role for this gene in tumor processes.GSTM1: Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens. Multiple protein isoforms are encoded by transcript variants of this gene.BAG1: The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein encoded by this gene binds to BCL2 and is referred to as BCL2-associated athanogene. It enhances the anti-apoptotic effects of BCL2 and represents a link between growth factor receptors and anti-apoptotic mechanisms. At least three protein isoforms are encoded by this mRNA through the use of alternative translation initiation sites, including a non-AUG siteThe Recurrence Score result ranges from 0 to 100. Expression for each individual gene is measured on a scale from 0 to 15, where an increase of 1 unit generally reflects a 2-fold increase in RNA quantity.Although the coefficients for each gene or gene group influence the Recurrence Score result, the quantitative expression for each gene can have a dominant effect. For example, there is a 200-fold range of expression of ER in the quantitative RT-PCR assay. For individual tumors, the expression of any one gene can affect the Recurrence Score result to a large degree.Recurrence Score =+ 0.47 × HER2 Group Score– 0.34 × Estrogen Group Score+ 1.04 × Proliferation Group Score + 0.10 × Invasion Group Score+ 0.05 × CD68– 0.08 × GSTM1– 0.07 × BAG1Paik et al. N Engl J Med. 2004;351:2817-2826.
- age (finding significant benefit even at ages 55-69 years; few were older, but their results suggest favourable effects of taxanes even in old age), nodal status before chemotherapy (4000 had node negative disease), and ER status. Results are also given for subsets of ER-positive disease by HER2 status (generally by immunohistochemistry, classified where possible by standard criteria for definite positivity8), age, and differentiation (with a trend towards greater taxane benefit in well differentiated [RR 0·68, SE 0·16, 2p=0·04, n=3000] or moderately differentiated [RR 0·77, SE 0·07, 2p=0·001, n=11,000] ER-positive tumours than in poorly differentiated ER-positive tumours).
- In ER +ve, 5 years TAM reduce the annual reccurence rate by the half, recurrence rate ratio 0.59The effect of tam on survival cont to increase till it reach greater by 3 times in after 15 years than after 5 years
- BMD, bone mineral density; DFS, disease-free survival; EBC, early breast cancer; ZOL, zoledronic acid. Joyce O’Shaughnessy, MD: When considering the clinical applicability of these data, I am reminded that the National Comprehensive Cancer Network guidelines recommend that bone-directed therapy should be initiated in patients with a T-score < -2.0.[1] Based on these data from ZO-FAST, it is certainly reasonable to give patients zoledronic acid, particularly if they are at a higher risk of disease recurrence or fracture. With that said, I do not think these data are practice changing as the DFS data were a secondary endpoint in this study. I likely will not start all ER-positive patients on anastrozole combined with zoledronic acid every 6 months, particularly if they have normal BMD and are node negative. Peter Ravdin, MD, PhD: In addition,the World Health Organization Fracture Risk Assessment Tool (FRAX) can help determine need for bone-targeted treatment. FRAX accounts for secondary osteoporosis factors, such as aromatase inhibitor therapy. The guidelines recommend bone therapy for patients with a 10-year risk of major fracture that is > 20% or risk of hip fracture that is > 3% according to FRAX, but the absolute cutoff is a T-score of < -2.0 or a FRAX score > 3%. The guidelines also suggest a T-score cutoff of -1.5 to -2.0 to consider bone therapy. Reference1. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health in Cancer Care. J Natl Compr Canc Netw. 2009;7(suppl 3):S1-S32.
- Joyce O’Shaughnessy, MD: The GeparTrio Trial was a randomized phase III trial in women with operable or locally advanced breast cancer. Response was assessed after 2 cycles of docetaxel/doxorubicin/cyclophosphamide (TAC). Patients who responded to 2 cycles of TAC were randomized to receive 4 vs 6 additional cycles (ie, a total of 6 vs 8 cycles of TAC). Those with < 50% reduction in tumor size were randomized to receive 4 cycles of TAC plus vinorelbine/capecitabine (TAC-NX) vs 4 additional cycles of TAC. The pathologic complete response data had previously been reported.[1] It was initially disappointing that this trial looked negative in that the nonresponders, regardless of whether they received 6 cycles of TAC or TAC-NX, had pathologic complete response (ypT0 ypN0) rates of 5% to 6%. Among patients who were responding to TAC, the pathologic complete response rate was still only approximately 21%. In this report, von Minckwitz and colleagues presented an interesting 5-year follow-up analysis of systemic outcomes in secondary survival endpoints (DFS and OS). It is a little difficult to interpret the results of this report as the data for the 2 TAC x 6 (conventional chemotherapy) arms and the TAC x 8 and TAC-NX (response-guided chemotherapy) were combined. Peter Ravdin, MD, PhD: It is important to point out that the difference in the pathologic complete response rates between early responding and nonresponding patients were significantly different. However, there was no statistical difference in pathologic complete response between 6 and 8 cycles of TAC and nodifference between TAC and TAC-NX. Response-guided therapy did not seem to affect the short-term efficacy at surgery and the authors sought to determine if this strategy would influence long-term efficacy (ie, DFS, OS). Reference1. Huober J, von Minckwitz G, Denkert C, et al. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat. 2010;124:133-140.
- CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; OS, overall survival. Joyce O’Shaughnessy, MD: Professor von Minckwitz and colleagues showed that the patients given response-guided therapy (TAC x 8 or TAC-NX) had improved DFS and OS vs conventional chemotherapy (TAC x 6), even though switching mid-stream did not affect pathological complete response rates. As I mentioned on the previous slide, the analysis was complex because it combined the vinorelbine/capecitabine group, which had an unfavorable prognosis, with the group that received 8 cycles of TAC, which had a favorable prognosis, as part of the response-guided therapy analysis. However, von Minckwitz and colleagues then separated them and compared results of patients with favorable and unfavorable responses. This analysis showed an improvement in DFS in responding patients given TAC x 8 vs TAC x 6, which is interesting because these patients had a heavy enough tumor burden to warrant preoperative therapy and suggests that longer duration therapy may benefit these responding patients. In the nonresponding patients—and this is perhaps the most interesting finding—switching to vinorelbine and capecitabine was associated with significantly improved DFS vs finishing TAC x 6. Despite improvements in DFS in response-guided vs convention therapy as well as TAC x 8 and TAC-NX vs TAC x 6, there were not corresponding differences in pathologic complete response rates.
- CI, confidence interval; HR, hazard ratio. Joyce O’Shaughnessy, MD: The investigators looked at results by the biological subtypes of breast cancer. It is notable, that the HER2-positive patients entered on this trial did not have the advantage of trastuzumab, as the trial was initiated prior to its availability. Results show that the longer-duration TAC or switching over to vinorelbine/capecitabine (ie, response-guided therapy) had the greatest benefit in the ER-positive population. However, response-guided therapy, whether it was longer TAC or whether it was vinorelbine/capecitabine, made no significant difference in patients with triple-negative disease. These data are in keeping with my clinical experience. But in ER-positive patients, switching over to vinorelbine/capecitabine or giving longer duration therapy was associated with longer DFS. Interestingly, results also showed that in the slower-growing ER-positive group—luminal A, defined as Ki67 below 14%—a pathologic complete response did not predict for DFS. However, in the faster-growing ER-positive group—luminal B with Ki67 over 14%—a pathologic complete response did predict for improved DFS.
- pCR, pathologic complete response. Joyce O’Shaughnessy, MD: In general, lower rates of complete pathologic response were observed in luminal vs nonluminal tumors with the lowest proportion being those with luminal A and HER-positive, luminal B tumors.
- DFS, disease-free survival; OS, overall survival; pCR, pathologic complete response. Joyce O’Shaughnessy, MD: In summary, these data suggest that switching a ER-positive patient who is not responding well to preoperative TAC to a non–cross-resistant regimen is a reasonable approach. Both the luminal A and the luminal B groups benefited by switching over to vinorelbine/capecitabine. Of note, patients who received longer-duration TAC were included in the response-guided treatment category, so it is difficult to tease out the contribution of vinorelbine/capecitabine and to say that ER-positive patients who do not respond to 2 cycles of TAC should absolutely be switched over to vinorelbine/capecitabine. Peter Ravdin, MD, PhD: I agree that combining the groups confounded the interpretation of these data. Moreover, if a patient is doing great, I will not give more than 6 cycles of TAC, which is what these data suggest is optimal as 6 cycles is already challenging for patients to complete. Joyce O’Shaughnessy, MD: If I were giving TAC to an ER-positive patient and she did not respond after 2 or 3 cycles, I would consider switching her to vinorelbine and capecitabine based on these data. We conducted a study with a subset analysis that suggested a benefit with capecitabine in the adjuvant setting in ER-positive tumors that were more highly proliferative (Ki67 cutoff of 10%). As this was a subset analysis, it would be important to see a confirmatory trial, but I think these data are nevertheless interesting and provide us with another avenue to potentially improve systemic outcomes in the neoadjuvant setting. These data are probably not practice changing. This analysis is based on a secondary endpoint, and the study includes patients with HER2-positive tumors not treated with anti-HER2 therapy. I do think, though, that physicians could consider switching to vinorelbine/capecitabine in more highly proliferative ER-positive patients who are not responding well to TAC. Peter Ravdin, MD, PhD: I basically agree and also think physicians should consider switching patients to TAC-NX who are not achieving a good response after 2-4 cycles of TAC. I remember when the investigators published their data about pathologic complete response, which were tremendously discouraging because they did not show an improved pathologic complete response rate by switching. Many of us assumed that it meant there was just general chemotherapy insensitivity and, therefore, few options in terms of chemotherapy modifications. Now, I am revisiting that because, in my opinion, these data convincingly show that for patients who are not headed for a good response, it makes sense to switch therapy. Of note, the investigators used ultrasound instead of a physical examination to assess whether or not patients were responding; I find it very difficult to assess response with ultrasound, particularly after only 2 cycles.