Breast Cancer-1. Hacettepe University Institute of Oncology. Best of ASCO 2012, İstanbul, June 23, Dr. Kadri Altundağ

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1 Breast Cancer-1 Dr. Kadri Altundağ Hacettepe University Institute of Oncology Best of ASCO 2012, İstanbul, June 23, 2012

2 Bisphosphonates and Breast Cancer

3 Adjuvant Therapy In Early Breast Cancer With Zoledronic Acid (AZURE - BIG 01/04): Treatment Effects Are Influenced By Menopausal Status Rather Than Age. H. Marshall, W. Gregory, R. Bell, D. Cameron, D. Dodwell, M. Keane, M. Gil, C. Davies, & R. Coleman on behalf of the AZURE Investigators.

4 AZURE: Study Design Accrual September February ,360 Breast Cancer Patients Stage II/III R Standard therapy Standard therapy + Zoledronic acid 4 mg 6 doses 8 doses 5 doses Q3-4 weeks Q 3 months Q 6 months Months Coleman et al. N Engl J Med 2011; 365: Zoledronic acid treatment duration 5 years

5 AZURE: DFS and IDFS Definitions IDFS is a more robust & appropriate definition for assessing an adjuvant treatment Dates of recurrence/event = date first suspected Hudis C. et al. J Clin Oncol 2007;25, DFS = Disease Free Survival; IDFS = Invasive Disease Free Survival *EORTC Manual 2005

6 Menopause Affects Bone Cell Function and Bone Derived Growth Factors 5 10 years PREMENOPAUSAL PERI-MENOPAUSAL POSTMENOPAUSAL Cycling oestradiol Cycling oestradiol Oestradiol Cycling inhibin Inhibin B, FSH Inhibins A & B FSH Local activin, BMP Activin, BMP tone Activin, BMP tone Pre-osteoclast Pre-osteoblast Normal Turnover Turnover Turnover Nicks KM et al. Ann NY Acad Sci 2010; 1192: Adapted from Nicks KM, Fowler TW, Akel NS et al. Ann NYAS 2010;1192,

7 AZURE: Disease (DFS) and Invasive Disease Free Survival (IDFS) DFS IDFS % % Zoledronic acid: N= 1681 Control: N= Zoledronic acid N= 1681 Control N= ZOL: CONT: 0 0 No. at risk: Adjusted HR = % CI [0.85,1.13] p= TIME (YEARS) ZOL: CONT: 0 No. at risk: Adjusted HR = % CI [0.85,1.12] p= TIME (YEARS) Coleman et al. N Engl J Med 2011; 365:

8 Proportion Alive Proportion Alive Proportion Alive and invasive Disease Free Proportion Alive and invasive Disease Free AZURE: Invasive DFS and OS by Menopausal Status IDFS: Pre, Peri, and Unknown Menopause IDFS: > 5 Yrs Postmenopausal Adjusted HR: 1.15 (95% CI: ; P =.11) 288 vs 256 events Pts at Risk, n ZOL: No ZOL: Time From Randomization (Mos) Adjusted HR: 0.75 (95% CI: ; P =.02) 116 vs 147 events Pts at Risk, n ZOL: No ZOL: Time From Randomization (Mos) OS: Pre, Peri, and Unknown Menopause OS: > 5 Yrs Postmenopausal Adjusted HR: 0.97 (95% CI: ; P =.81) vs 165 events Pts at Risk, n 0.2 ZOL: No ZOL: Time From Randomization (Mos) Coleman RE, et al. N Engl J Med. 2011;365: Adjusted HR: 0.74 (95% CI: ; P =.04) 82 vs 111 events Pts at Risk, n ZOL: No ZOL: Time From Randomization (Mos)

9 Menopausal Status Interaction Effect For IDFS* Odds Reduction (+/- S.D.) Study Group ZOL BETTER CONTROL BETTER PRE, PERI & UNKNOWN MENOPAUSE STATUS (n = 2318) HR = 1.15; 95% CI, 0.97 to 1.36; P = 0.11 > 5 YEARS POSTMENOPAUSE (n = 1041) HR = 0.75; 95% CI, 0.59 to 0.96; P = 0.02 TOTAL: -1% +/- 7 Z = -0.13, P = ODDS RATIO * Planned analysis χ 2 1 (heterogeneity) = 7.91 P =.005

10 AZURE: Treatment Effects on First Bone IDFS Recurrence by Menopausal Status Menopausal Group Odds Ratio Pre, Peri and unknown menopause HR: 0.86 (95% CI: ) > 5 yrs postmenopause HR: 0.96 (95% CI: ) (heterogeneity) = 0.14; P =.70 Adjusted for imbalances in ER, lymph node status, and T stage. TOTAL: -18% +/- 12 Z = -1.58, P = No significant differences in bone recurrence by menopausal status or age

11 Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status Menopausal Group Odds Ratio Pre, Peri and unknown menopause HR: 1.32 (95% CI: ) > 5 yrs postmenopause HR: 0.70 (95% CI: ) (heterogeneity) = 14.00; P = <.001 Adjusted for imbalances in ER, lymph node status, and T stage. TOTAL: 6% +/- 8 Z =.79, P =

12 Effects of Adjuvant Bisphosphonates on DFS Postmenopausal Patients Only Study AZURE: >5 YEARS POSTMENOPAUSE ABCSG-12* GAIN: POSTMENOPAUSAL NSABP B-34: AGE 50 ZO-FAST Z-FAST E-ZO-FAST * Induced menopause Odds Reduction (+/- S.D.) TOTAL: -18% +/- 5 Z = -3.37, P = ODDS RATIO 2 6 χ 2 6 (heterogeneity) = 8.46 P =.21 Gregory et al. ASCO 2012, Abs 513.

13 Conclusions on Role of Adjuvant Zoledronic Acid in Early Breast Cancer No overall effect in an unselected population. Significant benefit in women with established menopause. Apparent harm in pre- and perimenopausal women. Differential effects by menopause driven by influences on recurrence rates outside bone. Benefits in postmenopausal women now supported by multiple data sets.

14 Osteoporosis and Breast Cancer

15 Effect of osteoporosis in postmenopausal breast cancer patients randomized to adjuvant exemestane or anastrozole: NCIC CTG MA.27 Lois E. Shepherd 1, Judy-Anne W. Chapman 1, Suhail M. Ali 2, Liting Zhu 1, Kim Leitzel 2, Paul Goss 3, Allan Lipton 2 1 NCIC Clinical Trials Group, Queen's University, Kingston, ON; 2 Penn State Hershey Medical Center, Hershey, PA; 3 Massachusetts General Hospital Cancer Center, Boston, MA

16 Osteoporosis Osteoporosis is characterized by decreased bone mineral density. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth.

17 Hypothesis Osteoporosis and/or osteoporosis therapy will impact outcomes in breast cancer patients treated with adjuvant therapy. An exploratory study looking at this hypothesis in the NCIC CTG MA.27 trial is being presented.

18 NCIC CTG MA.27 Open-label Postmenopausal ER+ve Early Breast Cancer R A N D O M I Z E Anastrozole 1 mg/day x 5 years n = 7576 patients May Jul 2008 Exemestane 25 mg/day x 5 years Participating Collaborative Groups NCIC CTG, ECOG, SWOG, CALGB, NCCTG, IBCSG

19 MA.27 Anastrozole vs. Exemextane : EFS EFS Events= 693 (9.15%)

20 Osteoporosis and Osteoporosis Therapy N (%) Patients 7576 (100%) Osteoporosis 1294 ( 17%) Osteoporosis Therapy* 2711 ( 36%) *116 patients took raloxifene prior to study 39 initiated raloxifene following randomization

21 Percent without Event P e r c e n t a g P e e r c e n t a MA.27 - KM Curve for EFS - KM Curve for EFS EFS 1 by 2 Osteoporosis 3 4 5Therapy 6 hosphonate Prior to 30 days before Relapse e Prior to 30 days before Relapse Time 2732 (Months) Time (Months) # At Risk(Yes) # At Risk(No) # At Risk(Yes) # At Risk(No) Yes No Yes No M A K M C u r v e f o r E F S b y B is p h o s p h o n a t e P r io r t o 3 0 d a y s b e f o r e R e la p s e T im e ( M o n th s ) # A t R is k ( Y e s ) # A t R is k ( N o ) Y e s No HR (Yes/No) = 0.70 p< Years T im e ( M o n th s ) # A t R is k ( Y e s )

22 Percent without Event Percentage Percentage Percentag BP and OP not-bp and OP BP and OP not-bp and OP Time (Months) 479 teoporosis 4226 Prior to days before 2636 Relapse EFS by Osteoporosis and Osteoporosis Therapy by Bisphosphonate and Osteoporosis Prior to 30 days before Relapse # At Risk(BP and OP) Time (Months) Time (Months) # At Risk(BP and not-op) MA.27 - KM Curve for EFS by Bisphosphonate and # Osteoporosis At Risk(BP and OP) Prior to 30 days before Relapse # At # At Risk(not-BP Risk(BP and and OP) OP) # At Risk(BP and not-op) # At # At Risk(not-BP Risk(BP and and not-op) not-op) # At Risk(not-BP and OP) # At Risk(not-BP and OP) # At Risk(not-BP and not-op) BP and No Osteoporosis / Osteoporosis Therapy not-bp and not-OP Time (Months) Time (Months) # Time At Risk(BP (Months) and OP) # Time At Risk(BP (Months) 0and OP) # At # At Risk(BP Risk(BP and and not-op) # At # At Risk(BP and and not-op) # At Risk(not-BP Risk(BP and and not-op) # At Risk(BP Risk(not-BP and and not-op) 0 # At # At Risk(not-BP 1 and and not-op) 2 3 # At # At Risk(not-BP and BP and not-op) and OP# At 1082 Risk(not-BP and BP 1021 not-op) and not-op 907 # At Risk(not-BP and 1610 not-bp not-op) BP and and not-op 1581 not-bp BP 1526 and and not-op not-op 1441 OP not-bp 193and and not-op not-op 187 not-bp 175 and not-op 156 OP 4672 not-bp and not-op BP Osteoporosis and not-op / No Osteoporosis Therapy Osteoporosis / Osteoporosis Therapy not-bp and 3 not-op 4 No Osteoporosis / No Osteoporosis Therapy BP and OP not-bp and OP # At Risk(not-BP and not-op) BP and not-op 5 not-bp and 5 not-op Years Time (Months) # At Risk(BP and OP) # At Risk(BP and not-op) p=

23 EFS Multivariate Model with Osteoporosis Therapy Hazard Ratio p-value Exe vs Ana Age >= <.0001 ECOG PS: fully active 0.68 <.0001 Prior Radiotherapy Adj. chemotherapy Osteoporosis Therapy 0.65 <.0001 Other significant factors in this model : Tumor size, Nodal status, bilateral oophorectomy, ER+/PR+, left sided tumor and prior fracture. Osteoporosis or interaction between Osteoporosis and Osteoporosis Therapy were not significant. Similar results were seen for DDFS

24 Limitations of Study Osteoporosis was self-reported Variable duration and type of osteoporosis therapy Low event rate (9.2%) and distant relapse rate (4.1%)

25 Conclusions Osteoporosis therapy was significantly associated with improved EFS and DDFS - both for patients with and without osteoporosis. These exploratory results suggest that recognition and treatment of osteoporosis and osteopenia may improve the outcome of adjuvant aromatase inhibitor therapy in breast cancer. Further studies are needed to confirm these results.

26 Radiotherapy in DCIS

27 RTOG 9804: A Prospective Randomized Trial for Good Risk Ductal Carcinoma in Situ (DCIS) Comparing Radiation to Observation Beryl McCormick, M.D.; Kathryn Winter, M.S.; Clifford Hudis, M.D.; Henry Mark Kuerer, M.D., Ph.D.; Eileen Rakovitch, M.D.; Barbara L. Smith, M.D.; Nour Sneige, M.D.; Amit Shah, M.D.; Isabelle Germain, M.D.; Alan C. Hartford, M.D., Ph.D.; Afshin Rashtian, M.D.; Eleanor M. Walker, M.D.; Albert Yuen, M.D.; Eric A. Strom, M.D.; Jeannette L. Wilcox, M.D.; Laura A. Vallow, M.D.; William Small, Jr., M.D, FACR; Anthony T. Pu, M.D.; Kevin Kerlin, M.D.; and Julia R. White, M.D.

28 Background and Rationale For DCIS, randomized trials have consistently demonstrated a 50-60% relative reduction of invasive and non-invasive cancer recurrence in the breast following lumpectomy with the addition of whole breast irradiation. These studies included both low grade, small, mammographically detected DCIS and larger, higher nuclear grade and symptomatic cases.

29 EBCTCG Overview: RT reduces events in DCIS Patients

30 Eligibility: Good Risk DCIS No symptoms: either mammographic finding or incidental finding in otherwise benign bx ONLY low or intermediate grade anywhere Size (defined on mammogram if possible) 2.5 cm Margin width 3 mm Stratified by age (+/- 50), size ( 1 cm, >1 cm), margin width (3-9 mm, >1 cm, negative re-exc)

31 Schema S T Age 1. < R A R A T I F Y Final Path Margins 1.Negative (re-excision) mm mm Mammographic/Pathologic Size of Primary 1. 1 cm 2. > 1 cm to 2.5 cm Nuclei Grade 1. Low 2. Intermediate N D O M I Z E Arm 1 Observation ± tamoxifen, 20 mg per day for 5 years Arm 2 Radiation therapy to the whole breast, ± tamoxifen, 20 mg per day for 5 years Tamoxifen Use 1. No 2. Yes

32 Local Failure (invasive and noninvasive) in the Treated Breast Observation RT (n=298) (n=287) Total Failures 15 (5%) 2 (0.7%) Same quadrant 10 0 Other quadrant 5* 2 *2 of these patients also failed in the same quadrant.

33 Local Failure (%) Local Failure Ipsilateral Breast FailedTotal Observation RT Gray's test p-value= HR = 0.14 (0.03,0.61) Patients at Risk Observation 298 RT Years after Randomization Years Rates: % 0.4%

34 Neoadjuvant Chemotherapy for Breast Cancer

35 Prognostic and predictive impact of Ki-67 measured after neoadjuvant chemotherapy for primary breast cancer in the GeparTrio study Gunter von Minckwitz, Berit Müller, Jens Uwe Blohmer, Manfred Kaufmann, Holger Eidtmann, Wolfgang Eiermann, Bernd Gerber, H. Tesch, Jörn Hilfrich, Jens Huober, Tanja Fehm, Jana Barinoff, Christian Jackisch, Judith Prinzler, Thomas Rüdiger, Erhard Erbstößer, Sibylle Loibl, Carsten Denkert for the GBG and AGO-B study groups

36 Background We reported previously from the GeparTrio study that response-guided neoadjuvant chemotherapy can improve survival over conventional neoadjuvant chemotherapy. As this benefit was not predicted by pathological complete response (pcr), better surrogate efficacy markers are needed. We investigated in how far tumor proliferation measured by Ki-67 after treatment has the potential for such a new surrogate marker.

37 Patients & Methods 1151 participants of the GeparTrio trial with available tumor tissue had Ki-67 levels measured centrally before and after neoadjuvant treatment Patients randomly received neoadjuvant responseguided (8 x TAC in responding and TAC-NX in nonresponding patients) or conventional (6 x TAC) CT according to interim response assessment. Ki-67 in residual disease was low (0-15%; N=488), intermediate ( %; N=77), or high ( %; N=102). Additionally 484 pts had a pcr.

38 DFS (A) and OS (B) in patients with different post-treatment KI-67 status A B

39 DFS according to post-treatment Ki-67 in HRpositive (C) and HR-negative (D) disease C D

40 Conclusions Centrally assessed post-treatment Ki-67 adds independent and additional prognostic information of the outcome after surgery Ki-67 levels after neoadjuvant chemotherapy correlated with prognosis in all patients subgroups except for patients with lobular cancers. Post-treatment Ki-67 identifies groups of patients at high risk for relapse, for which additional post-surgical treatment options should be developed.

41 Vitamin D3 in prevention of musculoskeletal events in breast cancer patients receiving letrozole

42 The VITAL trial Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole. Qamar J. Khan Bruce F. Kimler Pavan S. Reddy Priyanka Sharma Jennifer R. Klemp Carol J. Fabian The University of Kansas Medical Center Cancer Center of Kansas, Wichita KS

43 Musculoskeletal Symptoms & Fatigue on Aromatase Inhibitors New or worsening musculoskeletal pain reported by ~ 50% of women taking adjuvant Aromatase Inhibitors (AIs) for breast cancer 18-30% women report fatigue Symptoms a major cause of premature discontinuation of these important agents Crew JCO 2007, Hershman JCO 2010

44 Estrogen Deprivation: Underlying Cause of AI Induced Musculoskeletal Symptoms Estrogen has tissue-specific effects on inflammatory cytokines Lack of estrogen may result in inflammation and enhanced pain sensitivity (nociception) Women on AIs have MRI findings of tenosynovitis suggestive of local inflammation Felson Arthritis and Rheumatism 2005, Morales JCO 2006

45 Plotnikoff Mayo Clinic Proceedings 2003, Taylor Br Ca Res Treat 2004 Clinical Rationale for Vitamin D in AI Associated Musculoskeletal Symptoms A syndrome similar to AI induced musculoskeletal pain is seen in subjects with severe vitamin D deficiency And in women with breast cancer undergoing adjuvant chemotherapy despite supplementation Vitamin D deficiency is prevalent in women with breast cancer who have musculoskeletal symptoms Crew KD et al. JCO 2009

46 Proposed Mechanism of Vitamin D Benefit in AI Induced Musculoskeletal Symptoms Locally produced 1,25(OH) 2 D (from 25(OH)D in macrophages) limits joint inflammation Higher dose 25(OH)D would provide substrate for increased local production of 1,25(OH) 2 D AI induced estrogen deprivation reduces tissue production of 1,25(OH) 2 D increasing inflammation Inflammation Hayes Cell. Mol. Biol. 2003, Cheema JCI 1989, Buchanan Calc tissue Int 1986

47 Vitamin D Optimal Levels Optimal level of serum 25-hydroxyvitamin D the best indicator of vitamin D stores unclear < 20 ng/ml is considered deficient for bone health 40 ng/ml optimal for musculoskeletal function Serum 25(OHD) levels (ng/ml) Deficient <20 Insufficient Sufficient >30 Preferred range Toxic >150 Bischoff-Ferrari AJCN 2006, Holick NEJM 2007

48 VITAL: VITamin D for Arthralgias from Letrozole 2 arm, randomized, double-blind, placebo-controlled KU (university) and CCK Wichita (community practice) Postmenopausal stage I-III breast cancer starting adjuvant Letrozole 25(OH)D levels 40 ng/ml or less 80 Stratification: Use of chemotherapy 80 Letrozole 2.5 mg daily Vit D3 30,000 IU weekly RDA of Ca + D 24 wks Letrozole 2.5 mg daily Matching placebo weekly RDA of Ca + D RDA = Recommended Daily Allowance All agents provided by the study

49 Eligibility Post-menopausal women with Stage I-III hormone receptor positive invasive breast cancer about to start an adjuvant aromatase inhibitor Completed local treatment and adjuvant chemotherapy Serum 25(OH)D level of 40 ng/ml or less No severe or debilitating musculoskeletal pain No history of renal stones No history of hypercalcemia or hyperparathyroidism

50 25(OH)D Level, ng/ml Median 25OHD Levels Over Time Placebo VitD Median values Interquartile and total ranges P=0.001 P= Baseline 12 wks 24 wks

51 Frequency of QOL event, % Secondary Endpoint: Incidence of an Adverse QOL Event: A Musculoskeletal Event + Worsening of Fatigue 80 P=< % 42% 0 Placebo Placebo arm VitD3 arm

52 Conclusions Six months of vitamin D3, 30,000 IU/week Is safe in women starting an aromatase inhibitor for adjuvant treatment of breast cancer Is associated with less worsening of AI-related musculoskeletal symptoms Is associated with fewer overall adverse quality of life events

53 Adjuvant Chemotherapy in Early Breast cancer

54 NSABP B-38: Definitive Analysis of a Randomized Adjuvant Trial Comparing Dose-dense (DD) AC Paclitaxel (P) plus Gemcitabine (G) with DD AC P and with Docetaxel, Doxorubicin, and Cyclophosphamide (TAC) in Women with Operable, Node-positive Breast Cancer Swain SM, Tang G, Geyer Jr CE, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Perez EA, Paik S, Costantino JP, Mamounas EP, Wolmark N LBA1000: Tuesday June 5, 2012 Presented at the 2012 ASCO Annual Meeting. Presented data is the property of the author.

55 NSABP B-38 Background DD AC P optimal paclitaxel-based adjuvant regimen (CALGB 9741) Gemcitabine + paclitaxel improved outcome in metastatic breast cancer (Albain 2008) TAC optimal docetaxel-based adjuvant regimen (BCIRG 001) Regimens have different toxicity profiles

56 NSABP B-38 Schema Stratification: # nodes, Hormone receptor, Surgery and RT TAC q 3 wk All arms pegfilgrastim or filgrastim AC q 2 wk P q 2 wk EPO: rec for Hgb 11 gm/dl N+ AC q 2 wk PG q2 wk ER positive: hormonal therapy for 5 yrs after chemo

57 NSABP B-38 Completion of Chemotherapy (%) N=4883 TAC AC P AC PG Treatment completed per protocol criteria

58 Disease-Free Survival NSABP B-38 Disease-Free Survival Treat N Events P-value* (vs AC PG) TAC AC P AC PG # at risk Years since Randomization * Stratified log-rank test adjusting for randomization factors

59 Disease-Free Survival NSABP B-38 Disease-Free Survival Treat N Events P-value* TAC AC P Years since Randomization # at risk * Stratified log-rank test adjusting for randomization factors

60 Overall Survival NSABP B-38 Overall Survival Treat N Deaths P-value* (vs AC PG) TAC AC P AC PG # at risk Years since Randomization * Stratified log-rank test adjusting for randomization factors

61 GRADE NSABP B-38 Overall Toxicity* (%) TAC (1607) AC P (1623) AC PG (1612) <1 <1 <1 * Up-to-date Toxicity information available from 4842 patients

62 NSABP B-38 Toxicity: Grade 3/4 (%) Febrile Neutropenia TAC (1607) AC P (1623) AC PG (1612) P-value <0.001 Diarrhea <0.001 LVEF Systolic Dysfunction <

63 Sensory Neuropathy Allergic Reaction NSABP B-38 Toxicity: Grade 3/4 (%) TAC (1607) AC P (1623) AC PG (1612) P-value <1 7 6 <0.001 < ALT < Rash <

64 Conclusion Addition of G to DD AC P did not improve outcomes No significant differences in efficacy between DD AC P and TAC Toxicity profiles differed with more neuropathy and anemia on DD arms and more diarrhea and febrile neutropenia on TAC Exploratory analyses: No outcome differences with or without erythropoietin

65