BREAST CANCER
      TRIALS AND TRIBULATIONS


       Vivien Bramwell, MBBS, PhD, FRCPC
    Clinical Professor, Department ...
Objectives

 1. To review the development, conduct and results of
    selected Cooperative Group (NCIC CTG)
    randomized...
NCIC CTG trials reviewed

 Trial    Dates        Accrual         Outcomes
MA.5     1989 – 1993    710      (1) RFS
       ...
NCIC CTG TRIALS − correlative studies
MA.5       •   prognostic impact of amenorrhea
           •   prognostic/predictive ...
Translational studies of osteopontin (OPN)

    OPN is a secreted integrin-binding protein that has been
    associated wi...
OPN      − experimental studies


•   OPN is a secreted integrin-binding protein produced in a
    variety of tissues and ...
OPN − clinical studies (using OPN ELISA)

   •   OPN plasma levels in 35 healthy women
              median 47 (22 – 122) ...
OPN − study population and treatment
Accrual                                   July 1997 – November 1999
Total Population ...
OPN − sample collection

Number of samples:
      total samples                         1378
      median (range)/patient ...
OPN - Survival according to baseline OPN levels
OPN − conclusions
  •   in univariate analysis, elevated baseline OPN was associated
      with decreased survival (p = 0....
NCIC CTG           MA.5 −          rationale (1988)

•   trials of adjuvant chemotherapy (CMF or AC) in EBC
    showed imp...
NCIC CTG      MA.5 - outcomes

                           5 y DFS    10 y DFS   5 y OS 10 y DFS
  CMF (100/40/600)        ...
NCIC CTG          MA.12 − rationale

•   protocol developed in 1992

•   data very limited on premenopausal women, ER +ve/...
NCIC CTG             MA.12 − schema

Biopsy                                RANDOMIZE
                                     ...
NCIC CTG        MA.12 − planned analysis
• planned sample size 800 pts accrued over 5 yrs (160/yr)
    detect 8% differenc...
NCIC CTG         MA.12 − compliance issues

• only 52% women (similar T/P) completed full 5 yrs study medication
• rate of...
NCIC CTG MA.12 − compliance comparison other studies


• 3 other studies of similar design also had similar compliance
 pr...
NCIC CTG MA.12 − key findings

• 672 premenopausal women, after completion of adjuvant CT,
 were randomized to T vs P for ...
NCIC CTG         MA.12 − serum collection − objectives
Objectives
1. To determine if there is a difference in effect of T ...
NCIC CTG          MA.12 − serum collection – status (2005)

     Total # specimens*          :   approx 2800

     Total p...
DNA MICROARRAY GENE
                                     EXPRESSION PROFILING
                                     REVEALS...
The Major Breast Cancer Intrinsic
              Biological Subtypes

                           Lum A   Lum B   HER2   bas...
BIOLOGICAL CLASSIFICATION
              Immunohistochemistry (IHC)


Luminal A      ER+ or PR+   AND   HER2– Ki67–

Lumina...
NCIC CTG          MA.12 − OPN study

Hypothesis : OPN expression by IHC, and its prognostic
             significance will...
NCIC CTG        MA.14      − outcomes

   Tamoxifen (T) 20 mg/d x 5 yr                  Serum collected for
              ...
NCIC CTG       MA.14 − OPN study objectives

 Objectives:

 1. To evaluate whether baseline plasma OPN levels are
    prog...
NCIC CTG MA.14 − OPN study collection (started Nov 1998)
 Plasma collection
       Time period                # plasma sam...
NCIC CTG        MA.21 − rationale

•   AC is equivalent to CMF (NSABP B15, B23)

•   CEF is better than CMF (NCIC MA.5)

•...
NCIC CTG            MA.21        − outcomes
                                                             3 y DFS
         ...
NCIC CTG      MA.21 − correlative science studies

M. Burnell   J Clin Oncol 26:18S A550, 2008

  • 1623/2104 (77%) primar...
Lessons learned

•   there are many excellent reasons to participate in
    Cooperative Group activities (vs Industry)

• ...
Acknowledgements
NCIC CTG Breast          Chair                Kathy Pritchard
Disease Site Committee   Trial PIs         ...
Breast Cancer Trials And Tribulations Revised Oct 09
Breast Cancer Trials And Tribulations Revised Oct 09
Upcoming SlideShare
Loading in...5
×

Breast Cancer Trials And Tribulations Revised Oct 09

842

Published on

Published in: Health & Medicine, Business
1 Comment
1 Like
Statistics
Notes
No Downloads
Views
Total Views
842
On Slideshare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
27
Comments
1
Likes
1
Embeds 0
No embeds

No notes for slide

Breast Cancer Trials And Tribulations Revised Oct 09

  1. 1. BREAST CANCER TRIALS AND TRIBULATIONS Vivien Bramwell, MBBS, PhD, FRCPC Clinical Professor, Department of Oncology, University of Calgary Head of Medical Oncology, Tom Baker Cancer Centre Cancer Care, Alberta Health Services October 2009
  2. 2. Objectives 1. To review the development, conduct and results of selected Cooperative Group (NCIC CTG) randomized clinical trials of treatment for early breast cancer (EBC) 2. To illustrate opportunities that arose, during the conduct of these trials, to explore additional endpoints/outcomes 3. To share lessons learned
  3. 3. NCIC CTG trials reviewed Trial Dates Accrual Outcomes MA.5 1989 – 1993 710 (1) RFS (2) OS, toxicity, QOL MA.12 1993 – 2000 672 (1) OS (2) DFS, toxicity, compliance MA.14 1996 – 2000 667 (1) EFS (2) OS, toxicity, QOL MA.21 2000 – 2005 2,104 (1) RFS (2) OS, toxicity, QOL
  4. 4. NCIC CTG TRIALS − correlative studies MA.5 • prognostic impact of amenorrhea • prognostic/predictive value of HER2 overexpression • prognostic/predictive value of TOPO IIα alteration • anthracyclines in basal breast cancer MA.12 • compliance with oral hormone therapy* • relationship of sequential hormone levels to outcomes* • relationship of biological classification to outcome • differential expression of OPN in biological subtypes • estrogen receptor profiling to better predict response to hormone therapy MA.14 • metabolic markers of insulin resistance* • markers of bone resorption and outcomes • OPN as a tissue and blood prognostic marker MA.21 • triple negative breast cancer and prognosis *pre-planned analysis, integral to study
  5. 5. Translational studies of osteopontin (OPN) OPN is a secreted integrin-binding protein that has been associated with cancer and other pathologies. It can be measured in blood and tissue using an ELISA developed by Dr. Ann Chambers Clinical studies in breast cancer (London Regional Cancer Centre) • assays in blood plasma of normal women 1994 • assays in different stages of breast cancer 1995-1996 • assays in primary tumor tissue 1997 onwards • prospective study in metastatic breast cancer 1997-1999
  6. 6. OPN − experimental studies • OPN is a secreted integrin-binding protein produced in a variety of tissues and cell types • OPN is a tumor associated protein • OPN contributes functionally to tumor progression/metastasis • OPN is linked with angiogenesis, cell survival, resistance to to apoptosis
  7. 7. OPN − clinical studies (using OPN ELISA) • OPN plasma levels in 35 healthy women median 47 (22 – 122) ng/ml • OPN plasma levels in 44 controls (completed treatment for early breast cancer) median 60 (15 – 117) ng/ml • OPN plasma levels in 70 metastatic breast cancers median 142 (38 – 1312) ng/ml • OPN expression (IHC) in 154 primary breast cancers correlates with survival (p = 0.014) • OPN expression is higher in 33 sentinel LN than in paired primary tumors (p <0.001) • OPN is expressed in other human cancers
  8. 8. OPN − study population and treatment Accrual July 1997 – November 1999 Total Population 158* Age (yrs) 61 (20-84) Postmenopausal 138 (87%) Stage localized → metastatic 123 (78%) metastatic (initial) 35 (22%) First systemic treatment for metastasis hormone 111 (70%) chemotherapy 43 (27%) none 4 (3%) Database closed July 2003 − median survival 20 mos − patients alive 26 (16.5%) *one patient registered but withdrew before baseline OPN collected
  9. 9. OPN − sample collection Number of samples: total samples 1378 median (range)/patient 9 (1-26) baseline level median 177* (1-2648) ng/ml # with elevated levels 99 (63%) Time interval: from first to last sample median 13 (1-61) mos from last sample to death median 2 (1-35) mos *upper limit of normal 123 ng/ml
  10. 10. OPN - Survival according to baseline OPN levels
  11. 11. OPN − conclusions • in univariate analysis, elevated baseline OPN was associated with decreased survival (p = 0.02) • in a multivariate model incorporating standard prognostic factors, baseline OPN was significantly associated with survival duration (RR = 1.001 ; p = 0.038) MFI, visceral metastases, low ECOG also significant • in a multivariate model incorporating standard prognostic factors and changes in sequential OPN levels – OPN increase >250 ng/ml at any time was most prognostic for poor survival (RR = 3.26 ; P = 0.0003) – low ECOG also significant • sequential monitoring of OPN may have utility in making management decisions for women with metastatic breast cancer V. Bramwell Clin Cancer Res 12:3337, 2006
  12. 12. NCIC CTG MA.5 − rationale (1988) • trials of adjuvant chemotherapy (CMF or AC) in EBC showed improved RFS/OS compared with no chemotherapy • benefit was greatest in premenopausal women • dose intensity seemed to be important • anthracyclines showed superior activity in metastatic BC • 1985-1988 pilot dose escalation study (OCOG) performed to develop dose intense CEF* regimen • plan to compare CEF vs CMF in premenopausal population with node positive BC *Cyclophosphamide/Epirubicin/Fluorouracil
  13. 13. NCIC CTG MA.5 - outcomes 5 y DFS 10 y DFS 5 y OS 10 y DFS CMF (100/40/600) 53% 45% 70% 58% q4w x 6 CEF (75/60/500) 63% 52% 77% 62% q4w x 6 p=0.009 p=0.005 p=0.03 p=0.047 M. Levine J Clin Oncol 16:2651, 1998 23:5166, 2005 • 710 women; all premenopausal • Node +ve; approx 70% ER+ve, no Tam • HR recurrence 1.30; HR death 1.22 5 yr • HR recurrence 1.31; HR death 1.18 10 yr LRCC highest accrual 125 pts
  14. 14. NCIC CTG MA.12 − rationale • protocol developed in 1992 • data very limited on premenopausal women, ER +ve/unknown tumors <200 women entered trials CT ± T for 5 yrs • adjuvant CT frequently causes premature menopause − benefits both cytotoxic and endocrine, especially if ER +ve • effect T in ER poor/-ve tumors uncertain • experimental data − CT less effective if given concurrent with T • need for study in premenopausal women with EBC, evaluating efficacy of 5 yrs of T following completion adequate adjuvant CT • placebo (P) control facilitated evaluation of toxicity and compliance
  15. 15. NCIC CTG MA.12 − schema Biopsy RANDOMIZE Tamoxifen 20 mg/day x 5 yrs Surgery Chemotherapy, last IV dose Start within 6 weeks (concurrent with XRT, if given) total/partial mastectomy Placebo 20 mg/day + axillary node REGISTRATION x 5 yrs dissection Objectives − Premenopausal women with EBC 1. To compare duration of overall survival (OS) in premenopausal node positive* breast cancer patients given T vs P for 5 yrs after adjuvant CT 2. To compare disease-free survival (DFS) and toxicities between the two arms *1995 – include high risk node negative (≤ 1 cm and high grade or LVI +ve)
  16. 16. NCIC CTG MA.12 − planned analysis • planned sample size 800 pts accrued over 5 yrs (160/yr) detect 8% difference in overall survival 70% (P) 78% (T) HR 0.69 80% power 2 sided p = 0.05 requires 242 deaths for final analysis • 2 planned interim analyses 80 and 160 deaths • July 1993 – April 2000: 672 pts accrued (1999−2000 42 pts) • April 2000: DSMC recommended closure, due to slow accrual, projected still possible to observe 242 deaths with further 5 yrs FU • Sept. 2000: first interim analysis to DSMC – continue study • April 2006: overall survival in study better than projected second interim analysis to DSMC • Sept. 2006: futility analysis, DSMC agreed to release results, possibility of combining data with other similar studies in IPDMA
  17. 17. NCIC CTG MA.12 − compliance issues • only 52% women (similar T/P) completed full 5 yrs study medication • rate of discontinuation due to recurrence/death lower in T vs P (15% vs 23%) • more women stopped T vs P (8.5% vs 5%) because of toxicity, − unlikely most of these took additional hormonal therapy • rates of refusal T vs P (13% vs 11%) similar − probable that many went on to receive open-label T • greater attrition occurred during first 24 mos therapy − when T most likely to be effective (EBCTCG analyses 1992) • around 50% of women developed amenorrhea after completion CT before starting T/P − menopausal symptoms attributed as toxicity of study medications may have reduced compliance
  18. 18. NCIC CTG MA.12 − compliance comparison other studies • 3 other studies of similar design also had similar compliance problems • compliance rates were better in AI studies, with about 20% of patients stopping AI or T, but women were already menopausal • in cohort of 2816 Irish women (pre & postmenopausal) receiving adjuvant T, many stopped medication early (22% by 1 yr, 35% by 3.5 yrs) • in a cohort of 1633 Scottish women, longer duration of adjuvant T was associated with improved OS
  19. 19. NCIC CTG MA.12 − key findings • 672 premenopausal women, after completion of adjuvant CT, were randomized to T vs P for 5 yrs • at median FU 9.7 yrs, for T vs P at 5 yrs OS 87% vs 82% HR 0.78 (95% CI 0.57-1.07), p = 0.12 DFS 78% vs 71% HR 0.77 (95% CI 0.59-1.01), p = 0.055 • no evidence of greater benefit for hormone receptor +ve subgroup (75%) • compliance with T vs P was suboptimal in both arms, only 52% completing 5 yrs of treatment • poor compliance is likely to have influenced the efficacy of treatment in this trial, and other similar studies • these findings have implications for use of oral anti-cancer medications in many settings V. Bramwell Ann Oncol. Epub ahead of print, July 2009
  20. 20. NCIC CTG MA.12 − serum collection − objectives Objectives 1. To determine if there is a difference in effect of T on OS, based on menopausal status (defined by FSH/LH, estradiol levels) at randomization (post-chemotherapy) 2. To determine if T increases the probability of becoming biochemically postmenopausal within 5 yrs of randomization 3. To determine if T causes higher estradiol levels in patients who are premenopausal at randomization Collection plan Prechemotherapy (registration) Prerandomization T/P Postrandomization 3 mos, 6 mos year 1 every 6 mos years 2−5 Relapse
  21. 21. NCIC CTG MA.12 − serum collection – status (2005) Total # specimens* : approx 2800 Total patients Pre-chemo specimen : 225 (33%) During chemo : 262 (39%) Pre-chemo and/or : 325 (48%) during chemo Pre-randomization : 313 (46%) Multiple post TP : 320 (48%) randomization Relapse : unknown *based on case report forms
  22. 22. DNA MICROARRAY GENE EXPRESSION PROFILING REVEALS SIGNATURES OF BREAST CANCER SUBTYPES WITH PROGNOSTIC VALUE Perou CM et al Nature 2000; 406:747. Sorlie T et al PNAS 2001; 98:10869. BASAL HER2 LUMINAL B LUMINAL A
  23. 23. The Major Breast Cancer Intrinsic Biological Subtypes Lum A Lum B HER2 basal Estrogen Response genes: ESR1, PGR, GATA3, FOXA1 + + - - Proliferation genes: MKI67, CCNB1, CENPF, FOXA1, MYBL2, ORC6L - + + + HER2-associated: ERBB2, GRB7 - +/- + - Basal markers: KRT5, KRT17, ERBB1, - - - + TRIM29, CRYAB
  24. 24. BIOLOGICAL CLASSIFICATION Immunohistochemistry (IHC) Luminal A ER+ or PR+ AND HER2– Ki67– Luminal B ER+ or PR+ AND Ki67+ OR HER2+ HER2+ ER–/PR– AND HER2+ Basal ER–/PR– AND HER2– AND CK5/6+
  25. 25. NCIC CTG MA.12 − OPN study Hypothesis : OPN expression by IHC, and its prognostic significance will differ across biological subtypes of BC – Luminal A, B, HER2+, basal Analysis : TMA (492 patient samples) (1) OPN expression (IHC) − scored by Dr. A. Tuck* (London) (2) OPN expression (IHC) − automated (AQUA) analysis by Dr. A. Magliocco (Calgary) *comparison with 72 MA.12 specimens scored in whole sections
  26. 26. NCIC CTG MA.14 − outcomes Tamoxifen (T) 20 mg/d x 5 yr Serum collected for markers of insulin resistance at Tamoxifen (T) 20 mg/d x 5 yr multiple time points Octreotide LAR (O) 90 mg IM/mos x 5 yr* over 5 yr M. Pollak J Clin Oncol 26:145 A532, 2008 • 667 women : all postmenopausal, receptor +ve • median FU 7.9 yrs, 220 events • no difference in EFS HR 0.93, p = 0.62 • unacceptable level of cholelithiasis, therefore duration O reduced to 2 yrs in July 2000*
  27. 27. NCIC CTG MA.14 − OPN study objectives Objectives: 1. To evaluate whether baseline plasma OPN levels are prognostic for RFS and/or OS 2. To explore changes in plasma OPN levels over time in relationship to RFS, or bone-only RFS 3. To explore differences in plasma OPN levels from baseline to recurrence 4. To evaluate whether baseline primary tumor OPN IHC levels are prognostic for RFS and/or OS 5. To explore whether baseline tumor OPN levels are associated with plasma OPN levels
  28. 28. NCIC CTG MA.14 − OPN study collection (started Nov 1998) Plasma collection Time period # plasma samples Baseline 331 4 mos 347 8 mos 387 12 mos 405 24 mos 209 36-48 mos 541 End treatment/60 mos 271 Recurrence 35 Total samples 2526 # with samples 656 (98% of 667) Tumor collection Time period # tumor samples Baseline 419 (63% of 667)
  29. 29. NCIC CTG MA.21 − rationale • AC is equivalent to CMF (NSABP B15, B23) • CEF is better than CMF (NCIC MA.5) • AC → Paclitaxel (P) is better than AC (CALGB 9344) • CEF is standard adjuvant regimen in Canada • AC → P is standard adjuvant regimen in US • by indirect comparison CEF and AC → P regimens may have similar efficacy • for locally advanced breast cancer EC and CEF have similar efficacy and toxicity • EC → P may be more effective than CEF or AC → P
  30. 30. NCIC CTG MA.21 − outcomes 3 y DFS CEF q4w x 6 90.1% EC q2w x 6 → P q3w x 4 89.5% (120/830) AC q3w x 4 → P q3w x 4 85% M. Burnell J Clin Oncol In Press, October 2009 • 2104 women*; pre/post menopausal age ≤60 y : median FU 30 m • 82% node +ve; 60% receptor +ve → sequential T; 16% HER2 +ve • 3 y DFS AC → P vs CEF RR 1.49 p = 0.005 AC → P vs EC/P RR 1.68 p = 0.0006 EC → P vs CEF RR 0.89 p = 0.46 *V. Bramwell in London/Calgary contributed 118 pts
  31. 31. NCIC CTG MA.21 − correlative science studies M. Burnell J Clin Oncol 26:18S A550, 2008 • 1623/2104 (77%) primary tumors had assays performed for ER, PR and HER2 (local institutions) • 551 (34%) were triple negative • compared with all other groups, triple negative had worse 3 yr RFS 80.5% vs 86.5%, p<0.0002 • too early to evaluate whether triple negative group benefit more from one of the 3 types of chemotherapy MA.21 Tumor bank status October 2009 Tissue 1370/2104 (65%) Blocks 1120/2104 (53%) Slides 914/2104 (43%)
  32. 32. Lessons learned • there are many excellent reasons to participate in Cooperative Group activities (vs Industry) • make active contributions – these will be noticed and recognized • if invited to be a Principal Investigator – make your mark! • incorporate a tumor specimen bank into the clinical trial protocol • tumor banks need to be well-organized and adequately funded • be open/search for opportunities for trial-related translational research studies • cultivate collaborations with scientists in your own institution, but also establish networks across the country
  33. 33. Acknowledgements NCIC CTG Breast Chair Kathy Pritchard Disease Site Committee Trial PIs Mark Levine (MA.5) Michael Pollak (MA.14) Margot Burnell (MA.21) Statisticians Dongsheng Tu Judy-Anne Chapman Pathologist Lois Shepherd OPN Team Leader/Scientist Ann Chambers Pathologist Alan Tuck Scientist Allison Allan London, ON Statisticians Gordon Doig Larry Stitt Other Collaborators Pathologist Tony Magliocco Clinician Marc Webster Calgary, AB Pathologist/Scientist Torsten Nielsen Vancouver BC Clinician Stephen Chia WOMEN WHO PARTICIPATED IN OUR BREAST CANCER STUDIES
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×