1. Advances in Adjuvant Systemic Therapy of Breast Cancer
Anne F. Schott, MD
University of Michigan
October 18, 2008

2. Current struggles in the real world…
Who to Treat With What?
Current struggles in the real world…
October 18, 2008

3. When all you have is a hammer…
Chemotherapy
Endocrine therapy
Targeted therapy (ie trastuzumab)
Radiotherapy

4. Patient Example
A 44 year old healthy premenopausal woman has the following pathologic diagnosis:
Left breast lumpectomy: Invasive ductal carcinoma (1.8 cm), Bloom-Richardson grade 2. No angiolymphatic invasion.
Sentinel lymph node biopsy: 2/4 lymph nodes positive, ALND no more nodes +
ER positive (96%), PR positive (84%), Her-2/neu 2+, FISH negative (ratio 1.37)

5. Adjuvant! 8.0 10-Year Prognosis

6. NCCN Guidelines 2008

7. Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4
Age
ER-poor
ER+
<50
0.57 (0.07)
0.51 (0.06)
50-59
0.65 (0.07)
0.75 (0.05)
60-69
0.78 ( 0.08)
0.81 (0.05)
Sir Richard Peto, SABCS, 2007

8. Common Adjuvant Regimens
First Generation →
Second Generation
Third Generation
CMF*6
CAF*6, CEF*6
FAC*6
TAC*6
CE(50)F*6
CE(100)F*6
FEC*3→D*3
AC*4
AC*4→Txl*4
q3wk
Dose Dense (CA*4→Txl*4 q2wk)
TC*4
20%
20%

9. Worldwide Overview: Taxane vs no chemo: Age <50
RECURRENCE rate ratio
years 0-4 only
BREAST CANCER MORTALITY
rate ratio
CMF vs no chem
0.56 (0.05)
0.68 (0.05)
Anthr. Vs CMF
0.84 (0.05)
0.81 (0.05)
Taxane vs Anthr.
0.84 ( 0.04)
0.86 (0.05)
Taxan vs no chem (0.07)
Multiplying 3 RR p<
0.46 (0.08)
2p>
Sir Richard Peto, SABCS, 2007

10. What is “standard treatment”?X
Trastuzumab-containing regimen
Oncotype Dx, treat if intermediate or high risk
No chemotherapy
2nd Generation chemotherapy (TC, FEC)
3rd Generation chemotherapy (TAC, FEC-D, ddAC-Taxol) X X

11. 2nd Versus 3rd Generation Regimen: Differences in Relapse at 10 years (Adjuvant! 8.0)
2nd Generation Regimen
3rd Generation Regimen

12. HER2 is Predictive of Paclitaxel Benefit
By Estrogen Receptor
Disease Free Survival
These curves represent DFS of the combined sets 1 and 2 by ER and by HER2, as assayed by immunohistochemistry with MAb cb11.
Shown on your left, patients who were ER negative benefited from paclitaxel,
RETURN
but the benefit appears smaller in HER2 negative patients, in the top panel, than in HER2 positive patients, shown in the bottom panel.
ER positive patients are illustrated in the right panels. While HER2 positive patients, shown in the lower right bottom panel, again appeared to benefit from paclitaxel,
In this analysis there was no apparent benefit from paclitaxel for those women whose cancers were ER Positive and HER-2 negative.
This subgroup, ER Positive HER-2 Negative patients, represents more than ½ of the subjects in this study.
Evaluation of paclitaxel benefit according to ER and HER-2 was highly exploratory, and not powered for appropriate statistical analyses for a 3 way interaction.
n = 1322
ER Neg
ER Pos
paclitaxel
paclitaxel
No paclitaxel
HER2 NEG
No paclitaxel
n=390 (29%)
n=144 (11%)
n=703 (53%)
n=79 (6%)
paclitaxel
paclitaxel
HER2 POS
No paclitaxel
No paclitaxel
Hayes D.F., et al. N Engl J Med. 357: , 2007
Years

13. Common Adjuvant Regimens
First Generation →
Second Generation
Third Generation
CMF*6
CAF*6, CEF*6
FAC*6
TAC*6
CE(50)F*6
CE(100)F*6
FEC*3→D*3
AC*4
AC*4→Txl*4
q3wk
Dose Dense (CA*4→Txl*4 q2wk)
TC*4
20%
20%

14. US Oncology: TC vs AC RANDOMIZE Doxorubicin 60 mg/m2 IV Day 1
Cyclophosphamide 600 mg/m2 IV Day 1
Every 21 days x 4 cycles
RANDOMIZE
Docetaxel mg/m2 IV Day 1
Cyclophosphamide 600 mg/m2 IV Day 1
Every 21 days x 4 cycles

17. 2nd Generation Adjuvant Chemo Trials
First Generation →
Second Generation
Third Generation
CMF*6
CAF*6, CEF*6
FAC*6
TAC*6
CE(50)F*6
CE(100)F*6
FEC*3→D*3
AC*4
AC*4→Txl*4
q3wk
Dose Dense (CA*4→Txl*4 q2wk)
TC*4
CALGB 40101
ddAC versus ddTaxol

18. 3rd Generation Adjuvant Chemo Trials
Trial Name
Patient Population
Control Arm
Experimental Therapy
Concept
S0221
High Risk
Dose dense AC-Taxol
metronomic AC-Taxol
Optimal scheduling
E5103
Her-2 negative
AC-weekly Taxol
bevacizumab
Adds new agent
PACS08
Triple Negative
FEC-docetaxel
ixabepilone
Substitutes new agent
ALTTO
Her-2 positive
Anthracycline regimen and trastuzumab
lapatinib
Adds/substitutes new agent

19. Can Bisphosphonates Prevent Bone Metastasis?
October 18, 2008

20. Effects of Bisphosphonates on Antitumor Activity in Preclinical Models
Tumor-induced osteolysis
Tumor cell proliferation and viability
Metastatic behavior of tumor cells
Activity of cytostatic drugs
Angiogenesis
Tumor burden in vivo
In summary, zoledronic acid has a variety of both direct and indirect antitumor effects
In vitro studies have shown that zoledronic acid
Inhibits the proliferation and viability of human tumor cells
Inhibits the metastatic potential of tumor cells
Enhances the activity of cytostatic drugs
Has angiostatic effects
In vivo studies in animal models have shown that zoledronic acid
Inhibits tumor-induced osteolysis
Reduces tumor burden
Inhibits angiogenesis

21. Comparison of Adjuvant Breast Cancer Trials of Clodronate vs
Comparison of Adjuvant Breast Cancer Trials of Clodronate vs. Placebo/Control
Diel/Jaschke Powles Saarto
No. of patients
Treatment site single multi-center single institution institution
Selection BM+ Stage I-III LN+
Treatment length (y)
Control arm observation placebo observation
Follow-up time (y)
Skeletal effect + (5 yrs) + NS
Overall survival NS
Jaschke et al. Proc ASCO, Powles et al. Breast Cancer Res, 2006
Saarto et al. Acta Oncol 43:80-82, 2004

22. Adjuvant Clodronate vs Placebo: Survival
Powles TJ et al, Br Cancer Res, 2006

23. Ibandronate 50 mg po qd vs observation
Phase III Studies of Bisphosphonates Vs. Placebo/Control as Adjuvant Therapy for Breast Cancer with DFS Endpoint
NSABP B-34: (3 years) n=3, stage I-II
Placebo
vs.
Clodronate 1,600 mg po qd
Closed
BIG/AZURE: (5 years) n=3, stage II-III
Control
vs.
Zoledronic acid 4 mg IV q mo x 6, followed by q3 mo x 2 yrs, followed by q6 mo
Closed
German/GAIN: (2 years) LN positive
ETC vs. EC-TX x
Ibandronate 50 mg po qd vs observation
Open

24. ABCSG-12 Trial Design 1,803 premenopausal breast cancer patients
Endocrine-responsive
Stage I&II, <10 positive nodes
No chemotherapy except neoadjuvant
Treatment duration: 3 years
Surgery
(+RT)
Goserelin
3.6 mg q28d
Randomize 1:1:1:1
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d + Zoledronic Acid 4 mg q 6 mo
Anastrozole 1 mg/d
Anastrozole 1 mg/d + Zoledronic Acid 4 mg q 6 mo

25. First DFS Events (ITT Population)
60 months
HR=0.64
P=.011
ASCO 2008 meeting, Gnant

26. SWOG 0307 Drug Dose Route Interval Current accrual 1958/4500 Arm 1
Zoledronic acid 4 mg* IV q4 wks x 6, then q mo x 2.5 yrs
Arm 2
Clodronate 1,600 mg oral daily x 3 yrs
Arm 3
Ibandronate 50 mg oral daily x 3 yrs
*Zoledronic acid dose adjusted for baseline renal function

27. First DFS Events (ITT Population)
60 months
HR=1.096
P=.593
ASCO 2008 meeting, Gnant

28. What Endocrine Therapy?
Aromatase inhibitors are indicated in the adjuvant treatment of postmenopausal women, either alone or following tamoxifen
Early data does not support superiority of aromatase inhibitors in premenopausal women
Many women become menopausal with chemotherapy

29. Bleeding after Chemotherapy by Patient Age
Women over 40: most become amenorrheic, plateaus at 70% amenorrhea by 9-12 months
Women under 35 have 60-70% chance of amenorrhea, most have recovered by 6 months
Petrek et al JCO 2006

30. Bleeding after Chemotherapy by Type of Regimen
CMF gradually induces amenorrhea
AC and AC-T cause amenorrhea in most women, but by 9-12 mo only 40% with AC have amenorrhea, 50% with AC-T
Petrek et al JCO 2006

32. HR+ patients with postmenopausal E2,
Schema
HR+ patients with postmenopausal E2,
amenorrhea > 8 weeks
Start AI therapy
Monitor E2 levels at 2, 4, 6, 8, 10, 12 wks
Measure other hormone levels less often
E2<10 E
E2>20
Continue AI therapy,
monitoring (18 mo)
Recheck E2
levels
in 1 week
Off study
E2<10
E2>10

33. Patient Example: Adjuvant Systemic Therapy Recommendations
2nd or 3rd generation chemotherapy
Chemotherapy trial
Bisphosphonate trial – S0307
Tamoxifen
SOFT clinical trial
If menopausal, switch to AI after 2-5 years of tamoxifen
“Early switch” endocrine therapy trial APPEL

34. Neoadjuvant Chemotherapy: Issues and Controversies
October 18, 2008

35. Patient Example
BL is a 58 year old postmenopausal woman who was discovered to have a 3.0 cm breast mass on imaging
ER 89%, PR 7%, H2N 1+
Surgeon feels breast conservation possible but better cosmesis after neoadjuvant therapy

36. Operable Breast Cancer
NSABP B-18
Operable Breast Cancer
Stratification
• Age
• Clinical Tumor Size
• Clinical Nodal Status
Operation
AC x 4
+ TAM if >50 yrs.
AC x 4
Operation
+ TAM if >50 y

37. B-18 Lumpectomy Rate P < 0.01 68% 60% 80% 60% 40% 20% Postop Chemo
Postop
Chemo
Preop
Chemo

38. Local Therapy Pros Downstaging of primary tumor and lymph nodes
Less radical local-regional therapy needed
Breast conservation possible more often
Cons
Pathologic nodal staging requires additional procedure
FNA of nodes
up-front SLNB
Local treatment delayed for nonresponders
Decisions for XRT complicated

39. Systemic Therapy
Pros
In vivo assessment of response, could potentially improve treatment by “tailoring” based on response
Good biologic model to evaluate effects of chemotherapy tumors
Predicitve factor development
Acceleration of adjuvant regimen development
Cons
Potential for overtreatment in some subsets of patients
Unclear what to do in ER positive, node negative disease

40. Which tumors > 1, <5 cm definitely get chemotherapy (pre or post)?
ER or PR positive
ER/PR both negative
Node negative ?? ++
Node positive

41. Which tumors > 1, <5 cm definitely get endocrine therapy (pre or post)?
ER or PR positive
ER/PR both negative
Node negative ++ -
Node positive

42. Patient Recommendations
Sentinel Lymph Node Biopsy
0/1 lymph node positive

43. Patient Example: OncotypeDX Results
I would then refer back again to the patient KL, whose Adjuvant! Predictions we saw earlier. She underwent Oncotype Dx testing and, perhaps surprisingly, her risk turne out to be in the “low risk” category. What should be recommended for her? According to Adjuvant, she would expect an 8% absolute risk reduction with chemotherapy. According to Oncotype Dx, with only a 9% rate of distant recurrence, chemotherapy could only benefit her by 3%-4%.

44. Probability of pathologic complete response (pCR) as a function of Recurrence Score
doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) every 3 weeks x 3, followed by weekly paclitaxel (80 mg/m2) x 12.
Gianni, L. et al. J Clin Oncol; 23:
Gianni, L. et al. J Clin Oncol; 23:

45. Recurrence Score Predicts CR to Neoadjuvant Docetaxel (Chang, BCRT 2008)

46. Patient Recommendations (Level 3 evidence)
Sentinel Lymph Node Biopsy
0/1 lymph node positive
Begin neoadjuvant hormonal therapy
Send Recurrence Score
Low risk, no chemotherapy
Intermediate risk, consider chemotherapy if poor response
High risk, chemotherapy

47. What’s the Goal?
Select patients who will require systemic therapy for neoadjuvant treatment
Find predictive factors (either before or early in treatment) that allow for accurate tailoring of therapy