Dr. Cliff Hudis on the latest information on new breast cancer treatments. Dr. Hudis is Chief of Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center.

1. Newest treatments for all stages of breast
cancer including hormonal treatments and
developments in HER2 positive breast
cancer
Clifford Hudis, M.D.
Chief, Breast Medicine Service, MSKCC
Professor of Medicine, Weill Cornell Medical College
Immediate Past President, American Society of Clinical Oncology

2. Cancer in general
300,000,000 Americans
• 560,000 cancer deaths (2/1000/year = 0.2%)
– lung cancer, (160,000)
– colorectal (53,000)
– breast (41,000)
– pancreas (33,000)
– prostate (27,000).
• Mostly age 55 and older.
• Deaths in childhood (0 and 14) are rare (1,500)

3. Epidemiology
200,000 new cases
Approx 40,000 deaths
Lifetime risk: Approximately 1:8 will develop
breast cancer (cumulative risk)
American Cancer Society. Detailed Guide: Breast Cancer: What are the Key Statistics for
Breast Cancer? Available at: http://www.cancer.org. Accessed Sept. 14, 2009.

5. Breast Pathology
Breast Carcinoma
In situ
Infiltrating Carcinoma
Ductal Carcinoma In Situ
Lobular Carcinoma In Situ
Infiltrating Ductal, nos (70 - 80%)
Invasive Lobular (5 - 10%)
Others
From: DeVita VT et al. Cancer: Principles and Practice of Oncology. 7th Ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2005:1415-1477.

6. Risk Factors for Breast Cancer
• Gender
• Age
• Race
• Diet high in fat
• Early onset of menses and late menopause
• Late or no pregnancies
• Family history (BRCA1, BRCA2)
• Dense breast tissue
• Alcohol consumption
• Hormone supplementation
American Cancer Society. Breast Cancer Facts and Figures 2005-2006.

7. Sub-classification of BC:
Three Diseases
ER and/or PR (+) ER and PR (-)
HER2
(+)
“Triple Positive”
“HER2
positive”
HER2
normal
“Hormone
sensitive”
“TNBC”

8. Sub-classification of BC:
Three Diseases
ER and/or PR (+) ER and PR (-)
HER2
(+)
“Triple Positive”
“HER2
positive”
HER2
normal
“Hormone
sensitive”
“TNBC”

9. Sub-classification of BC:
Three Diseases
ER and/or PR (+) ER and PR (-)
HER2
(+)
“Triple Positive”
“HER2
positive”
HER2
normal
“Hormone
sensitive”
“TNBC”

10. Sub-classification of BC:
Three Diseases
ER and/or PR (+) ER and PR (-)
HER2
(+)
“Triple Positive”
“HER2
positive”
HER2
normal
“Hormone
sensitive”
“TNBC”

11. How Long Should Post-Operative
Hormone Therapy Last?

12. Survival after a Diagnosis of Breast Cancer.
Foulkes WD et al. N Engl J Med 2010;363:1938-1948.
Breast Cancer Recurrences Occur Late

13. 13
SUPPORTING TRIALS
• ATAC – updated at SABCS 2004
• BIG FEMTA
• TEAM (not yet reported)
SUPPORTING TRIALS
• no reported trials
• BIG FEMTA
SUPPORTING TRIALS
• IES – updated at SABCS 2004
• ITA
• ARNO/ABCSG - reported at SABCS 2004
Adjuvant AI Hormonal Therapy Trial Designs
*
* Note that some patients from the original newly diagnosed population
are lost due to recurrence or adverse events prior to randomization
DIRECT COMPARISON
SWITCHING
*
SEQUENCING
EXTENDED ADJUVANT
SUPPORTING TRIALS
• MA-17 – updated ASCO 2004

14. MA.17 Letrozole in the Extended Adjuvant Setting
Improved DFS with 5 yrs of Letrozole After 5 yrs of Tamoxifen
Goss. PE. Breast Cancer Res Treat. 2007 October; 105(Suppl 1): 45–53. Epub 2007 Oct 3.

15. B33: (Stopped Early) Exemestane versus placebo
(intent-to-treat, eligible patients, w/follow-up): DFS
Mamounas E P et al. JCO 2008;26:1965-1971
©2008 by American Society of Clinical Oncology

16. NSABP B14: Patients Re-randomized After 5 years of
Tamoxifen to Either Placebo or Prolonged Tamoxifen
(10 vs 5 years)
Fisher B et al. JNCI J Natl Cancer Inst 2001;93:684-690
n=117
2

17. Objectives of ATLAS & aTTom
• Randomise at least 20,000 women
between 10 and 5 years of tamoxifen
(to detect reliably, or refute reliably, a
2-3% improvement in survival)
• Follow-up randomised women for at
least 15 years (because 10 or more
years is needed to see full benefits
from longer tamoxifen*)
*Peto R, Five Years of Tamoxifen—or More? JNCI 1996

18. ECOG, Scottish &
NSABP B-14 1,588
ATLAS 11,646
aTTom 6,953
ALL TRIALS 20,187
20,187 women with ER-positive or ER-
unknown disease randomised in 5 trials
of 10 vs 5 years of tamoxifen:
ATLAS, Lancet 2013; 381: 805–16
aTTom: Proc ASCO 2013

19. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
This presentation is the intellectual property of ATLAS. Contact ATLAS@CTSU.ox.ac.uk for permission to reproduce or distribute.
ATLAS: 6846 women, ER+, 10 vs 5 years tamoxifen
RECURRENCE BREAST CANCER MORTALITY

20. aTTom: 10 vs 5 years of tamoxifen:
Recurrence by treatment ASCO 2013
580 vs 672 recurrences
RR=0.85 (95%CI 0.76-0.95)
p=0.003
Presented ASCO 2013

21. Concepts to consider
•Chronic, relatively steady recurrence risk
•Relatively low rate of mortality
•Time Dependent Effects:
Duration of effect on the rate
Development of resistance
Development of intolerance
•Long term toxicities
•Absolute benefit to the individual
•DRUG-SPECIFIC or DURATION (of any rx)?

22. ASCO’s CancerLinQ: Big Data
Sledge GW, Hudis CA, Swain SM, et al: ASCO's approach to a learning health care system in oncology. J Oncol Pract 9:145–148, 2013

23. ASCO’s CancerLinQ prototype
• Development began in June of 2012.
• Completed in eight months.
• Included more than 170,000 de-identified
patient records.
• Demonstrated that the full CancerLinQ
system could be a reality.
Kolacevski A, Mann JT, Hauser R, et al: Using Big Data to Track Trends in Medical Practice. Journal of Oncology Practice 11:JOP.2014.001541–70, 2014

24. Tamoxifen Duration & Survival In CLQ Pilot
Accessed 16 March 2015 at: http://bcove.me/evt9lbbp

25. Do Young Women Need To Be
Made Menopausal?

26. Hormone Therapy Was The
First Targeted Therapy
1896 GT Beatson - Oophorectomy in
premenopausal women
1944 A Haddow - Synthetic estrogen
(stilbestrol) as treatment of breast cancer
1952 C Huggins - Adrenalectomy
(1966 Wins Nobel Prize for development of
endocrine therapy in prostate cancer)
1958 E Jensen - Characterization of the
estrogen receptor (ER)

27. TEXT and SOFT Designs
Presented by: Olivia Pagani, MD ASCO 2014
R
A
N
D
O
M
I
Z
E
Tamoxifen+OFS x 5y
Exemestane+OFS x 5y
R
A
N
D
O
M
I
Z
E
Tamoxifen x 5y
Tamoxifen+OFS x 5y
Exemestane+OFS x 5y
Tamoxifen+OFS x 5y
Exemestane+OFS x 5y
Joint Analysis
(N=4690)
• Premenopausal
• ≤12 wks after surgery
• No chemo
OR
• Remain premenopausal
≤ 8 mos after chemo
• Premenopausal
• ≤12 wks after surgery
• Planned OFS
• No planned chemo
OR planned chemo
SUPPRESSION OF OVARIAN
FUNCTION TRIAL (N=3066)
TAMOXIFEN AND EXEMESTANE
TRIAL (N=2672)
OFS=ovarian function suppression
Enrolled: Nov03-Apr11
Median follow-up 5.7 years
TEXT
SOFT

28. Exemestane+OFS Reduced Recurrence
• 4% absolute improvement in 5-yr freedom from breast cancer for exemestane+OFS
• No significant difference in overall survival
Presented by: Olivia Pagani, MD ASCO 2014

29. SOFT: Tam vs OS/Tam
Francis P et al, NEJM DOI: 10.1056/NEJMoa1412379

30. HER Family Receptors
Hudis C. N Engl J Med 2007;357:39-51

31. H Trastuzumab
Doxorubicin
Cyclophosphamide
Paclitaxel
Docetaxel
Carboplatin
Adjuvant Trastuzumab
NSABP B-31
NCCTG 9831
BCIRG 006
H… x 1 year
H… x 2 years
No therapy
Standard
ChemoRx
HERA
FinHer PACS 04
H…x9
H…x9
H…x 52
No therapy
Epirubicin
Vinorelbine
Fluorouracil
H…x 52
H…x 52
H…x 52
H…x 52
H…x 52

32. Can We Accelerate?
Is Change In pCR A
Reliable Surrogate?

33. Neoadjuvant Trastuzumab + Pertuzumab
Regimen Duration pCR P value
NEOSPHERE
(N=417)
DH 29%
DP 12 w 24%
DHP 45.8% 0.0141
HP 16.8%
TRYPHAENA
(N=225)
FECHP → DHP 61.6%
FEC → DHP 24 w 57.3%
DCbHP 66.2%
E=epirubicin; C=cyclophosphamide; F=fluorouracil;
D=docetaxel;
Cb=carboplatin; H=trastuzumab; P=pertuzumab

34. NeoAdjuvant Approval: Pertuzumab
Unique circumstances?
-Significant improvement in pCR
-Significant increase in OS (MBC)
- Completed, fully powered adjuvant trial
-Significant safety experience (MBC & ongoing)
Implications?
Is Accelerated Approval a public health benefit? Why?
- Because increased pCR is a leading indicator for OS?
- If so, why not give a full year of pertuzumab?
(Since that is what APHINITY tests.)

35. Neoadjuvant Lapatinib Trials
Regimen Duration pCR P value
NSABP B-41
(N=529)
AC → PH 28 w 52.5%
AC → PL 53.2% 0.99
AC → PHL 62% 0.095
NEOALTTO
(N=455)
*PH 18 w 29.5%
*PL 24.7% 0.34
*PHL 51.3% 0.0001
CHERLOB
(N=121)
PH → FEC/H 24 w 25%^
PL → FEC/L 26.3%^ NR
PHL → FEC/HL 46.7%^ 0.019
GEPAR-QUINTO
(620)
EC/H → DH 24 w 30.3%#
EC/L → DL 22.7%# 0.04
A=doxorubicin; E=epirubicin; C=cyclophosphamide; F=fluorouracil; P=paclitaxel q w ; D=docetaxel q 3 w; H=trastuuzmab; L=lapatinib;
*In NEOALTTO, 6 w of H or L or HL preceding P; ^ pCR (no invasive tumor breast and nodes);
# pCR (no invasive or in situ tumor in breast and nodes; NR=not reported

36. •Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started
after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years
• Radiotherapy if indicated
ALLTO
3-weekly
Trastuzumab
for 52 weeks
Lapatinib
for 52 weeks
Weekly
Trastuzumab (12
weeks)
Lapatinib
+ 3-weekly
Trastuzumab for
52 weeksWashout (6 weeks)
Lapatinib (34
weeks)
Anti-HER2 therapy can overlap chemotherapy

37. San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013
Study Design
(APT Trial)
This presentation is the intellectual property of the author/presenter. Contact them at stolaney@partners.org for permission to reprint and or distribute
HER2+
ER+ or ER-
Node Negative
< 3 cm
Enroll
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12
TT T T T T T T T T T T T
FOLLOWED BY 13 EVERY 3 WEEK DOSES
OF TRASTUZUMAB (6 mg/kg)*
Planned N=400
*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks
** Radiation and hormonal therapy was initiated after completion of paclitaxel

38. San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013
Time (Months)
Disease-FreeSurvival(Probability)
0 12 24 36 48 60
0.00.20.40.60.81.0
0 12 24 36 48 60
0.00.20.40.60.81.0
All patients
Number at risk
406 390 382 307 126 27
Disease-Free Survival
This presentation is the intellectual property of the author/presenter. Contact them at stolaney@partners.org for permission to reprint and or distribute
3-year DFS 95% Conf. Interval
98.7% 97.6% to 99.8%
Poisson p-value: <0.0001

39. San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013
Change Is Happening
(Personalization Is Possible)
Anatomy (risk) drives treatment (1990)
Biology (responsiveness) drives treatment (2014)

41. US Health Spending at 17.7% of GDP is ~50%
Greater than Others (and Still Rising)
Projected US Health Spending 2020 → 20% GDP
Kehhan SP, Cuckler GI, Sisko AM, Madison AJ, Smith SD, Lizonito JM, Poisal JA and olfe CJ. National Health Expenditure Projections: Modest Annual Growth
Until Coverage Expands And Economic Growth Accelerates. Health Affairs. 2012 Jul;31(7):1600-12.

42. Higher Spending Does Not Increase Life Expectancy
Health Care
Expenditures
and
Life Expectancy
(2005)
Fuchs VR, Milstein A. N Engl J Med 2011;364:1985-19

43. Projected family health insurance premium costs and
average household income
HouseholdIncome
YearAnnals of Family Medicine: 2012: 10: 156-162
Patients are Bearing More of the Costs

44. Growing Numbers Of Survivors
From: The State of Cancer Care in America, 2015: A Report by the American Society of Clinical Oncology. Journal of Oncology Practice 11:JOP.2015.003772–113, 2015

45. Thank You