40 Years of Progress

Clifford Hudis, MD, FACP, FASCO Hormone Therapy Was The First Targeted Therapy

1896 GT Beatson - Oophorectomy in premenopausal women

1944 A Haddow - Synthetic estrogen (stilbestrol) as treatment of breast 1952 C Huggins - Adrenalectomy (1966 Wins Nobel Prize for development of endocrine therapy in )

1958 E Jensen - Characterization of the estrogen receptor (ER) ASCO’s First Meeting: 1964

“….common concern for the patient with cancer.”

Edgewater Hotel Chicago, Illinois Founders

Jane C. Fred J. Harry F. Robert Herman H. Wright, MD Ansfield, MD Bisel, MD Talley, MD Freckman, MD

Arnoldus William Goudsmit, MD, Edgewater Hotel, Chicago, Illinois Wilson, MD PhD http://www.asco.org/about-asco/founders

http://www.ecr.co.za/media/uploads/2013/06/10/rivonia.jpg http://atyourlibrary.org/sites/default/files/sites/files/default/images/220px- FBI_Poster_of_Missing_Civil_Rights_Workers.jpg 1st ASCO Meeting in Chicago November 5, 1964

• Development of an annual meeting • Building educational material • Publication of a specialty journal • Collaboration with other organizations • Research initiatives, and

• Development of an organizational framework to support our efforts A brief history of platinums

1845 – Peyrone described cis-PtCL2(NH3) “Peyrone’s Salt” Ann Chemie Pharm 1845, 51: 129

1893 – Werner deduced structure

1960s – Rosenberg and van Camp discover that electrolysis of a electrode produces CDDP. This inhibits E. coli.

(They grow very large but don’t divide.) Nature 1965, 205 (4972): 698–699.

A brief history of platinums

1971 – Clinical trials begin

1978 – FDA approval: ovary and testes

1989 – FDA approval: for CBDCA in ovary (similarly forms preferential cross-links with guanine in DNA, cross- resistant w/ CDDP)

“Class” now includes alkylating-like agents: , , , &

Minotti et al Pharmacol Rev 56:185-229, 2004 We Had Drugs ( & Endocrine) 1977

• FLASCO was formed and committed to facilitating and promoting multidisciplinary efforts to improve patient care in Florida.

• Chemotherapy was established as potentially curative therapy:

o HD o NHL o Early Stage o Testes Cancer Systemic RX: Historical Perspective

1985 NIH Consensus Conference: Premenopausal, node (+) : Chemotherapy Premenopausal, node (-) : treatment not recommended, consider chemotherapy if "high risk" Postmenopausal, node (+), ER (+) : tamoxifen Postmenopausal, node (+), ER (-) : consider chemotherapy, but cannot be recommended as standard practice Postmenopausal, node (-) : no routine adjuvant therapy, may be considered for certain "high-risk" patients EBCTCG - 2000

•Almost all women on (194) randomized trials Randomized < 1995 w/ 5+ years f/u and survival main endpoint

•Tamoxifen: •50,000: tamoxifen (15,000: 5 yrs vs none) 28,000 (polychemo) •Ovarian Ablation: 4900 + 4200 for Goserelin •Chemotherapy:

Lancet 2005; 365:1687-1717 Tamoxifen or nil 15 years Follow-Up For Invasive Breast Cancer

Proportional Annual Treatment: Recurrence Reduction:

Tamoxifen x 5 years 40% (+/- 3) Combination Chemotherapy 24% (+/- 2) (CMF, AC, etc…) Ovarian Ablation 31% (+/-8) [ 7% +/- 4% w/ chemo]

Lancet 2005; 365:1687-1717 We Learned We Needed Major Impact Or Large Trials Time to Relapse in Patients with Myeloid or Lymphoid Blast Crisis Who Had a Response to STI571.

http:\\wikipedia/imatnib Druker BJ et al. N Engl J Med 2001;344:1038-1042. HER Family Receptors

Hudis C. N Engl J Med 2007;357:39-51

Olaparib in Ovarian Cancer

Interim survival analysis (ASCO 2013) •HR 0.18 (95% CI 0.11-0.31) in gBRCAm •PFS 11.2 v 4.3 mo •No difference in OS (?xover)

Ledermann J et al. N Engl J Med 2012;366:1382-1392. Prognostic Performance: Relapse-free Survival and Overall Relapse-free Survival and Overall Survival Survival among all 295 Patients among the 225 Patients with ER+ Disease

Intrinsic Subtype (Panels A and B)

Recurrence Score (Panels C and D)

70-Gene Profile (Panels E and F)

Wound Response (Panels G and H)

Two-Gene Ratio (Panels I and J).

Fan C et al. N Engl J Med 2006;355:560-569. Precise Terminology Is Important

PROGNOSTIC FACTORS

Poor: - Node # - Tumor Size - HER2 (+)

Favorable: - ER/PR (+)

PREDICTIVE FACTORS (predict better response)

Endocrine Rx - ER/PR (+) Anti-HER2: - HER2 (+) Idealized Biomarker Examples Biomarker Negative vs Biomarker Positive Purely prognostic biomarker: Treated Untreated

Purely predictive marker:

Both predictive and prognostic:

Karla V. Ballman JCO doi:10.1200/JCO.2015.63.3651 We Identified & Exploited New Targets (For Targeted & Conventional Treatment Decision-making) Ipilimumab Augments T-Cell Improves OS/PFS Activation & Proliferation

T-cell T-cell T-cell activation inhibition remains active

T-cell T-cell

T-cell CD28 CTLA-4 TCR CD28 CTLA-4 TCR HLA CD CD8 HLA CD 80/ TCR 0/ 80/ APC CD CD8 APC CD Ipilimumab 86 HLA 6 86 blocks APC CTLA-4

Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010. Hodi FS et al. N Engl J Med 2010;363:711-723. Blocking CTLA-4 and PD-1

Tumor Microenvironment

Activation (cytokines, lysis, proliferation, migration to tumor)

TCR TCR MHC MHC ++ + Dendritic ++ + B7 CD28 Tumor cell cell ++ + T cell T cell PD-1 PD-L1 B7 CTLA-4 ------anti-PD-1 anti-CTLA-4 PD-1 PD-L2 - - - anti-PD-1

CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) We Have Immunotherapy Options Cancer Remains A Challenge 325,000,000 Americans

• 560,000 cancer deaths (2/1000/year = 0.2%) – , (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) Looking Ahead

• Accelerating research

• Applying advances in the clinic

http://www.battelle.org/docs/tpp/2014_global_rd_funding_forecast.pdf?sfvrsn=4 Stagnant Research Budget President’s “Skinny”Budget Proposal NIH Funding: Bipartisan Support

Thank you