Mello Abrams Lecture: Ovarian Cancer Update: Beth Karlan, MD

Beth Y. Karlan, M.D. Director, Women’s Cancer Program and Division of Gynecologic Oncology, Cedars-Sinai Medical Center

Ovarian Cancer National Alliance Annual Conference 2015, San Diego, CA

Genomics in Risk Assessment and Tailoring Treatment for Women with Ovarian Cancer

Ovarian Cancer Update 2015

Precision Cancer Medicine

• Has captured the imagination and hopes of patients, physicians, scientists, and industry

• Treatments custom-tailored to patients’ and tumors’ genetic makeup to improve survival

• Would avoid “wasted time” on ineffective strategies and also reduce toxicity

• Successes to date have been exhilarating but approach still not standard for most

State of the Union Address 2015

Precision Medicine Initiative Includes plan to collect genetic data on one million Americans so scientists can develop drugs and treatments tailored to the individual characteristics of individual patients.

$215 million Budget Request Includes: $130 million for research consortium $70 million for the NCI $10 million for the FDA $5 million for health information technology

• Goes beyond single gene test approach

• Multiplex sequencing is becoming affordable and available in a clinically relevant timeframe

• Can be done on tumor biopsy tissue or even “liquid biopsy” with CTCs or cfDNA

• Opening the door to new era of clinical cancer genomics

Corless; Science, 2011

Precision Cancer Medicine

Precision Medicine has Already Transformed the Therapeutic Approach to Lung Cancer

Traditionally lung cancer was treated according to histology A growing list of genetic alterations have helped define subgroups Molecular therapeutics to target these mutations have

demonstrated improved responses in clinical trials Companion diagnostics have been developed to match molecular

target and treatment Lung Cancer outcomes have been improved by this individualized approach to therapy

Survival of patients with an oncogenic driver mutations who received targeted therapy was >1 yr longer compared to those without a driver mutation or targeted rx

2014

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8 10

Pro

po

rtio

n S

urv

ivin

g

Years After Diagnosis

1973-79

1980-89

1990-97

Progress Towards Improving Ovarian Cancer Survival Has Been Insufficient

Progress Towards Improving Ovarian Cancer Survival Has Been Insufficient

Multiple Strategies are needed to Reduce the Number of Women Dying

from Ovarian Cancer • Improved therapeutic approaches:

Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis

Targeted agents and immunotherapies

Timing and Approach to Optimizing Cytoreductive Surgical Outcomes

• Professional and Public Education

• Early detection and Prevention



• Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis

• Targeted agents and immunotherapies

• Timing and Approach to Optimizing Cytoreductive Surgical Outcomes



Survival Correlates with Adherence to NCCN Guidelines

Stage III/IV

Women live twice as long when care is in accordance with standard guidelines (20 mos vs. 40 mos)

Bristow RE, et al: JNCI 105:825, 2013

Gynecologic Cancer Education and Awareness Act: Johanna’s Law, signed in 2007

Testimony Before the United States House of Representatives:

Gynecologic Cancer Education and Awareness Act Johanna’s Law


from Ovarian Cancer • Professional and Public Education

• Improved therapeutic approaches:

• Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis

• Targeted agents and immunotherapies

• Timing and Approach to Optimizing Cytoreductive Surgical Outcomes


Early Detection Would have a Greater Impact on Ovarian Cancer Survival than a

New Therapy for Advanced Disease

Early Detection Would have a Greater Impact on Ovarian Cancer Survival than a

New Therapy for Advanced Disease

Stage at diagnosis

5 Year Survival

Early detection alone, with current day therapies, could increase overall survival by over 100%

Most ovarian cancers are detected after they have already spread beyond the ovary and the 5 yr survival is < 30%

I II III IV 0

25

50

75

100

0

25

50

75

100

I II III IV

Thousands of Lives Could be Saved by Early Detection but an Effective Test Remains Elusive

Ovarian Cancer Screening in Asymptomatic Healthy Women (at average risk) is NOT Effective

WOMEN > 55 - 74 years

STUDY GROUP 34,253 eligible women 212 primary invasive

ovarian/tubal/peritoneal cancers 118 deaths

CONTROL GROUP 34,304 eligible women 176 ovarian/tubal/peritoneal cancers

100 deaths

• Annual screening with TVS and CA125 • Median follow up 12.4 years (10.9 -13) • No reduction in Ovarian Cancer Mortality

(odds ratio 1.18; 95%CI 0.91-1.54) • 15% (163/1080) of patients who had ‘false

positives’ went to surgery and had major complications

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial

Buys, et al. JAMA 2011

• Ovarian cancer screening cannot be recommended

in the general population

• Screening using TVU and serum CA125 was

harmful to some

• This does not mean screening for ovarian cancer is

not possible, but this strategy will not save lives.

• We need to focus our efforts on understanding the

origin and natural history of ovarian cancer and

individualize risk groups to maximize the use of

screening resources

PLCO: Implications for Clinical Practice

Buys, et al. JAMA 2011

UK Collaborative Trial of Ovarian Cancer Screening (UKTOCS) Trial

200,000 >50 years & post-

menopause

MULTIMODAL SCREEN GROUP

CA 125 50,000

CONTROL GROUP 100,000

ULTRASOUND GROUP

TV Ultrasound 50,000

OBJECTIVES

Primary: Ovarian Cancer Mortality

Secondary: Morbidity

Health Economics Quality of Life Acceptability Compliance

Additional: Serum Bank

Ian Jacobs, Usha Menon, et al

UKCTOCS Multimodal Protocol

USS

Annual CA 125

ROC Algorithm

SURGERY

ABNORMAL

INTERMED

NORMAL

Repeat CA 125

Ian Jacobs, Usha Menon, et al

Multimodality Strategy (MMS) Arm 46,237 women >50 yo

(296,911 woman-yrs of annual screens)

640 surgeries, 133 primary invasive EOCs

Sensitivity 85.8% (95% CI, 79.3%-90.9%)

Specificity 99.8% (95% CI, 99.8%-99.8%)

4.8 surgeries/invasive EOC Detected

ROCA alone detected 87.1% invasive EOCs

** Nearly double the performance of fixed cut off CA125s

May 2015

CA125 used as a “Dynamic Biomarker” Finds

More Early Cancers

No mortality data yet, but disease “downstaging” seen as a

result of MMS screening intervention:

• 41.4% invasive EOC were Stage 1 or 2 disease

• 82% were type II HGSC

Menon U, et al JCO 2015

Perhaps we need to rethink our approach…

• Early detection trials have not YET

been able to reduce mortality

• Many candidate biomarkers have

been identified but none have

performed well enough to apply to screening

• Thus far, imaging has underperformed and remains expensive

• Recent evidence points to precursor lesion in fallopian tube for high grade serous cancers

• Primary prevention may be a better strategy than early detection for the majority ovarian cancers

EOC Subtypes and Unique Characteristics

Bookman, et al. JNCI, 2014

Recent Findings Point to the Fallopian Tube as the Origin of Most HGSC

• Occult cancers found at prophylactic surgeries on BRCAmut carriers are usually seen in the fimbria of the fallopian tube

• In ovarian cancer cases, the fallopian tubes frequently contain serous tubal intraepithelial carcinoma (STIC) precursor lesions

• Virtually all STICs contain TP53 mutations identical to those seen in almost all HGSC

• Most high grade serous ovarian cancers originate in the fallopian tube

Ear

Secretory Cell Transformation and Tumor Progression in the Fallopian Tube Fimbria Results in HGSC and Peritoneal Metastasis

Ronny Drapkin, with permission

Author Number Tumor (%) Tubal Involvement (%)

Colgan (2001) 39 5 (13) 4 (80)

Leeper (2002) 30 5 (17) 3 (60)

Powell (2005) 67 7 (10) 4 (57)

Carcangiu (2006) 50 6 (12) 4 (67)

Finch (2006) 159 7 (4) 6 (86)

Callahan (2007) 100 7 (7) 7 (100)

Hirst (2009) 45 4 (9) 4 (100)

TOTAL 490 41 (8) 32 (78)

Most Occult Cancers at RRSO in BRCAmut

Carriers are in the Fallopian Tubes


Colgan (2001) 39 5 (13) 4 (80)

Leeper (2002) 30 5 (17) 3 (60)

Powell (2005) 67 7 (10) 4 (57)

Carcangiu (2006) 50 6 (12) 4 (67)

Finch (2006) 159 7 (4) 6 (86)

Callahan (2007) 100 7 (7) 7 (100)

Hirst (2009) 45 4 (9) 4 (100)

TOTAL 490 41 (8) 32 (78)




Colgan (2001) 39 5 (13) 4 (80)

Leeper (2002) 30 5 (17) 3 (60)

Powell (2005) 67 7 (10) 4 (57)

Carcangiu (2006) 50 6 (12) 4 (67)

Finch (2006) 159 7 (4) 6 (86)

Callahan (2007) 100 7 (7) 7 (100)

Hirst (2009) 45 4 (9) 4 (100)

TOTAL 490 41 (8) 32 (78)




Colgan (2001) 39 5 (13) 4 (80)

Leeper (2002) 30 5 (17) 3 (60)

Powell (2005) 67 7 (10) 4 (57)

Carcangiu (2006) 50 6 (12) 4 (67)

Finch (2006) 159 7 (4) 6 (86)

Callahan (2007) 100 7 (7) 7 (100)

Hirst (2009) 45 4 (9) 4 (100)

TOTAL 490 41 (8) 32 (78)



Kim et al. PNAS, 2012

Animal Models Further Highlight the Tubal Origin of Serous “Ovarian Cancer”

Animals with conditional Dicer-Pten deletions develop ascites, fallopian tube tumors that spread to ovaries, and have extensive peritoneal metastasis resembling human disease.

Kaplan-Meier survival curve of control and DKO animals demonstrate lethality of lesion.

Tumor histology with papillary structures and nuclear polymorphism is characteristic of HGSC

Kim et al. PNAS, 2012

Unilateral oophorectomy

Bilateral oophorectomy

Unilateral salpingectomy

Bilateral salpingectomy

Bilateral Salpingectomy Prevents Tumor Development, Metastasis and Death

Animal Models Further Highlight the Tubal Origin of Serous “Ovarian Cancer”

Ovarian Cancer May be a Preventable Disease

Serous Tubal in situ Carcinoma (STIC)

Removing the ovaries doesn’t prevent ovarian cancer, but removing the fallopian tube does.

Seems to be an important lesson there!

Salpingectomy significantly reduced ovarian cancer risk: HR 0.65 (95% CI=0.52-0.81) “Dose Response”: Bil-Salp twice as effective as Uni-Salp

HR 0.35 vs 0.71

>250,000 women who had surgery for benign indications and 5.5 million controls

Salpingectomy significantly reduced ovarian cancer risk: HR 0.65 (95% CI=0.52-0.81) “Dose Response”: Bil-Salp twice as effective as Uni-Salp

HR 0.35 vs 0.71

>250,000 women who had surgery for benign indications and 5.5 million controls

CONCLUSION: Removal of fallopian tubes by itself is an effective measure to reduce ovarian cancer risk in the general population

158 women undergoing TLH +/- BS-OR:

They assessed AMH, FSH, antral follicle count, ovarian size and blood flow (by TVS and Doppler)

April 2013


They assessed AMH, FSH, antral follicle count, ovarian size and blood flow (by TVS and Doppler)—and found no difference

April 2013



No difference in OR time, p-op Hgb, hospital stay, or recovery

April 2013



No difference in OR time, p-op Hgb, hospital stay, or recovery

CONCLUSION: BS-OR appears safe and should be widely considered to prevent ovarian cancer

April 2013

Pathologic Conditions that Could be Avoided with Routine Salpingectomy

Routine Salpingectomy Should Be A New Standard of Care

Routine Salpingectomy Should Be a New Standard of Care

• It’s safe and can prevent most ovarian cancers

• It can reduce rates of post-hysterectomy adnexal masses

• It should be performed:

– As a standard part of hysterectomy procedures

– In place of tubal ligation for sterilization

– At C-sections, if childbearing complete








Cytoreductive Surgery to NO visible disease has the greatest impact on Overall Survival

Dubois et al, Cancer, 2009

Is it Surgical Effort or Tumor Biology that determines cytoreduction status?

We need a way to reliably predict no visible residual disease preoperatively to better inform our clinical decision making

Individualize the Surgical Approach to Assess Likelihood of Optimal Cytroreduction

Women w/

suspected ovarian

cancer

Primary

Assessment

Ovarian

Cancer QI

Committee

Laparoscopy:

Validated score

R0 not

feasible

NACT

R0 feasible

Primary

TRS

Courtesy of A. Sood

Triage Laparoscopy

Optimal

Interval

Cytoreduction

Molecular Predictor of Residual Disease Could Help Direct Treatment and Improve Survival

Remission

Remission

Chemotherapy

Adjuvant RXs

Targeted +/-

Immuno- RXs

+

Tumor Signature

Or Serum Biomarkers








Molecularly Targeted Agent with Companion Diagnostic now available for some Ovarian Cancers

Cancer Immunotherapies Are Significantly Improving Treatment Responses and Survival

There are Many Opportunities for Immune Modulation in Ovarian Cancer: Especially in Certain Subtypes

Zsiros, E, et al Current Opinon-Oncology








Ovarian Cancer is Many Diseases and Molecularly Complex

Vaughan S, et al.: Nature Reviews 2011

EOC Subtypes and Unique Characteristics

Bookman, et al. JNCI, 2014

Jamal-Hanjani, M, et al. CCR, 2015

Selection pressures such as chemotherapy or microenvironment factors such as hypoxia, infiltrating stromal and immune cells can contribute to therapeutic failure and resistance

Tumor Heterogeneity and Clonal Evolution

Identifying Actionable Molecular Drivers at a Specific Point in Time Remains Challenging

• Establishing clonal dominance of a driver event from one biopsy is not trivial

• Need to determine stability of actionable alterations—both spatially and longitudinally through disease course in order to distinguish clonally dominant events

• Use of NGS for patient stratification and data interpretation will help determine drug-target interaction and response to therapy

• Need to keep in mind “inconsequential mutations” that accumulate over time, esp in hyper-mutant tumors. (Bioinformatic algorithms can help predict these somatic mutations)

Cellular and Genomic Context of Mutations to Guide Treatment Decisions

Cellular context matters: Melanomas vs Colon cancers with BRAFv600E mutations

Clonal diversity: Small cell hypercalcemic ovarian cancer vs high grade serous ovarian cancer

Acquired resistance mutations: To drug target or activated downstream or parallel pathway

Identification of Driver vs Passenger mutations

Horlings, et al, JAMA Oncology, 2015

Gerlinger M, et al.: NEJM 366:883; 2012

Tumor Heterogeneity Presents Significant

Challenge to Precision Cancer Medicine

Biopsies obtained from multiple tumor sites demonstrate marked molecular heterogeneity--with no two sites being identical.

Adapting Clinical Trials to Address Cancer Heterogeneity

• Current trials begin to address inter-patient heterogeneity—but not dynamic tumor changes or the intra-tumor clonal heterogeneity

• Frequently based on only one biopsy site, despite recognition of clonal and subclonal frequencies

• Often uses archival tissue vs freshly procured biopsy

• How do we maximize therapeutic benefits of molecular profiling information?

• Need to harness realities of cost, access to sufficient tumor tissue DNA quality/quantity

Tumor Biopsy

Sample Prep

Pathology Sequencing Analysis

Gene ALK BRAF EGFR ERBB2 PIK3CA PTEN

Status WT V600E WT WT WT WT

CLIA Pending

Sequence Results

Can this be done in a clinically relevant timeframe?

28 days

Tumor Biopsy to Sequencing Results

Roychowdhury S, et al.: Sci Transl Med; 2011

>60% tumor Tumor Biopsy

Sequencing & Analysis

Buccal swab or

Blood (germline)

Target X

Target Y

Target Z

Discovery

Trial: X

Trial: Y

Trial: Z

Basic Research

Treatment Recommendations Based on Molecular

Analysis, Targetable Genes, and Available Agents

Roychowdhury S, et al.: Sci Transl Med; 2011

Roychowdhury S, et al.: Sci Transl Med ; 2011

Treatment decisions now require a multidisciplinary discussion between clinicians, pathologists, geneticists, translational scientists and ethicists

A New Paradigm in Clinical Decision Making

Precision Cancer Medicine Clinical Trials

• Umbrella Trials: One histology (stem) but evaluates multiple predictive biomarkers (spokes) to offer drug matching under one protocol (e.g. I-SPY2, ALCHEMIST trials)

• Basket Trials: Histology agnostic but tumors share a common molecular aberration are in the same basket and matched with a targeted drug (e.g. NCI-MATCH trial)

NCI MATCH: Molecular Analysis for Therapy CHoice

NCI MATCH: Molecular Analysis for Therapy CHoice

Novel Precision Medicine Clinical Trials are Needed in Ovarian Cancer

• Trials utilizing “one size fits all” approach have yielded disappointing results—we need to move beyond Plat-S and Plat-R criteria!

• Molecular subgroups can be defined but tumor heterogeneity and adaptive changes remain poorly understood and difficult to target

• We need better (non-invasive) ways to molecularly profile tumors at recurrence (such as core biopsy(s), CTC, cfDNA, molecular imaging, etc)

• Individualized treatments to match tumors trajectory and heterogeneity are needed

Precision Cancer Medicine is Here to Stay

• Number of agents available to target molecular drivers is rapidly increasing

• Companion diagnositics enable matching of right agent to an individual patient/tumor

• Organ-agnostic clinical trials are in progress

• FDA Fast Track Designation Program was designed to get important new drugs to the patient faster

• Treatment algorithms based on molecular targets are already improving outcomes for some patients

BUT—”personalized medicine” is still a goal and not a reality for most patients. We need to advocate and fast track advances for ovarian cancer

Call to Action

• Ovarian cancer is a disease in urgent need of more effective therapies and improved outcomes

• Effective prevention and early detection strategies will offer an avenue to reduced mortality

• Molecular signatures may allow us to better triage patients to surgery and point to scientifically- informed therapeutic strategies

• “One size fits all” approaches need to be abandoned

• New insights into the tumor microenvironment, immune modulation, microbiome influences, lifestyle, etc—will further add to therapeutic success

Maintaining “Personable-ness” in Personalized Medicine: Doctoring Should Still Play a Role

Women’s Cancer Program Cedars Sinai Medical Center

Date post:	17-Aug-2015
Category:	Health & Medicine
Upload:	ovarian-cancer-national-alliance
View:	66 times
Download:	1 times

Mello Abrams Lecture: Ovarian Cancer Update: Beth Karlan, MD

Health & Medicine