exploring new strategies in cervical cancer · ocp use (adenoca > scca) the human papillomavirus...

Exploring New Strategies in Cervical Cancer

Susana M. Campos, MD, MPH Dana-Farber Cancer Institute

Boston, Massachusetts

Worldwide Incidence of Cervical Cancer

<91.5

<15.4

<33.2

<9.7

<25.3

/100.000 women Source : GLOBOCAN 2000; IARC

11,150 cases

3670 deaths

450,000 cases

250,000 deaths

Cervical Cancer

• Cervical cancer is the second leading cause of cancer deaths among women worldwide. 275,000 women die from it annually.

• Only 10%-20% of patients with recurrent or advanced disease survive 5 years.

• An estimated 12,360 cases of invasive cervical cancer are expected to be diagnosed in 2014. Median age at diagnosis is 49 years.1,2

1. SEER Stat Fact Sheets: Cervix Uteri Cancer. Available at: http://seer.cancer.gov/statfacts/html/cervix.html. Accessed April 15, 2015. 2. American Cancer Society. Cancer Facts & Figures 2014. Available at: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/. Accessed April 15, 2015.

Risk Factors for Cervical Cancer Early onset sexual activity Multiple sexual partners History of STDs History of vulvar or vaginal

dysplasia Immunosuppression Increased parity Non-white race OCP use (adenoca > SCCA)

The human papillomavirus (HPV) Type 16 and 18 DNAs have been well characterized as causative agents for cervical cancer. Two viral genes, E6 and E7. Their gene products are known to inactivate the major tumor suppressors, p53 and pRB, respectively.

HPV infection

Adenocarcinoma • Rising in incidence since 1970s

– Increasing prevalence of HPV infection

– Improvements in screening and prevention of squamous intraepithelial neoplasiahistologic shift

• HPV causal1,2

• More prominent in well-screened populations

• OCPs

Squamous • By far most common

Squamous

Adeno Small cell

Other

1. Zielinski GD, et al. J Pathol. 2003;201(4):535-543. 2. Madeleine MM, et al. Cancer Epidemiol Biomarkers Prev. 2001;10(3):171-177.

Other

• Villoglandular • Sarcoma • Glassy cell • Lymphoma • Adenosquamous

Cervical Cancer Histology

Stage 1A Preclinical invasive carcinoma diagnosed by microscopy only Stage IA1: Minimal microscopic stromal invasion <3 mm stromal invasion and less than 7 mm horizontal spread Definition: Stage IA2: Stromal invasion >3 mm but less than 5 mm and 7 mm or less in horizontal spread

Stage IB and IIA,IIB,III

Stage IB: Stage IB1: Clinical lesion no greater than 4cm Stage IB2: Clinical lesions >4 cm Stage II: Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of vagina

Stage IB2, IIA (>4 cm), IIB, IIIA, IIIB, IVA

Stage III A, B: Cervical carcinoma extends to the pelvic wall and/or involves the lower third of the vagina and /or causes hydronephrosis or non-functioning of the kidneys Stage IVA: Tumor invades the mucosa of the bladder or rectum and/or extends beyond the true pelvis

Cervical Cancer Staging

General Treatment Options IA1 Cone biopsy Simple hysterectomy IA1 w/ LVSI, IA2-IB1 Radical hysterectomy + LND IB2-IIA Chemoradiation Radical hysterectomy (controversial)

IIB-IVA Chemoradiation

IVB Palliative Chemotherapy

Robotic or Lap RH Simple Hyst + LND Sentinel Lymph node Trachelectomy + LND

Chemoradiation Studies

Study Pts Stages Regimen Survival P value

SWOG8797/GOG109*

GOG 123*

GOG 85*

RTOG 9001*

GOG 120*

NCIC*

243

369

368

388

526

253

IA2, IB, IIA

Bulky IB

IIB – IVA

IB – IVA

IIB – IVA

IB2 - IVA

ChemoRT vs RT

ChemoRT vs RT

ChemoRT vs. RT

Chemo/RT vs ExtField RT

ChemoRT vs ChemoRT

ChemoRT vs RT

80% vs 63%

83% vs 74%

55% vs 43%

73% vs 58%

66% vs 50%

62% vs 58%

.01

.01

.008

.004

.004

.002

.42

*s/p RadHyst with (+) nodes, parametrium, or margins, Cisplatin + 5FU

*Adjuvant hyst in both arms

*Cisplatin + 5FU vs hydroxyurea

*Cisplatin + 5FU

*Cisplatin vs Cisplatin + 5FU + hydroxyurea vs hydroxyurea

*No surgical staging, significant anemia in chemoRT group

Existing Treatment Strategies for Advanced Cervical Cancer

Metastatic Disease De Novo or

Distant Recurrence

Chemotherapy

Best Supportive Care

Recurrent Disease Treatment depends on location of recurrence

and can include:

Chemotherapy

Best Supportive Care

Radiation

Surgery

Results From Previous Cervical Cancer Clinical Trials

Months

Months

Response Rate, %

Cis/Pac

Cis/Topo

Cis/Vin

Cis/Gem

Cis/Pac

Cis/Topo

Cis/Vin

Cis/Gem

Cis/Pac

Cis/Topo

Cis/Vin

Cis/Gem

GOG 169

GOG 179

GOG 204 (closed

for futility)

GOG 169

GOG 179

GOG 204 (closed

for futility)

GOG 169

GOG 179

GOG 204 (closed

for futility)

2004

2009

2005

2004

2009

2005

2004

2009

2005

GOG 169: Moore DH, et al. J Clin Oncol. 2004;22(15): 3113-3119. GOG 179: Long HJ 3rd, et al. J Clin Oncol. 2005;23(21):4626-4633. GOG 204: Monk BJ, et al. J Clin Oncol. 2009;27(28): 4649-4655.

Median

OS

Median

PFS

ORR

PFS – 3.4 mo

OS – 7.3 mo

GOG 227 C

Monk BJ, et al. J Clin Oncol. 2009;27(7):1069-1074.

http://jco.ascopubs.org.ezp-prod1.hul.harvard.edu/content/vol27/issue7/images/large/zlj9990982160001.jpeg

GOG 240 Trial Design and Endpoints

Stratification factors: • Stage IVB vs recurrent/persistent disease • Performance status • Prior cisplatin treatment as radiation sensitizer

1:1:1:1

Primary endpoints • OS • Safety

Secondary endpoints • PFS • ORR

Carcinoma of the cervix • Primary stage IVB • Recurrent/persistent • Measurable disease • ECOG PS 0/1 • No prior chemotherapy

for recurrence (N = 452)

RANDOMIZE

q21d treatment to PD, toxicity,

CR

Bevacizumab + Chemotherapy

(n = 227)

Chemotherapy Alone (n = 225)

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel

Characteristic All Patients n = 452

Median age (range) 48 years (20-85) Race Caucasian Non-Caucasian

78% 22%

Prior radiation 80% Prior chemotherapy concurrent with radiation 74% Platinum-free interval of ≤6 months 32% GOG PS 0 1

58% 42%

GOG 240 Trial: Demographics and Baseline Characteristics

• Demographic and disease characteristics were balanced across study arms1

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. 1. Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.

GOG 240 Trial: Overall Survival Outcomes

Chemotherapy Alone vs Bevacizumab + Chemotherapy

Months on Study 0 6 12 18 24 30 36 42

0.0

1.0

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

Prop

ortio

n Su

rviv

ing

With a 16.8-month median OS (vs 12.9 months), Bev + chemotherapy demonstrated a statistically significant increase in

overall survival vs chemotherapy alone in the GOG 240 study

3.9-month increase in median OS

(HR = 0.74 [95% CI, 0.58-0.94] P = .0132)

Bev + chemotherapy (n = 227) Chemotherapy alone (n = 225)

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. Tewari KS, et al. N Engl J Med. 2014;370(8):734-743. Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.

GOG 240 Trial: Summary of Clinical Efficacy

Median Overall Survival

Median Progression-Free

Survival

Overall Response Rate

16.8 8.3 45.4% months

(vs 12.9 months with chemotherapy alone)

(HR = 0.74 [95% CI, 0.58-0.94],

P = .0132)

months (vs 6.0 months with

chemotherapy alone) (HR = 0.66

[95% CI, 0.54-0.81], P<.0001)

(vs 33.8% with chemotherapy alone) (Difference 11.60%)

[95% CI for difference, 2.4-20.8], P = .0117)

Bevacizumab plus chemotherapy demonstrated statistically significant increases in OS, PFS, and ORR compared to chemotherapy alone.

Bev plus chemotherapy demonstrated: • A median OS increase of 3.9 months vs chemotherapy alone • A 38% increase in progression-free survival vs chemotherapy alone (8.3 vs 6.0 months) • Double the number of complete responses vs chemotherapy alone (19 vs 9)

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. Tewari KS, et al. N Engl J Med. 2014;370(8):734-743. Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.

GOG 240 Trial Efficacy Results: Chemotherapy vs Chemotherapy +

Bevacizumab

aKaplan-Meier estimates bLog-rank test (stratified)

Chemotherapy + Bevacizumab

n = 227

Chemotherapy n = 225

Overall Survival Median OS, monthsa 16.8 12.9 Hazard ratio [95% CI] P valueb

0.74 [0.58;0.94] .0132

Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.

Topotecan/Paclitaxel +/- Bevacizumab

(n = 223)

Cisplatin/Paclitaxel +/- Bevacizumab

(n = 229)

GOG 240 Trial: Platinum Doublet vs Nonplatinum Doublet Chemotherapy Backbone

• OS results by chemotherapy regimen (platinum doublet vs nonplatinum doublet) were also evaluated in the GOG 240 study, regardless of combination with bevacizumab

ORR, objective response rate Tewari KS, et al. N Engl J Med. 2014;370(8):734-743.

Stratification factors: • Stage IVB vs recurrent/persistent disease • Performance status (PS) • Prior cisplatin treatment as radiation

sensitizer

Primary endpoint: • OS

Secondary endpoint: • ORR

Carcinoma of the cervix • Primary stage IVB • Recurrent/persistent • Measurable disease • GOG PS 0-1 • No prior

chemotherapy for recurrence

(N = 452)

RANDOMIZE

GOG 240 Trial Efficacy Results: Platinum Doublet vs Nonplatinum

Doublet

• The study results for overall survival for patients who received the non-platinum doublet vs the platinum doublet show no statistical difference in OS between the two chemotherapy backbones

aKaplan-Meier estimates

Topotecan + Paclitaxel +/- Bevacizumab

n = 223

Cisplatin + Paclitaxel +/- Bevacizumab

n = 229 Overall Survival Median, monthsa 13.3 15.5 Hazard ratio [95% CI] P value

1.15 [0.91, 1.46] .23


National Comprehensive Cancer Network (NCCN) Guidelines

• Bevacizumab plus chemotherapy is included in the National Comprehensive Cancer Network (NCCN) recommendations for the first-line treatment of advanced cervical cancer

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in OncologyTM: Cervical Cancer. V.2.2015. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf . Accessed April 15, 2015.

Category 1

Category 1

Bevacizumab + cisplatin/paclitaxel

Bevacizumab + topotecan/paclitaxel

Grade 1-4 and 3-4 Adverse Events Observed in the GOG 240 Trial (Incidence Difference of ≥5% Between Treatment

Arms)

Adverse Event

Grade 1-4 Grade 3-4 Bevacizumab + Chemotherapy,

n = 218

Chemotherapy Alone, n = 222

Bevacizumab + Chemotherapy,

n = 218


Metabolism and nutrition disorders

Decreased appetite 34% 26% - -

Hyperglycemia 26% 19% - -

Hypomagnesemia 24% 15% - -

Hyponatremia 19% 10% - -

Hypoalbuminemia 16% 11% - -

General disorders and administration site conditions

Fatigue 80% 75% - -

Edema peripheral 15% 22% - -

Investigations

Weight decreased 21% 7% - -

Blood creatinine increased 16% 10% - -

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.

Grade 1-4 and 3-4 Adverse Events Observed in the GOG 240 Trial (Incidence Difference of ≥5% Between Treatment Arms)

Adverse Event


n = 218



n = 218


Infections and infestations

Urinary tract infection 22% 14% - -

Infection 10% 5% - -

Vascular disorders

Hypertension 29% 6% 11.5% 0.5%

Thrombosis 10% 3% 8.3% 2.7%

Nervous system disorders

Headache 22% 13% - -

Dysarthria 8% 1% - -

Gastrointestinal disorders

Stomatitis 15% 10% - -

Proctalgia 6% 1% - -

Anal fistula 6% - - -


Grade 1-4 and 3-4 Adverse Events Observed in the GOG 240 Trial (Incidence Difference of ≥5% Between Treatment Arms)

Adverse Event


n = 218



n = 218


Blood and lymphatic system disorders

Neutropenia 12% 6% - -

Lymphopenia 12% 5% - -

Psychiatric disorders

Anxiety 17% 10% - -

Reproductive system and breast disorders

Pelvic pain 14% 8% - -

Respiratory, thoracic, and mediastinal disorders

Epistaxis 17% 1% - -

Renal and urinary disorders

Proteinuria 10% 3% - -


Gastrointestinal-Vaginal Fistulae Reported in the GOG 240 Study

• The incidence of gastrointestinal-vaginal fistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation

• The majority of gastrointestinal perforations reported during the study were gastrointestinal-vaginal fistulae (15 out of 22)

• <1% of patients in the bevacizumab plus chemotherapy arm had grade 5 gastrointestinal perforation

• All patients with gastrointestinal perforations had a history of prior pelvic radiation


Genomic Profiling

Clinical Differences Between AC and SCC

• AC worse prognosis: independent risk factor for recurrence, 10%-20% lower 5-year OS, and higher rates of local and distant spread.

• Currently, AC and SCC are treated the same.

Characteristic Adenocarcinoma (AC)

Squamous Cell Carcinoma (SCC)

HPV Infection, % HPV-16 (+) HPV-18 (+)

72 64 50

85 73 15

Smoking is a RF No Yes Nodal metastases, % 32 15 Ovarian metastases, % 5 0.8

Look KY, et al. Gynecol Oncol. 1996;63(3):304-311. Samlal RA, et al. Cancer. 1997;80(7):1234-1240. Galic V, et al. Gynecol Oncol. 2012;125(2):287-291. Park JY, et al. Br J Cancer. 2010;102(12):1692-1698.

Reported Alterations in Cervical Cancer Gene Sample Reported

EGFR1,2 n = 89 n = 111

No mutations (exons 19 and 21) No mutations; 10.2% of SCC had amplification

PIK3CA3,4 n = 14 n = 40

36% SCC mutations 70% amplification

KRAS5,6 n = 47 n = 258

6.3% mutations 0.7% SCC and 13.9% AC

HRAS/NRAS7 n = 9 No mutations; increased gene expression

STK11 (LKB1)8 n = 86 9% deletions and mutations

BRAF5,6 n = 47 n = 258

No mutations 0% SCC and 4.3% AC

1. Arias-Pulido H, et al. Int J Gynecol Cancer. 2008;18(4):749-754. 2. Iida K, et al. Br J Cancer. 2011;105(3):420-427. 3. Janku F, et al. PLoS One. 2011;6(7): e22769. 4. Bertelsen BI, et al. Int J Cancer. 2006;118(8):1877-1883. 5. Pappa KI, et al. Gynecol Oncol. 2006;100(3);596-600. 6. Kang S, et al. Gynecol Oncol. 2007;105(3):662-666. 7. Mammas IN, et al. Gynecol Oncol. 2004;92(3):941-948. 8. Wingo SN, et al. PLoS One. 2009;4(4):e5137.

“OncoMap” Strategy for Profiling Genomic Mutations

• Examined 1250 mutations in 139 genes • 80 archival tumor samples; areas >80% tumor cored and DNA

extracted • Tumor-derived DNA was subjected to whole genome

amplification; multiplexed PCR performed to amplify regions harboring loci of interest

• MALDI-TOF mass spectrometry used to determine the mutation status

• Results validated by hME with unamplified tumor DNA • EGFR mutations further validated by massive parallel

sequencing (Illumina) • HPV genotyping performed with F-HPV typing™ • PTEN loss examined by IHC

Thomas RK, et al. Nature Genetics. 2007;39(3):347-351. MacConaill LE, et al. PLoS One. 2009;4(11):e7887. Dias-Santagata D, et al. EMBO Mol Med. 2010;2(5):146-158.

PIK3CA Mutations in Both AC and SCC

Gene

Total N = 80

SCC N = 40

AC N = 40

P Value

PIK3CA 31.3% 37.5% 25.0% .33

E542K 12.5% 15.0% 10.0%

E545K 20.0% 25.0% 15.0%

E453K/3R88Q 2.6% 0.0% 5.0%

PTEN loss 7.8% 13.0% 3.6% .32

Wright AA, et al. Cancer. 2015;119(21):3776-3783.

KRAS Mutations Only Found in AC

Gene

Total N = 80

SCC N = 40

AC N = 40

P Value

KRAS 8.8% 0.0% 17.5% .01

G12A 1.3% 0.0% 2.5%

G12D 3.8% 0.0% 7.5%

G12V 2.5% 0.0% 5.0%

G13D 1.3% 0.0% 2.5%

EGFR 3.8% 7.5% 0.0% .24


PIK3CA Mutations Confer Survival Disadvantage

0 50 100 150 200

0.00.2

0.40.6

0.81.0

Months from Diagnosis

Survi

val P

robab

ility

No PIK3CA MutationsAt least one PIK3CA mutation

Number at Risk No PIK3CA 55 16 1 PIK3CA 25 9 1

Median overall survival: 67.1 vs. 90.3 months


Clinical Correlations

• PIK3CA mutations associated with shorter survival (67.1 months versus 90.3 months) in analyses adjusted for stage and nodal involvement

• KRAS mutations not associated with survival

PI3-Kinase Inhibitors Should Be Explored in Cervical Cancer

• PIK3CA mutations were present in 31%, across histologic subtypes, and were associated with decreased survival.

McIntyre JB, et al. Gynecol Oncol. 2013;128(3):409-414; Schwarz JK, et al. Clin Cancer Res. 2012;18(5):464-471; Janku F, et al. J Clin Oncol. 2012;30(9):777-782; Catalogue of Somatic Mutations in Cancer (COSMIC). Available at: http://cancer.sanger.ac.uk/cosmic; National Institutes of Health. www.clinicaltrials.gov.

Cancer

PIK3CA Mutation

Rate

Registered

Trials

Breast 26% 24

Uterine 24% 9

Colon 12% 7

Ovary 10% 6

Cervix 10% 1

Distinct Genomic Alterations in AC and SCC

• KRAS mutations were detected exclusively in AC in 17.5% of samples

• Most were missense mutations of codon G12, activating mutations; may explain resistance to EGFR-targeted therapies in past trials

• Future studies should explore whether KRAS mutations have prognostic or therapeutic implications in cervical cancer.

Goncalves A, et al. Gynecol Oncol. 2008.;108(1):42-46. Schilder RJ, et al. Int J Gynecol Cancer. 2009;19(5):929-933. Santin AD, et al. Gynecol Oncol, 2011;122(3):495-500. Wegman P, et al. Int J Gynecol Cancer. 2011;21(1):86-91. Zimmerman G, et al. Nature. 2013. Jänne PA, et al. Lancet Oncol, 2013;14(1):38-47.

Conclusions • Cervical cancer survival: improved by the

addition of bevacizumab

• Data reveal distinct genomic alterations in SCC and AC, which should encourage further studies to better understand these mutations and exploit them for clinical use

• Efforts to identify distinct molecular sub-populations within cervical cancer may allow us to better tailor treatment strategies (eg, incorporating PI3K and MEK inhibitors)

Worldwide incidence of cervical cancer

< 91.5

< 15.4

< 33.2

< 9.7

< 25.3

/100.000 women

11, 150 cases

3,670 deaths

450,000 cases

250,000 deaths

HPV vaccine

Source : GLOBOCAN 2000; IARC

exploring new strategies in cervical cancer · ocp use (adenoca > scca) the human papillomavirus...

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