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Update on new treatments for recurrent cervical cancer

Ursula Matulonis, M.D.Associate Professor of Medicine, Harvard Medical SchoolDirector/Program Leader, Medical Gynecologic Oncology

Dana-Farber Cancer InstituteBoston MA

Email: Umatulonis@partners.org

Agenda

Discuss new treatments for recurrent cervical cancer:--available therapies--biologic agents and new therapies based on rationale signaling pathway aberrations

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, despite treatment.

• Urgent need to develop new therapies.

Jemal A, et al., CA Cancer J Clin, 2011

Chemotherapy for recurrent cervical cancer

• Chemotherapy agents with activity in recurrent cervical cancer: platinum (carboplatin, cisplatin)1,2

platinum doublets3,4,5

Paclitaxel6

Ifosfamide7

Topotecan8

Others: gemcitabine, VP-16, altretamine• Equivalency of carboplatin and cisplatin9,10 1Bonomi et al, JCO 1985, 2ASCO 20123Long et al, JCO 2005,4 Moore et al, JCO 2004, 5GOG 204, 6McGuire et al, JCO 1996, 7Sutton et al, Am J Obstet Gynecol 1993, 8Muderspach, Gyn Onc 2001, 9Kitagawa et al, ASCO 2012, 10Moore et al, Gyn Onc 2007

Biologic agents tested in cervical cancer

• Anti-angiogenicsBevacizumab1 Sunitinib2

Pazopanib3

• EGFR inhibitorsCetuximab4,5

--alone and in combination with cisplatinGefitinib Erlotinib -- alone and in combination with cisplatin6,7

• PDGFR inhibitorsImatinib8

• Otherscelebrex 1Monk et al, JCO 2009, 2Mackay et al, Gyn Onc 2011

3Monk et al, JCO 2010 4Santin et al, Gyn Onc 20115Farley et al, Gyn Onc 2011, 6Schilder et al, Int J Gynecol Cancer 20097Ferreira et al, ASCO 2008, 8Candelaria et al, Int J of Gyn Cancer, 2009

Bevacizumab in recurrent cervical cancer

Overall RR 11% and 6 month PFS rate of 24%

Monk et al, JCO 2009

Pazopanib vs Lapatinib versus combination

• 230 pts with recurrent cervix cancer• 1:1:1

1) pazopanib 800 mg PO daily2) lapatinib 1500 mg PO daily3) combination (pazopanib 400/lapatinib 1000 or pazopanib 800/lapatinib 1500); Combination arm eventually dropped

• Primary endpoint: PFS

Monk et al, JCO 2010

Results: PFS 18.1(P) vs 17.1(L) weeks

Monk B J , Pandite L N JCO 2011;29:4845-4845

Topotecan 0.75 mg/m2 IV days 1,2,3 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks x 6*

Paclitaxel 135 mg/m2 IV over24 hours and cisplatin 50 mg/m2 IV day 1cycles repeated q 3 weeks x 6*

Vinorelbine 30 mg/m2 IV days 1and 8 cisplatin 50 mg/m2 IV day 1cycles repeated q 3 weeks x 6

Gemcitabine 1000 mg/m2 IV, days1 and 8 along withcisplatin 50 mg/m2 IV day 1cycles repeated q 3 weeks x 6

GOG 204

JCO 2009

Eligibility:•measurable disease•GOG performance status 0-1•ANC ≥ 1500/mcl•platelets ≥100,000/mcl•serum creatinine <1.5 mg/dl•no CNS disease•no past or concomitant invasive cancer •no prior chemotherapy (unless concurrent with radiation)

Primary Stage IVB or recurrent/persistent carcinoma of the cervix

N=513

GOG 204

GOG 204 conclusions:

VC, GC, and TC are not superior to PC in terms of overall survival (OS).

However, the trend in RR, PFS, and OS favors Paclitaxel/cisplatin

Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.

GOG 240

Does addition of bevacizumab to chemotherapy improve efficacy and does a non-platinum doublet have efficacy in advanced cervical cancer?

Eligibility: • Primary Stage IVB or recurrent/persistent carcinoma of the cervix

• Measurable disease

• GOG performance status 0-1

GOG 240

GOG 240

Eligibility confirmed

Paclitaxel +cisplatin

Paclitaxel +cisplatin +bevacizumab

Paclitaxel +topotecan

Paclitaxel +topotecan +bevacizumab

Primary Endpoints: • Overall survival (OS) • Frequency and severity of toxicity

Secondary Endpoints: • Progression-free survival (PFS) • Tumor response Opened: 4/6/2009

accrual met 450 pts.

Identification of molecular alterations in subtypes

• Epidemiological shift in cervical cancer: squamous cell cancers (SCC) decreasing and adenocarcinomas (AC) rising from 5%24%.

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

• Currently SCC and AC are treated similarly.

Wang SS, et al., Cancer, 2004; Gien LT, et al., Gynecol Oncol, 2010.

A Paradigm Shift: The Genomic View of Cancer

Slide courtesy of Levi Garraway

Reported Alterations in Cervical Cancer

1Arias-Pulido H, Int J Gynecol Cancer, 2008; 2 Iida K, Br J Cancer, 2011; 3Janku F, PLoS One, 2011, 4 Bertelsen BI, Int J Cancer, 2006; 5 Pappa KI, Gynecol Oncol, 2006; 6 Kang S, Gynecol Oncol, 2007; 7 Mammas IN, Gynecol Oncol, 2004; 8

Wingo SN, PLoS One, 2009.

1Gene Sample Reported EGFR 1,2 n=89

n=111 No mutations (exons 19 and 21) No mutations; 10.2% SCC had amplification

PIK3CA 3,4 n=14 36% SCC mutations n=40 70% amplification KRAS 5,6 n=47 6.3% mutations n=258 0.7% SCC and 13.9% AC HRAS/NRAS 7 n=9 No mutations; increased gene expression STK11 (LKB1) 8 n=86 9% deletions and mutations BRAF 5,6

n=47 n=258

No mutations 0.0% SCC and 4.3% AC

Genomic analysis reveals PI3K pathway mutations

in cervical cancer

Key components of the PI3kinase pathway:

Receptor tyrosine kinasePI3kinase PTEN AKT, mTORC1 and 2

PIP2 PIP3PI3K

mTORC1

mTORC2

AKT

Many other targets that regulate:Growth, energy utilization and cell

survival

RTK

PTEN

Study Aims

1) Describe the most common oncogenic mutations in cervical cancer.2) Compare the type and frequency of somatic mutations present in cervical AC versus SCC. 3) Identify novel therapeutic targets.

Wright, ASCO 2012

“OncoMap” Strategy for Profiling Known Genomic Mutations

• Archival tumor samples examined by a gynecologic oncology pathologist. Areas >80% tumor cored and DNA extracted.

• Tumor-derived DNA was subjected to whole genome amplification, and multiplexed PCR was performed to amplify regions harboring loci of interest.

• Primer extension products were spotted onto a specially designed chip and analyzed by MALDI-TOF mass spectrometry to determine the mutation status.

• Results were validated by hME with unamplified tumor DNA.• Examined 1284 mutations in 172 genes.• Also examined PTEN loss by immunohistochemistry.

Thomas et al., Nature Genetics, 2007; MacConaill et al., PLoS One, 2009; and Dias-Santagata et al., EMBO Mol Med, 2010.

Patient Characteristics (n=78)

Age, mean (SD) 44.5 (11.0)

Race White 63 (80.8%) Black 9 (11.5%) Other 4 (5.1%)

Histology Adenocarcinoma 41 (52.6%) Squamous cell carcinoma 37 (47.4%)

Stage IA2 11 (14.1%) IB1 34 (43.5%) IB2 2 (2.6%) IIA 8 (10.2%) IIB 13 (16.7%) IIIB 5 (6.4%) IV 5 (6.4 %)

Grade Well differentiated 23 (29.5%) Moderately differentiated 32 (41.0%) Poorly differentiated 21 (21.8%)

Wright, ASCO 2012

Results

• 43/78 (55.1%) of cervical cancer specimens harbored candidate mutations.

• 6/78 (7.7%) had ≥2 co-mutations. 5/6 of these had co-mutations in exon 9 of PIK3CA; only 1 sample had coexisting PIK3CA and KRAS mutations.

• 3/48 (4.9%) had evidence of PTEN loss on immunohistochemistry (both AC and SCC).

Wright, ASCO 2012

High Rates of PIK3CA Mutations in Both AC and SCC

0 2 4 6 8

Patients

R88Q

E453k

E542K

E545K

Mut

atio

ns AC (n=41; 32%)

SCC (n=37; 35%)

Overall n=78

P=0.47

Wright, ASCO 2012

KRAS Mutations Detected in AC Only

0 1 2 3

Patients

G13D

G12V

G12D

G12A

Mut

atio

ns

AC (n=41; 17%)

SCC (n=37; 0%)

Overall n=78

P=0.004

Wright, ASCO 2012

Clinical Correlations

• We did not observe any associations between validated mutations and patient characteristics:– Stage, grade, tumor size– Lymph node involvement– Disease free survival– Overall survival

• Limited by small sample size, low frequency of events, and short follow-up time (median 27 months).

Wright, ASCO 2012

Conclusions of mutational data

• First report of a high throughput mutational analysis of cervical cancer.

• Data revealed distinct genomic alterations in SCC and AC; KRAS mutations found in AC and PIK3CA mutations found in SCC.

• This data supports the importance of further studies to better understand these mutations and exploit them for clinical use.

Wright, ASCO 2012

Conclusions: Overall

• Cervical cancer is the 2nd leading cause of cancer death in the world.

• Existing treatment for recurrent cancer has little effectiveness

• Newer therapies are needed Aberrant signaling pathwaysImmunologic therapies