Exploring New Strategies in Cervical Cancer · OCP use (adenoca > SCCA) The human papillomavirus...
Transcript of 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.
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
Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.
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
Chemotherapy Alone, n = 222
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
Grade 1-4 Grade 3-4 Bevacizumab + Chemotherapy,
n = 218
Chemotherapy Alone, n = 222
Bevacizumab + Chemotherapy,
n = 218
Chemotherapy Alone, n = 222
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% - - -
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
Grade 1-4 Grade 3-4 Bevacizumab + Chemotherapy,
n = 218
Chemotherapy Alone, n = 222
Bevacizumab + Chemotherapy,
n = 218
Chemotherapy Alone, n = 222
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% - -
Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.
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
Avastin® (bevacizumab) [prescribing information]. San Francisco, CA: Genentech, Inc.; 2014.
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
Wright AA, et al. Cancer. 2015;119(21):3776-3783.
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
Wright AA, et al. Cancer. 2015;119(21):3776-3783.
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