Anal Cancer in Women and the Human Papilloma Virus

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Anal Cancer in Women and the Human Papilloma Virus




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Presentations text content in Anal Cancer in Women and the Human Papilloma Virus

Slide1

Anal Cancer in Women and the Human Papilloma Virus

Kimberly Perez, MD

Gastrointestinal Medical Oncology

November 6, 2015

Slide2

Disclosures

I

have no relationships to

disclose.

I

will

discuss the use vaccines in a manner not approved by the U.S. Food and Drug Administration.

But in accordance with ACIP recommendations.

Slide3

Epidemiology: Anal Cancer in Women

Represents 0.4% of all new cancer cases in the United States.Incidence is 1.8 per 100,000 persons overall, with 2 per 100,000 in women.Incidence has been rising 2.2%/year in men and women.It is estimated that 4,630 women in 2015 will be diagnosed with anal cancer in the United States, and 610 will die of their disease.

American Cancer Society, 2015

Slide4

Human Papilloma Virus – HPV

Genome consists of a circular double-stranded DNA molecule of ~8000bp

HPV types differ by >10% in the LI gene sequence

199 different HPV types have been fully sequenced, and nearly all cluster into three genera: α-HPV, β-HPV, and

γ

-HPV

α

-HPV isolate from mucosal and genital lesions; β and

γ

isolate from skin

Slide5

Anal cancer and HPV

Distribution of HPV genotypes in the anus is more heterogeneous than in the cervix, and it has been demonstrated that a greater proportion are of low-risk HPV types

Most common non-oncogenic HPV-53 and -66

Most common oncogenic HPV-51, -52 and -16

Detection of anal HPV

i

s associated with:

a higher lifetime number of anal and vaginal sex partners

younger age at first anal intercourse

history of Chlamydia and

anogenital

warts.

Slide6

Types by histologic/genomic subtypes

Castro et al. J Infect Dis. 2012; 206: 1103

Overall Distribution, Overall Prevalence of HPV among 2107 Young Adult Women from Costa Rica

Slide7

Mechanism of HPV Infection

Progression of infection is similar to cervical cancer which occurs over 1 to 3 decades.

Persistent infectio

n

of the

same HPV type

leads to high-grade squamous intraepithelial anal lesions eventually resulting in anal

cancer

Despite

this similarity, cervical cancer is 4 times more common than anal cancer. This may be due to higher clearance rate in anal cancer.

Slide8

Clearance of HPV anal infections

87% of anal HPV infections are cleared within the 1st yearRate of clearance of HPV from those with HPV anal infection: 9.2 per 100 woman-months with a median duration of 150 days. Slowest clearance were HPV-59 (350 days) and HPV-58 (252 days). Median clearance for HPV-16 and -18 were 123 and 212 days respectively.

Clin

Infect Dis. 2009; 48(5): 536

Slide9

Sequential cervical and anal HPV infection

Acquisition of anal HPV infection increases significantly among women with a cervical HPV co-infection with 1 or more additional HPV typesRisk of incidental cervical HPV infection increases significantly among women with an anal HPV infection of 1 or more additional HPV types compared to women without a preceding anal HPV infection.Risk of acquisition of a new anal HPV infection increased 20-29% among women with an cervical co-infection with any HPV type

Goodman et al. The Journal of Infectious Diseases 2011; 203: 335-340

Castro et al. J Infect Dis. 2012; 206; 1103

Slide10

Cancer Risk based on HPV subtype

Relative Risk varied by phylogenetic speciesα3/α15 and α1/α8/α10 types are associated with a greater likelihood of infecting the anus among women with a preceding same-type infection at the cervix.Risk of cervical HPV infection following an anal HPV infection with a concordant genotype was 8.8 (95% CI: 6.4-12.2). α 9/α11 had a slightly higher probability than other HPV types

Goodman et al. J Infect Dis 2011; 201(9): 1331

Slide11

Co-infection correlation with cervical cancer

Veo

et al. Tumor Biol. 2015; 36: 5399

Slide12

Prognostic implications

Single-institution, retrospective analysis50 patients; stage I-III anal squamous cell carcinoma treated with concurrent chemotherapy and radiation84% were HPV+ (90% HPV-16)HPV+ had more advanced disease at diagnosis (stage IIIA 45.2%, stage IIIB 28.6%) compared to HPV- (stage IIIA 37.5%, stage IIIB 0%)Results:5yr DFS – HPV+ 92.5% vs HPV- 50%5yr OS – HPV+ 93.3% vs HPV- 66.7%

Rivenda

et al.

ecancer

. 2015; 9:529

Slide13

Therapeutic Implications

- 9-valent HPV Vaccine

- ADVAXIS immunotherapy–

BrUOG

study

Slide14

Will the 9-valent vaccine impact the incidence of anal cancer?

Serrano et al.

Eur J of Cancer. 2015; 51:1732

Slide15

ADXS11-001 Lm-LLO Immunotherapy and Chemo/IMRT for Anal Cancer

Kimberly Perez, Howard Safran, Kara-Lynne Leonard, Thomas Dipetrillo, Nicholas Oldenburg, Adam Klipfel, Steven Schecter, Matthew Vrees, Leslie Roth, Nishit Shah, Lakshmi Rajdev, Kayla RosatiBrown UniversityOncology Group Research Consortium

Slide16

ADXS11-001

HPV DNA is present in the majority of anal cancer ADXS11-0011 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete an HPV-16 E7 protein fused with a truncated fragment of listeriolysin O (tLLO) tLLO is a virulence factor of Lm. It enables the bacterium to escape from the phagolysosome.Innate powerful immune response to Lm, especially to listeriolysin (tLLO). Unlike peptides or viruses, there is no immune tolerance or neutralizing antibodiesBiosafety level 1-2. No fecal, urine shedding or person-to-person transmission; vector cleared within 24 hours with antibiotics.

Slide17

ADXS11-001 Is Taken Up By Antigen Presenting Cells (APC)

After infusion of

Lm-LLO immunotherapy, Lm are taken up by APC. Since listeriolysin can break through the phagolysosome, the fusion protein tLLO-E7 is free in the cytoplasm of APC and activate MHC class I and class II immune responsesHPV transformed tumors now “seen” as pathogen-infected and targeted by T-Cells

Slide18

ADXS11-001 with mitomycin/5-FU/IMRT for Locally Advanced Anal Cancer: Brown University Study

Premeds with Naprosyn (500 mg BID, day -1 & 0) & Promethazine (25 mg BID, predose 8 hr)Ampicillin is given day 3-9 after each ADXS11-001 dose

N = 25Primary stage II-III anal cancerHigh risk of recurrenceHPV-positive

ADXS11-001

1x109 cfu x 4 (1 prior to chemoRT and 3 post, q 28 days) as a 500 ml infusion over 30 min

ADXS11-001 #1

Day -10 to 14

Mito/5-FU

ADXS11-001 #2Day +10 post IMRT

6 weeks IMRT

28 days

Open Label

Phase 1/2 Study

Primary Efficacy Endpoint:

6-month CR-rate

Mito/5-FU

28 days

Follow up

ADXS11-001 #3

ADXS11-001 #4

Biopsy

Diagnosis

Biopsy

6

months

Slide19

Patient Characteristics (N=11)

Age, yearsNo. <50 1>50 but <75 9Median62Range37-71Sex Male5Female6Stage II4III7Lymph node involvement N06N10N21N34

Slide20

ADXS11-001 Related Toxicities

Acute Grade 3 toxicities related to ADXS11-001: Chills/rigors (N=2)Back pain (N=1) All toxicities were within 24 hours of dosing

*These AEs occurred during dosing time point but are also included with overall AEs.

Slide21

Preliminary RFS Data

Relapse Free

Survival (Days)*

T3N3

T2N2

T4N0

T3N3

T4N0

T3N3

T3N0

*

as of

Sep 27, 2015

T2N0

T3N0

T4N3

Note: Patient #1 enrolled but was never treated on study

Patient expired unrelated to study treatment

Patient progressed systemically

Slide22

Conclusion

It is common for anal and cervical HPV infections to occur consecutively

The high degree of genotype-specific concordance indicates a common source of infection.

HPV+ anal carcinoma may be associated with an improved prognosis.

Due to the significant correlation between anal cancer and HPV, immunotherapy will be playing a larger role in therapeutic protocols.

Slide23


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