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Cancer/Pathology

WIHS Cancer Summary 2-4-13 page 1

WIHS V CANCER PROJECT SUMMARY 2/4/2013 [HPV is reported separately]

Overarching aims Aim 1. To determine if the incidence of specific types of cancers is increased among HIV-infected women as compared to HIV-uninfected women and to the general population, and whether cancer incidence and survival are affected by use of HAART. Aim 2: To investigate risk factors for specific cancers (breast, cervical, lung cancer, and non-Hodgkin lymphoma) with an emphasis on potential strategies for cancer prevention and cancer therapy. Aim 3. To collect fresh-frozen tissue from biopsies of the cervix, vagina, and vulva and accompanying blood specimens and oral rinses for donation to the NCI-sponsored AIDS Cancer and Specimen Resource (ACSR). For select malignancies, to collect and donate paraffin-embedded formalin-fixed tissue specimens from WIHS women with confirmed incident cancers. Overall Research Design and Methods: For the start of WIHS V, there are no newly proposed cancer-specific concept sheets that have requested additional funding. There are, however, several existing cancer and HPV-related projects that require the current infrastructure and activities outlined below.

We will continue to identify and confirm all cancers that occur in the WIHS participants using the following ascertainment methods: (1) searches of statewide cancer registries, (2) medical record confirmation of self-reported cancer diagnoses, and (3) WIHS-initiated gynecologic biopsies. Cancers that are initially identified by self-report or death certificate via a National Death Index (NDI) search will be classified as ‘confirmed cancers’ only if they are subsequently confirmed by medical record review or cancer registry matching. The state cancer registry matches are performed every two years and the NDI is matched every year.

We will document the diagnosis date, primary site/tumor type, and cancer treatment information for each cancer identified from the medical records or the WIHS gynecologic biopsy. For all cancers documented via the state cancer registries, we also obtain the ICD-O-3 coded tumor site, histological type, tumor behavior (in-situ or malignant), and treatment information directly from the registry. The Cancer WG will continue to attempt to obtain detailed pathology reports and, when deemed necessary, available biopsy specimens to confirm or refute the information obtained from the original source.

WIHS continues to be a major donator to the ACSR of tissue, blood, and oral rinses from HIV-infected and comparative group of HIV-uninfected women. Our protocol involves donations from at least 10 women per WIHS site, per WIHS visit, who undergo colposcopy. If a lesion is present, the colposcopist is to biopsy the lesion, split it in two, send one section for clinical pathology review and flash-freeze the other section in liquid nitrogen. Another biopsy of nonlesion tissue is then collected and flash-frozen; also blood is collected for plasma and PBMCs, and an oral rinse is collected and frozen. These specimens are then sent to either the west coast or east coast ACSR repository according to the WHIS protocol. Corresponding demographic and clinical data are also transmitted to the ACSR by the WIHS data center (WDMAC). Progress highlights: During WIHS IV, we were able to look more closely as specific cancers, such as cervical, lung and breast, and below are three examples of these investigations.

Long-term incidence of cervical cancer in women with human immunodeficiency virus. Massad LS, Seaberg EC, Watts DH, Minkoff H, Levine AM, Henry D, Colie C, Darragh TM, Hessol NA. Cancer. 2009 Feb 1;115(3):524-30. Massad et al. reported that among women with HIV in a prospective study that incorporated cervical cancer prevention measures, the incidence of invasive cervical cancer (ICC) was not significantly higher than that in a comparison group of HIV-uninfected women.

HIV as a risk factor for lung cancer in women: data from the Women's Interagency HIV Study. Levine AM, Seaberg EC, Hessol NA, Preston-Martin S, Silver S, Cohen MH, Anastos K, Minkoff H, Orenstein J, Dominguez G, Watts DH. J Clin Oncol. 2010 Mar 20;28(9):1514-9. Levine et al. reported that the incidence rates of lung cancer were similar among HIV-infected and uninfected WIHS women. Lung cancer standardized incidence ratios (SIRs) were increased in both HIV-infected and -uninfected women compared with population expectations, but did not differ by HIV status. Among HIV-infected women, lung cancer incidence rates were similar in pre-HAART and HAART eras.

http://www.ncbi.nlm.nih.gov/pubmed/19127538


WIHS Cancer Summary 2-4-13 page 2

HIV tropism and decreased risk of breast cancer. Hessol NA, Napolitano LA, Smith D, Lie Y, Levine A, Young M, Cohen M, Minkoff H, Anastos K, D'Souza G, Greenblatt RM, Goedert JJ. PLoS One. 2010 Dec 16;5(12):e14349. Hessol and colleagues used both WIHS and HERS data and found that low breast cancer risk with among women with HIV infection was specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells.

For WIHS IV a heightened focused was placed on collaborations to increase the power and scientific validity of the cancer initiatives. Below are two recent publications resulting from the NA-ACCORD collaboration.

Invasive cervical cancer risk among HIV-infected women: A North American multi-cohort collaboration prospective study. Abraham AG, Strickler HD, Jing Y, Gange SJ, Sterling TR, Silverberg M, Saag M, Rourke S, Rachlis A, Napravnik S, Moore RD, Klein M, Kitahata M, Kirk G, Hogg R, Hessol NA, Goedert JJ, Gill MJ, Gebo K, Eron JJ, Engels EA, Dubrow R, Crane HM, Brooks JT, Bosch R, D'Souza G; for the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA. J Acquir Immune Defic Syndr. 2012 Dec 18. This study found elevated incidence of ICC in HIV-infected compared to -uninfected women, and these rates increased with immunosuppression.

Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Silverberg MJ, Lau B, Justice AC, Engels E, Gill MJ, Goedert JJ, Kirk GD, D'Souza G, Bosch RJ, Brooks JT, Napravnik S, Hessol NA, Jacobson LP, Kitahata MM, Klein MB, Moore RD, Rodriguez B, Rourke SB, Saag MS, Sterling TR, Gebo KA, Press N, Martin JN, Dubrow R; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA. Clin Infect Dis. 2012 Apr;54(7):1026-34. Investigators reported that anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued. Collaborations within and external to WIHS: The WIHS Cancer/Pathology working group works closely with the WIHS HPV working group (many of the members overlap) to ensure the WIHS data is collected and used to the best of its ability and that newly proposed projects do not overlap. The Chairs of the WIHS Cancer/ Pathology and MACS Malignancy working groups are also in close contact and are members of both working groups. In addition, the Chairs of the WIHS Cancer/Pathology and HPV working groups are active members of the NA-ACCORD Malignancy working group and serve as advisors to the NA-ACCORD regarding the WIHS. Collaborations with funding external to WIHS: The WIHS will continue to serve as a platform for RO-1 related studies; two recently funded studies are described below.

Strickler H, PI. Grant title: Molecular Methods for Cervical Cancer Screening in HIV+ Women. The overall specific aims are: 1) to determine the relative sensitivity, specificity, PPV, and NPV of several promising molecular assays for detection of cervical pre-cancer in HIV(+) women; 2) to assess these assays in combination with one another as well as in combination with routine cytology and HC2, to determine the optimal cervical cancer screening approach in HIV(+) women; 3) to collect and store appropriate specimens from HIV(+) women to test future cervical cancer screening methods when they become available.

Silverberg M, Dubrow R, PIs. Grant title: Antiretroviral therapy strategies to lower cancer risk in HIV-infected persons. The overarching goal of the current proposal is to formulate evidence-based recommendations about the optimal CD4 T-cell count at which to initiate ART and the optimal ART regimen, in order to would minimize cancer incidence among HIV-infected persons. New Directions for WIHS V: Now that WIHS follow-up time has increased, the numbers of new cancers has grown, and the study population is reaching the age where rate of several common tumors begins to rapidly rise, we are better positioned to evaluate the impact of host and viral risk factors on these malignancies. One new area of investigation for the WIHS focuses on modifiable risk factors for cancer which could lead to interventional studies of cancer prevention. Another area leverages the recently completed genotyping of five million single nucleotide polymorphisms (SNPs) in all participants, which will permit the identification of risk alleles for ancestry and candidate genes associated with cancer risk.





HIV Tropism and Decreased Risk of Breast CancerNancy A. Hessol1, Laura A. Napolitano2,3, Dawn Smith4, Yolanda Lie2, Alexandra Levine5,12, Mary

Young6, Mardge Cohen7, Howard Minkoff8, Kathryn Anastos9, Gypsyamber D’Souza10, Ruth M.

Greenblatt1, James J. Goedert11*

1 Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, United States of America, 2 Monogram Biosciences, South San

Francisco, California, United States of America, 3 Department of Medicine, University of California San Francisco, San Francisco, California, United States of America,

4 Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America, 5 City of Hope National Medical Center, Duarte, California, United States of

America, 6 Georgetown University School of Medicine, Washington D.C., United States of America, 7 Departments of Medicine, Stroger Hospital and Rush University,

Chicago, Illinois, United States of America, 8 Maimonides Medical Center and State University of New York, Health Sciences Center at Brooklyn, Brooklyn, New York, United

States of America, 9 Montefiore Medical Center, Bronx, New York, United States of America, 10 Johns Hopkins School of Public Health, Baltimore, Maryland, United States

of America, 11 Infections & Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH),

Bethesda, Maryland, United States of America, 12 Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America

Abstract

Background: During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk wassignificantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. Thisdeficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing orother breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 orCXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIVenvelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, wehypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.

Methods and Findings: We conducted a breast cancer nested case-control study among women who participated in theWIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women(mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load$500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age andplasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95%confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breastcancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly andindependently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002–0.84) and with menopause (adjustedodds ratio, 0.08, 95% CI 0.001–0.83). Adjustment for CD4+ cell count, HIV viral load, and use of antiretroviral therapy did notattenuate the association between infection with CXCR4-tropic HIV and breast cancer.

Conclusions: Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thoughtto exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast ductcells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breastcancer risk.

Citation: Hessol NA, Napolitano LA, Smith D, Lie Y, Levine A, et al. (2010) HIV Tropism and Decreased Risk of Breast Cancer. PLoS ONE 5(12): e14349. doi:10.1371/journal.pone.0014349

Editor: Genevieve Chene, INSERM, France

Received July 16, 2010; Accepted November 19, 2010; Published December 16, 2010

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the publicdomain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Funding: Funded in part by the Intramural Research Program of the National Cancer Institute (JJG), by other components of the National Institutes of Health, andby the Centers for Disease Control and Prevention. The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834,UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development(UO1-HD-32632). The WIHS is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and OtherCommunication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The HIVEpidemiology Research Study (HERS) was funded through Centers for Disease Control and Prevention cooperative agreements U64/CCU106795, U64/CCU206798,U64/CCU306802, and U64/CCU506831. Monogram Biosciences supported tropism testing and all assays were performed by the Monogram Clinical ReferenceLaboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: Two authors, LAN and YL, are employed by Monogram Biosciences. All other authors declare that they have no competing interests. Thisdoes not alter the authors’ adherence to all PLoS ONE policies on sharing data and materials.

* E-mail: [email protected]

Introduction

Human immunodeficiency virus type-1 (HIV) envelope protein

binds to the CD4 receptor and to chemokine coreceptors CCR5 or

CXCR4, leading to infection and destruction of the CD4-bearing

immune cells: T lymphocytes and macrophages [1]. Although HIV

infection increases the risk of several malignancies,[2] from 1980–

2002 breast cancer risk in the United States was 31% lower among

women with AIDS compared to the general population [3]. This

cancer deficit was unrelated to crude measures of immune

deficiency, was most pronounced before 1990, and gradually

disappeared with improving antiretroviral therapy (ART) [3].

PLoS ONE | www.plosone.org 1 December 2010 | Volume 5 | Issue 12 | e14349

The CXCR4 receptor is commonly expressed not only on

immune cells, but also on hyperplastic and especially on malignant

breast duct cells [4–6]. CXCR4 may play an essential role in

metastasis and, indirectly, earlier stages of tumor growth [4,5,7–9].

Linking HIV with breast cancer was the observation that

programmed cell death (apoptosis) was induced in human breast

cancer cell lines through binding of CXCR4-tropic, but not

CCR5-tropic, HIV envelope protein [10]. Based on both the

pattern of breast cancer risk in women with AIDS and the in vitro

findings that CXCR4-tropic HIV induced apoptosis of breast

cancer cells, we postulated that HIV strains tropic for CXCR4

may account for the reduction in breast cancer observed in HIV-

infected women. To test this hypothesis, we studied HIV tropism

in women with breast cancer and in matched controls.

Methods

Cohorts, Covariate Data and Specimens, and EthicsStatement

The study population was drawn from two large multisite

longitudinal studies of HIV infection in women in the United

States, the Women’s Interagency HIV Study (WIHS) and the HIV

Epidemiology Research Study (HERS). Study protocols were

reviewed and approved by the institutional review boards, and

written informed consent was obtained from the participants.

The WIHS is a prospective study of HIV infection in women,

conducted in New York City, Washington D.C., Chicago,

Southern California and the San Francisco Bay Area. The WIHS

methods and baseline cohort characteristics have been previously

described [11]. Briefly, between October 1994 and November

1995, 2056 HIV-infected and 569 uninfected women were

enrolled. A second enrollment between October 2001 and

September 2002, added 737 HIV-infected and 406 HIV-

uninfected women [12]. Follow-up of the women enrolled in the

WIHS is ongoing.

The HERS was a collaborative, multicenter (Baltimore, MD;

Bronx, NY; Providence, RI; and Detroit, MI) prospective study

that enrolled 871 HIV-seropositive and 439 HIV-seronegative

women with acknowledged HIV risk behavior from April 1993 to

January 1995. Women were enrolled on the basis of either

injection drug-use or sexual risk, as has been reported previously

[13]. Follow-up of the women enrolled in the HERS ended in

March 2000.

The WIHS and HERS protocols for core study visits and the

questionnaires used were, by design, extremely similar. At every

six month core visit, women participants were interviewed,

received a physical examination, and provided multiple gyneco-

logic and blood specimens. Among HIV-infected women, blood

samples collected at the core study visit were tested for CD4+

lymphocytes and HIV RNA load.

Selection of Cases and ControlsBreast cancer cases were identified and confirmed through

medical records and state cancer registry matches, and date of

diagnosis determined. In the WIHS, cancers were identified from

January 1993 through June 2009 and in the HERS from April

1993 through March 2000. Cases for the current investigation

were HIV-infected women for whom we had stored plasma

samples that were within 24 months (either before or after) of their

cancer diagnosis and in which the HIV RNA viral load was 500

copies/mL or greater. A random sample program selected three

HIV-infected control women who did not have breast cancer, had

HIV RNA viral loads $500 copies/mL, and who matched to each

case based on cohort, age (plus or minus 2 years), and date of

plasma specimen collection (within six months).

HIV Tropism DeterminationThe primary independent variable was HIV coreceptor usage

(tropism), which was determined by the original Trofile assay

(Monogram Biosciences, South San Francisco CA. Figure S1).

Women were classified as having exclusively CCR5-tropic HIV

(‘‘R5’’) or as having CXCR4-tropic HIV (‘‘X4’’ or dual/mixed

tropism ‘‘R5/X4’’). The original Trofile assay has .99%

sensitivity to detect low levels of CXCR4 and CCR5 variants

that comprise at least 5–10% of a viral population, and the positive

and negative predictive value of the assay has been verified in

clinical trials of CCR5 antagonists [14].

Statistical AnalysesAll analyses were pre-specified. Contingency table analyses were

conducted to compare the distribution of participant characteris-

tics by case-control status, and chi-square or Fisher exact tests

measured statistical significance. Paired t-tests were used to

measure equality of means for continuous variables. Unadjusted

and adjusted exact conditional, matched-pair, logistic regression

was performed. The following continuous variables were trans-

formed for the regression analyses: body mass index was divided

by 10, CD4+ cell count was divided by 100, and HIV viral load

was the log10. Variables that were significant at the P-value ,0.10

level in the unadjusted regression models were included in the

adjusted analysis. Statistical analyses were performed using SASHsoftware version 9.2 [15].

Results

There were 29 confirmed breast cancer cases identified, 27 in

the WIHS and 2 in the HERS. Of 29 confirmed breast cancer

cases, three were excluded due to HIV viral load ,500 copies/

mL, and tropism results could not be determined in three others. A

total of 23 breast cancer cases, who had a mean age of 46 years,

were included in the analyses. Nearly all of these cancers were

invasive infiltrating ductal carcinoma, and they were distributed

across the years 1993–2009 (Table 1). Of 69 randomly selected

controls, tropism could not be determined in seven, who were

replaced with other cohort participants using the same random

selection program.

HIV Tropism in Cases and ControlsThe characteristics of the 23 cases and 69 controls with HIV

tropism results are shown in Table S1. Only 2 (9%) breast cancer

cases had CXCR4-tropic HIV, compared to 19 (28%) of the

matched controls (Fisher’s exact P = 0.09, Table S1). Two of the

seven replacement controls had CXCR4-tropic HIV, for a

prevalence of 29%, essentially the same as the originally selected

controls. Compared to participants with CCR5-tropic HIV, those

with CXCR4-tropic HIV had lower mean CD4+ counts (213.5 vs

389.8 cells/uL, P = 0.001) but similar mean HIV viral loads (4.4 vs

4.1 log10 copies/mL, P = 0.21). In addition, tropism was not

associated with history of clinical AIDS or HIV viral load

(P = 0.26).

Breast Cancer Risk by HIV Tropism and Other VariablesIn unadjusted exact conditional regression analysis of 20

variables (Table S1), breast cancer was marginally inversely

associated with CXCR4-tropic HIV (Odds Ratio (OR) = 0.20,

95% confidence interval (CI) 0.02–1.1) as well as menopause

(OR = 0.13, 95% CI 0.003–1.0), defined as not having a menstrual

CXCR4 and Breast Cancer Risk


period for one year or more. Breast cancer was not associated with

any other variables (exact P-values all .0.1), including CD4+ cell

count, HIV viral load, ART, race/ethnicity, and classical breast

cancer risk factors (Figure 1). In multivariable analysis, cancer risk

was reduced in women with CXCR4-tropic HIV (adjusted

OR = 0.10, 95% CI 0.002–0.84) and with menopause (adjusted

OR = 0.08, 95% CI 0.001–0.83). In additional multivariable

analyses, the adjusted OR and significance level for CXCR4-

tropic HIV was not attenuated by the inclusion of CD4+ cell

count, use of ART, or HIV viral load in the regression models.

Discussion

These findings show that the odds of breast cancer in women

with CXCR4-tropic HIV were 90% lower than in women with

CCR5-tropic HIV. This is large enough to account for most of the

breast cancer deficit for women with AIDS in the United States

[3]. Our findings support the hypothesis that the low breast cancer

incidence observed in women with HIV/AIDS is specifically

linked to HIV variants that bind to CXCR4, a receptor that is

commonly expressed on hyperplastic and neoplastic breast cells.

This hypothesis was developed from three observations: 1) the

utilization of CXCR4 as the coreceptor for HIV X4 and R5/X4

strains [1], 2) the common and often high level expression of

CXCR4 in breast neoplasia [4–6], and 3) the induction of

apoptosis of breast cancer cells by the specific binding of CXCR4-

tropic HIV envelope to CXCR4 [10].

CXCR4 in Breast NeoplasiaOur data showing a reduced risk of breast cancer among

women with CXCR4-tropic HIV may reflect an effect of CXCR4

at an intermediate stage of breast neoplasia. Muller and colleagues

first observed that CXCR4 is commonly and often highly

expressed in primary breast cancers and in breast cancer cell

lines [5]. This observation has been replicated and extended by

many others, as reviewed by Luker and Luker [4]. Mammary stem

cells express CXCR4 mRNA, as well as many other genes [16],

although the relevance of this to breast neoplasia is speculative [4].

Notably, CXCR4 protein was observed by Schmid and colleagues

in 13 of 14 cases of ductal carcinoma in situ of the breast, as well as

in 13 of 14 areas of atypical ductal hyperplasia of the breast [6].

However, Schmid et al did not detect CXCR4 protein in normal

breast epithelium [6], consistent with scanty or absent mRNA

expression in cells derived from mammary epithelial tissue [5].

Overall, these data imply that normal epithelial breast cells would

have few targets for, and thus probably not be directly affected by,

CXCR4-tropic HIV envelope.

CXCR4 by Cell TypeThe possibility that CXCR4-tropic HIV might inhibit tumor-

promoting macrophages [17] and that CXCR4 may differ

between mononuclear and breast cells should be considered.

CXCR4-tropic HIV envelope first binds to a CD4 epitope on T

lymphocytes or macrophages and then undergoes a conforma-

tional change that allows the virus to bind to surface CXCR4 and

enter the cell, causing death by various means including apoptosis

[1]. CXCR4-mediated apoptosis of uninfected bystander cells that

do not express CD4 has been reported, but this phenomenon

commonly involves a degree of interaction with CD4-bearing cells

[18]. In vitro experiments have reported that CD4-independent

interaction of CXCR4-tropic HIV mediates apoptosis of breast

cells, apparently requiring no CD4 expression or interaction to

mediate conformational change of HIV and occurring without

evidence of in vitro or ex vivo breast cell infection by HIV [10].

Conformational differences in the orientation or folding of surface

CXCR4 [19], including conformational differences between

immune versus breast cells [10], may be functionally important.

The additional possibility of HIV infection of breast cells should

also be considered [20].

Assessment of Potential Survivorship, Competing Risk,and Screening Biases

Women with HIV infection may have other causes of morbidity

and mortality that prevent them from being diagnosed with breast

cancer or living long enough to develop breast cancer. With the

increasing availability and potency of ART, these competing

causes of morbidity and mortality are reduced, and thus HIV-

infected women are living longer and reaching the age of higher

breast cancer incidence. By matching the controls to the cases on

date of plasma collection we controlled for temporal trends in the

availability and potency of ART. We also matched the controls to

the age of the cases. CD4+ cell counts were significantly lower in

our participants who had CXCR4-tropic HIV. This accords with

the well known tendency for patients infected with CXCR4-tropic

virus to have more rapid HIV disease progression compared to

those infected with only CCR5-tropic virus [1]. However,

CXCR4-tropic HIV was not significantly associated with HIV

viral load or history of clinical AIDS. Moreover, in multivariable

models that included CD4 cell count, use of ART, or HIV viral

load, the significance level for CXCR4-tropic HIV was not

attenuated. As a result, we have considered and minimized

competing risk as much as possible and still found a significant

association between CXCR4-tropic HIV and reduced risk of

breast cancer.

Screening bias may account for a fraction of the breast cancer

deficit. During ages 40–49, history of screening mammography

was reported by a smaller fraction of HIV-positive women in our

WIHS cohort (64%) compared to the general population

(79%).[21] Screening mammography history after age 50 was

nearly identical in the WIHS and general populations, although

the data were sparse.[21] Whether mammography screening is

related to HIV tropism is unknown.

Table 1. Histopathology and years of diagnosis of the 23breast cancer cases in the WIHS and HERS cohort studies.

Tumor description* Total Number

Invasive infiltrating ductal carcinoma 16

Invasive infiltrating ductal and lobular carcinoma 2

Infiltrating ductal carcinoma in situ 2

Lobular carcinoma in situ 1

Adenocarcinoma 1

Not specified 1

Year of cancer diagnosis

1993–1996 6

1997–2000 3

2001–2004 9

2005–2008 4

2009 1

*Data obtained from medical records (pathology reports) and cancer registries(histology and behavior).doi:10.1371/journal.pone.0014349.t001



Trends in HIV Tropism and ART UseInitial HIV infection with HIV subtype B is almost always

CCR5-tropic, with CXCR4-tropic virus emerging later, a shift

that may be retarded by highly active ART (HAART) [1]. We

postulate that gradual increases in HAART use and efficacy since

1996 may have been sufficient to account for the increasing trend

in breast cancer incidence [3]. In 2008, 71% of HIV-infected

women in the WIHS cohort were receiving HAART [N. Hessol,

unpublished data]. The observed 28% prevalence of CXCR4-

using HIV in our control group and 90% lower risk of breast

cancer associated with these HIV strains, would account for most

of the breast cancer deficit in women with AIDS [3,22].

Limitations and Contrary DataWe lacked ex vivo data to support the epidemiologic association

with CXCR4-tropic HIV. In addition to the reported induction of

apoptosis,[10] induction of various growth factors could contribute

to or account for the association.[7–9] Our study was very small

and limited to U.S. women who may not be representative of the

global HIV epidemic. In our evaluation of classical breast cancer

risk factors, we observed a lower risk associated with menopause.

This association is not surprising, especially in a population with a

mean age of 46 years, because early menopause is known to

decrease the risk of breast cancer [23]. Despite our hypothesis-

driven study that included many potential risk and confounding

factors, and our exclusion of survivorship and other potential

biases by matching and statistical adjustment, the association

between CXCR4-tropic virus and breast cancer may be spurious

due to an unmeasured viral or other exogenous or endogenous risk

factor.

It should be noted that during severe immune deficiency, when

CXCR4-tropic HIV is most prevalent, risks for Kaposi sarcoma

and central nervous system lymphoma are very high despite tumor

expression of CXCR4 [24,25]. Nevertheless, these particular

malignancies are distinct as they are known to be driven by herpes

virus transformation and thus may not utilize CXCR4 as a major

means of oncogenesis and metastasis. It is possible that our

observed association of CXCR4-tropic HIV is unique to breast

neoplasia due to conformational heterogeneity or variable surface

expression of CXCR4 epitopes on neoplastic breast duct cells

[10,19].

Summary and ImplicationsWe found a 90% lower risk of breast cancer for women who

have circulating CXCR4-tropic HIV envelope, which points to

the possibility of a novel protective interaction between a specific

viral protein and cancer risk. The prototype selective antagonist of

CXCR4, AMD3100 (Plerixafor) [26], was reported to inhibit

apoptosis of breast cancer cells by CXCR4-tropic HIV [10], and

other inhibitors of CXCR4 are currently in development to treat

various cancers [27–29]. However, derivative studies should also

consider indirect pathways, such as blockade of pro-carcinogenic

effects of chemokines expressed by tumor-infiltrating macrophages

[17]. Continued studies of molecular interactions [8–10], of

patients with malignancies, and of populations at risk for these

diseases are needed to develop insight into the roles of CXCR4 in

breast and other cancers, which may lead to new approaches for

prevention or treatment.

Supporting Information

Table S1 Characteristics of the 23 breast cancer cases and 69

controls in the WIHS and HERS cohort studies. This table

provides the demographic characteristics, HIV-related parame-

ters, and breast cancer risk factor data, as well as univariate tests of

differences between cases and controls.

Found at: doi:10.1371/journal.pone.0014349.s001 (0.10 MB

DOC)

Figure S1 The Trofile Assay: RNA from patient plasma is

subjected to RT-PCR amplification to obtain a broad represen-

tation of envelope (env) genes from HIV populations. env

amplification products are then inserted into ‘‘HIV env expression

vectors’’ (A). Patient HIV env expression vectors are co-transfected

with an env-deleted ‘‘HIV genomic vector’’ (B) containing a firefly

luciferase reporter gene that is used to quantify viral infectivity.

Co-transfection of HIV env expression vectors and HIV genomic

vectors produces HIV-1 pseudoviruses (C) expressing the env

proteins derived from patient virus env sequences. Coreceptor

tropism is determined by measuring the ability of pseudovirus

populations to efficiently infect target cells co-expressing CD4 and

either CXCR4 (D) or CCR5 (E) co-receptors. Co-receptor

mediated infectivity is quantified by measuring luciferase infectiv-

ity in the CD4/CCR5 and CD4/CXCR4 target cells (portrayed

as yellow asterisks). In the depicted example, both CXCR4+ and

CCR5+ cells are infected by pseudoviruses using patient env and,

therefore, viral tropism would be classified as ‘‘R5/X4’’ or ‘‘dual/

mixed’’. To confirm co-receptor usage, CCR5 and CXCR4 entry

inhibitors are added to target cells (F). Viruses susceptible to

CCR5 and/or CXCR4 antagonists do not produce luciferase in

the corresponding target cells. env genes encoding envelope

proteins capable of using the CXCR4 co-receptor, the CCR5 co-

receptor, or both co-receptors are shown in green, orange and

blue, respectively.

Found at: doi:10.1371/journal.pone.0014349.s002 (0.27 MB PPT)

Acknowledgments

Data in this manuscript were collected by the Women’s Interagency HIV

Study (WIHS) Collaborative Study Group with centers (Principal

Investigators) at New York City/Bronx Consortium (Kathryn Anastos);

Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consor-

tium (Mary Young); The Connie Wofsy Study Consortium of Northern

California (Ruth Greenblatt); Los Angeles County/Southern California

Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen);

Data Coordinating Center (Stephen Gange). The contents of this

publication are solely the responsibility of the authors and do not

necessarily represent the official views of the NIH.

The authors also thank additional members of the HERS Study Group:

Dr. Ellie Schoenbaum, Montefiore Medical Center and Albert Einstein

College of Medicine, Bronx, New York; Dr. Paula Schuman, Wayne State

University School of Medicine, Detroit, Michigan; Dr. Anne Rompalo,

Johns Hopkins University School of Hygiene and Public Health, Baltimore,

Maryland; Dr. Charles Carpenter, Brown University School of Medicine,

Providence, Rhode Island; Drs. Lytt I. Gardner, Dawn K. Smith, and

Dora Warren, Centers for Disease Control and Prevention, Atlanta,

Georgia; and Katherine Davenny, National Institute of Drug Abuse,

Rockville, Maryland. The findings and conclusions in this report are those

of the author(s) and do not necessarily represent the official position of the

Centers for Disease Control and Prevention.

Figure 1. Breast cancer risk with each variable. Unadjusted conditional exact odds ratios (diamonds) and 95% confidence intervals (error bars)for breast cancer among 23 breast cancer cases and 69 controls from the WIHS and the HERS. Reference groups: no therapy (for current use of ART),African American (for race/ethnicity), high school degree (for education), and no alcohol consumption (for alcohol use).doi:10.1371/journal.pone.0014349.g001



Monogram Biosciences supported tropism testing and all assays were

performed by the Monogram Clinical Reference Laboratory.

We are sincerely thankful to the women who consented to be part of this

study. We are also grateful to Dr. Peter Bacchetti, University of California

San Francisco, and to Drs. Anil Chaturvedi and Nilanjan Chatterjee,

National Cancer Institute, for their statistical assistance.

Author Contributions

Conceived and designed the experiments: NAH LAN JG. Performed the

experiments: LAN YSL. Analyzed the data: NAH LAN. Contributed

reagents/materials/analysis tools: DS AML MY MC HM KA GD RG.

Wrote the paper: NAH LAN JG. PI for HERS cohort: DS. PI for WIHS

site: AML MY MC HM KA RG. WIHS analysis center: GD.

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Table S1. Characteristics of the 23 breast cancer cases and 69 controls in the WIHS

and HERS cohort studies.

Cases Controls Participant characteristic N (%) N (%) P-valueCXCR4-tropic 2 (8.7) 19 (27.5) 0.09* Menstrual period in the last 12 months 0.11 Yes 17 (73.9) 38 (55.1) No 6 (26.1) 31 (44.9) HIV RNA viral load [mean log10] [3.96] [4.21] 0.24** 500 – 4,000 copies 6 (26.1) 20 (29.0) 0.83 4,000 – 49,000 copies 11 (47.8) 28 (40.6) ≥50,000 copies 6 (26.1) 21 (30.4) CD4+ cell count/ mm3 [mean] [372] [342] 0.58** <200 4 (17.4) 23 (33.3) 0.39* 200 – 499 14 (60.9) 33 (47.8) ≥500 5 (21.7) 13 (18.8) Current HIV therapy 0.75* None 15 (65.2) 35 (50.7) Mono therapy 2 (8.7) 10 (14.5) Combination 1 (4.4) 4 (5.8) HAART 5 (21.7) 20 (29.0) Ever used ART 0.21 Yes 15 (65.2) 54 (78.3) No 8 (34.8) 15 (21.7) Ever used HAART 0.55 Yes 11 (47.8) 38 (55.1) No 12 (52.2) 31 (44.9) Self-reported clinical AIDS diagnosis 0.19 Yes 9 (39.1) 38 (55.1) No 14 (60.9) 31 (44.9) Age, years [mean] [46.3] [46.0] 0.91 31-40 5 (21.7) 21 (30.4) 0.72 41-50 10 (43.5) 26 (37.7) > 50 8 (34.8) 22 (31.9) Race/ethnicity 0.74* White, non-Hispanic 2 (8.7) 12 (17.4) White, Hispanic 2 (8.7) 4 (5.8) African American 15 (65.2) 40 (58.0) Other 4 (17.4) 13 (18.8) Educational attainment 0.37* < High school 10 (43.5) 22 (31.9) High school 10 (43.5) 25 (36.2) Some college 2 (8.7) 17 (24.6) ≥ 4 years college 1 (4.3) 5 (7.3)

Cases Controls Participant characteristic N (%) N (%) P-valueAge at menarche [mean] [12.6] [13.0] 0.43** <12 3 (16.7) 12 (20.3) 0.68* 12-13 11 (61.1) 28 (47.5) >13 4 (22.2) 19 (32.2) Missing 5 10 Number of term births [mean] [3.0] [2.3] 0.19** 0 4 (17.4) 12 (17.4) 0.54* 1-2 8 (34.8) 32 (46.4) ≥3 11 (47.8) 25 (36.2) Current cigarette smoker 0.45 No 7 (30.4) 27 (39.1) Yes 16 (69.6) 42 (60.9) Alcohol use in past six months 0.17* None 9 (39.1) 36 (52.2) <3 drinks per week 6 (26.1) 22 (31.9) 3-13 drinks per week 6 (26.1) 10 (14.5) ≥14 drinks per week 2 (8.7) 1 (1.5) History of injection drug use 0.27 No 11 (47.8) 42 (60.9) Yes 12 (52.2) 27 (39.1) HCV positive at baseline 0.38 No 8 (36.4) 32 (47.1) Yes 14 (63.6) 36 (52.9) Missing 1 1 Body mass index 0.98* Underweight <19.8 2 (9.1) 5 (7.8) Normal 19.8-26.0 9 (40.9) 30 (46.9) Overweight 26.1-29.0 4 (18.2) 11 (17.2) Obese >29.0 7 (31.8) 18 (28.1) Missing 1 5 Ever used oral contraceptives 0.60 Yes 17 (73.9) 47 (68.1) No 6 (26.1) 22 (31.9) Ever used hormone replacement therapy 0.31* Yes 2 (13.3) 13 (29.6) No 13 (86.7) 31 (70.4) Missing 8 25 * Fisher’s exact test; ** Equality of mean

HIV As a Risk Factor for Lung Cancer in Women:Data From the Women’s Interagency HIV StudyAlexandra M. Levine, Eric C. Seaberg, Nancy A. Hessol, Susan Preston-Martin, Sylvia Silver,Mardge H. Cohen, Kathryn Anastos, Howard Minkoff, Jan Orenstein, Geraldina Dominguez,and D. Heather Watts

From the City of Hope National MedicalCenter, Duarte; Keck School of Medicine,University of Southern California, LosAngeles; University of California, SanFrancisco, CA; Johns Hopkins School ofPublic Health, Baltimore; National CancerInstitute; Eunice Kennedy ShriverNational Institutes of Child Health andHuman Development, National Institutesof Health, Rockville, MD; George Wash-ington University School of Medicine andHealth Sciences, Washington DC;Departments of Medicine, Stroger(formerly Cook County Hospital) andRush University, Chicago, IL; MontefioreMedical Center, Bronx; and theMaimonides Medical Center and StateUniversity of New York, Health SciencesCenter at Brooklyn, NY.

Submitted August 14, 2009; acceptedNovember 11, 2009; published onlineahead of print at www.jco.org onFebruary 22, 2010.

WIHS is funded by Grants No. UO1-AI-35004, UO1-AI-31834, UO1-AI-34994,UO1-AI-34989, UO1-AI-34993, andUO1-AI-42590 from the National Instituteof Allergy and Infectious Diseases and byGrant No. UO1-HD-32632 from theNational Institute of Child Health andHuman Development; co-funded by theNational Cancer Institute, the NationalInstitute on Drug Abuse, and the NationalInstitute on Deafness and Other Commu-nication Disorders; and by UCSF-CTSIGrant No. UL1 RR024131 from theNational Center for Research Resources.

The contents of this publication are solelythe responsibility of the authors and donot necessarily represent the officialviews of the National Institutes of Health.

Presented in part in oral format at theInternational Conference on AIDS-Related Malignancies and Other Immu-nodeficiencies, Bethesda, MD,September 26-27, 2005.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Corresponding author: Alexandra M.Levine, MD, City of Hope NationalMedical Center, 1500 East Duarte Rd,Duarte, CA 91010; e-mail: [email protected].

© 2010 by American Society of ClinicalOncology

0732-183X/10/2809-1514/$20.00

DOI: 10.1200/JCO.2009.25.6149

A B S T R A C T

PurposePrior reports of an increased risk of lung cancer in HIV-infected individuals have not alwaysincluded control groups, nor considered other risk factors such as tobacco exposure. We soughtto determine the role of HIV infection and highly active antiretroviral therapy (HAART) on lungcancer incidence in 2,651 HIV-infected and 898 HIV-uninfected women from the Women’sInteragency HIV Study (WIHS).

MethodsA prospective study of the incidence rates of lung cancer was conducted, with cases identifiedthrough medical records, death certificates, and state cancer registries. Standardized incidenceratios (SIRs) were calculated to compare lung cancer incidence among HIV-infected and unin-fected WIHS participants, with population-based expectations using the Surveillance, Epidemiol-ogy, and End Results registry. Behavioral characteristics in the WIHS were compared to USwomen by age and race adjusting the population-based data from the National Health andNutritional Examination Survey (NHANES) III.

ResultsIncidence rates of lung cancer were similar among HIV-infected and uninfected WIHS women.Lung cancer SIRs were increased in both HIV-infected and -uninfected women compared withpopulation expectations, but did not differ by HIV status. Among HIV-infected women, lung cancerincidence rates were similar in pre-HAART and HAART eras. All WIHS women with lung cancerwere smokers; the risk of lung cancer increased with cumulative tobacco exposure. WIHS womenwere statistically more likely to smoke than US women studied in NHANES III.

ConclusionHIV infection is strongly associated with smoking behaviors that increase lung cancer risk. The roleof HIV itself remains to be clarified.

J Clin Oncol 28:1514-1519. © 2010 by American Society of Clinical Oncology

INTRODUCTION

Highly active antiretroviral therapy (HAART) hasbeen associated with a remarkable decline in theincidence of AIDS-defining cancers.1-3 However, anincrease in certain non-AIDS defining cancers, in-cluding lung cancer, has been reported.4-8 The num-ber of HIV-infected persons with lung cancer isrelatively small, and not all studies have confirmedan increase in risk.9-11

Factors associated with development of lungcancer in HIV-infected persons have included his-tory of cigarette smoking, lung disease,8 and pro-longed duration of HIV infection. The actual roleof profound HIV-related immunodeficiency re-mains unclear.6,8,11-13

Given these uncertainties, we wished to as-certain the incidence of lung cancer amongHIV-infected women enrolled in the Women’s In-teragency HIV Study (WIHS) in the pre-HAARTversus HAART eras, comparing incidence data tothat from a group of HIV-uninfected WIHS partic-ipants, all of whom were observed over prolongedperiods, and in whom behavioral characteristicswere carefully documented. We also examined riskfactors and disease characteristics of lung canceramong HIV-infected versus uninfected participants.

METHODS

Study Cohort

WIHS is a cohort study of women with or at risk forHIV infection, observed at six sites (Bronx/Manhattan,

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VOLUME 28 � NUMBER 9 � MARCH 20 2010

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Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved. 128.218.97.140.

Information downloaded from jco.ascopubs.org and provided by UCSF KALAMANOVITZ LIB CKM on March 29, 2010 from

NY; Brooklyn, NY; Metropolitan Washington, DC, and surrounds; NorthernCalifornia; Southern California; and Chicago, IL).14,15 The cohort included3,766 women enrolled during two recruitment waves: October 1994 to No-vember 1995, and October 2001 to September 2002. HIV-infected and-uninfected women were recruited from similar sources and frequencymatched on age, race/ethnicity, and risk for HIV acquisition. Semi-annualvisits included interviewer-administered questionnaires, physical and gyneco-logical examinations, and collection of biologic specimens. Study protocolswere reviewed and approved by each institutional review board; informedconsent was obtained from all participants.

The 3,678 women who gave additional written consent for cancer ascer-tainment through state registries were eligible. We excluded three women withlung cancer before enrollment, and another 126 women without known lungcancer, seen only at baseline. All analyses were conducted using the remaining3,549 women (94%), and were based on data entered into the database byMarch 31, 2008; follow-up was censored on September 30, 2006, to allow forlags in reporting and confirmation of incident cancers.

Study Outcome

All incident lung cancers were confirmed through medical record re-views of self-reported lung cancers, and/or through matching to statewidecancer registries (most recently performed in 2008), and the national deathindex. Lung cancer pathology reports were reviewed.

Exposures and Potential Confounders

The primary independent variables included HIV serostatus, history oftobacco use, and HAART use. HIV serology was tested by enzyme-linkedimmunosorbent assay with Western blot confirmation. Smoking history wassummarized at baseline using a categoric variable indicating never/former/current use; and, among current smokers, quantification of the total cumula-tive exposure in pack-years (total number of years smoking cigarettes times theaverage number of packs smoked/day). To account for selection by indicationbias resulting from the administration of HAART to women with more ad-vanced HIV, the population effectiveness of HAART at reducing lung cancerincidence was assessed by comparing the incidence rates during the pre-HAART (1994 to 1996) and HAART (1997 to 2006) eras. The onset of theHAART era was set at 1997, since � 25% of HIV-infected participants firstreported HAART use at that time. We also evaluated age, sex, race, education,income, employment status, insurance coverage, history of alcohol consump-tion, body mass index (BMI), CD4 cell count, and HIV RNA levels.

External Comparison Groups

SEER. Surveillance, Epidemiology and End Results (SEER) is an ongo-ing population-based surveillance program, documenting cancer incidenceand survival using selected US state cancer registries.16 We used age-, sex-, andrace-specific cancer incidence data from SEER from 1994 to 2004 to estimatethe number of lung cancers expected in WIHS. The SEER “site recode” num-ber 22030 was used to identify lung cancer cases in SEER, including cancerswith International Classification of Diseases O-2 site codes C34.0 to C34.9.

National Health and Nutrition Examination Survey III. The third Na-tional Health and Nutrition Examination Survey (NHANES III) used a com-plex multistage cluster sampling of the US civilian, noninstitutionalizedpopulation to develop a cohort to investigate risk factors to explain differencesin health in the US population.17 A random sample was selected and interviewswere conducted in three waves from 1988 to 1994. We used the NHANES IIIcohort to obtain population-based estimates of the prevalence of identifiedlung cancer risk factors.17-19 The 17,699 women included in NHANES III wereused to generate the US population–based control group to which we com-pared the WIHS women on behavioral characteristics.

Statistical Analyses

Baseline characteristics in WIHS were quantified descriptively. Compar-isons between HIV-infected and -uninfected women were performed using �2

tests of homogeneity and trend. Lung cancer incidence rates were estimated asthe number of incident cancers divided by total number of person-years (PYs)follow-up. Statistical comparisons between HIV-infected and -uninfectedwomen, and between the pre-HAART and HAART eras, assumed a Poissondistribution for lung cancer incidence rates. To compare the observed number

Table 1. Baseline Characteristics of the WIHS Participants at Study Entry byHIV Status (N � 3,549)

Characteristic

HIV PositiveHIV

Negative

PNo. % No. %

All 2,651 100.0 898 100.0Age group, years

� 30 622 23.5 360 40.130-39 1,265 47.7 340 37.9 � .001�

40-49 651 24.6 176 19.650� 112 4.3 22 2.4

Race/ethnicityNon-Hispanic Black 1,499 56.5 492 54.8Non-Hispanic White 396 14.9 126 14.0 .37Latina/Hispanic 681 25.7 247 27.5Other 75 2.8 33 3.7

Highest education level attainedDid not graduate from HS 1,014 38.3 316 35.4HS graduate 795 30.0 274 30.7 .12�

Post-HS education 838 31.7 302 33.9Annual household income, $

Fewer than 6,000 698 27.1 271 31.46,000-11,999 862 33.5 236 27.3 .57�

12,000-29,999 698 27.1 212 24.530,000 or greater 315 12.2 145 16.8

Currently employed 632 23.9 301 33.6 � .001Medical insurance coverage 2,187 83.2 548 61.5 � .001

Alcohol consumption during past 12months, drinks per week

Does not drink alcohol 1,230 47.6 351 38.8 � .001�

Fewer than 3 787 30.4 267 30.33 or more 569 22.0 263 29.9

Among drinkers, No. of drinks/weekMean 7.9 8.9SD 19.1 18.3Median 1.5 2.5IQR 0.5-6.0 1.0-9.0

Cigarette smoking historyNever smoked 852 32.3 274 30.6Former smoker 429 16.3 107 12.0 .001Current smoker 1,356 51.4 514 57.4

Lifetime cigarette consumptionamong current smokers,pack-years

Lower than 10 713 53.3 291 58.0 .07�

10-20 383 28.6 133 26.5Higher than 20 243 18.2 78 15.5Mean 13.0 11.6SD 19.7 15.7Median 9.0 7.5IQR 3.8-16.5 2.5-15.0

Body mass index, kg/m2

Lower than 20.0 225 8.8 74 8.620.0-24.9 871 34.1 271 31.325.0-29.9 758 29.7 247 28.5 .04�

30.0 or higher 697 27.3 274 31.6Mean 27.3 28.2SD 6.8 7.3Median 25.9 26.5IQR 22.4-30.5 22.9-32.1

Abbreviations: WIHS, Women’s Interagency HIV Study; HS, high school; SD,standard deviation; IQR, interquartile range.

�Test of trend.

HIV As a Risk Factor for Lung Cancer in Women

www.jco.org © 2010 by American Society of Clinical Oncology 1515



of lung cancers in the WIHS to the expected number documented by SEERbetween January 1, 1994, and December 31, 2004, we computed standardizedincidence ratios (SIRs)20 and exact 95% CIs21 adjusted for age (5-year catego-ries), sex, and race (African American, Latina/Hispanic, other white, andother). SIRs by HIV serostatus and calendar time were compared using SIRregression. Because of the small number of observed lung cancer cases, allincidence analyses were performed using exact statistical methods. Possibledifferences in behavioral or demographic characteristics between WIHS andUS women were determined comparing baseline characteristics. Data fromNHANES III women were directly adjusted to age and race distributions inWIHS, using Longenecker’s approach.22 Statistical comparisons of cross-sectional data were performed using Wilcoxon rank-sum and �2 tests ofhomogeneity and trend. All analyses used SAS, version 9.1 (SAS Institute,Cary, NC) or StatXact 8.0 (Cytel Software Corporation, Cambridge, MA). Pvalues lower than .05 indicated statistical significance.

RESULTS

WIHS Cohort

Median age at enrollment of all 3,549 WIHS participants was 34.9years (interquartile range [IQR], 29.3 to 40.4), and was higher inHIV-infected women (35.6 v 32.4 years; P � .001; Table 1). Theracial/ethnic composition of both groups was similar. At their baselinevisit, HIV-infected women were less likely to be currently employed,or to drink alcohol, and were more likely to have medical insurance(including Medicaid) than the HIV-uninfected comparators. TheHIV-infected women had lower baseline BMI. Two thirds of WIHSparticipants reported a history of smoking. While fewer HIV-infectedthan uninfected women were current smokers, the median lifetimecigarette consumption for current smokers was higher among HIV-infected women. The median lifetime cigarette consumption amongall WIHS women who reported smoking at enrollment was 8.4 pack-years (IQR, 3.5 to 16.0).

Lung Cancer Incidence

With 25,000 PYs follow-up, and median follow-up for individualwomen of 5.8 years (IQR, 4.8 to 12.1), we observed 14 incident lungcancers, yielding an overall lung cancer incidence rate of 56.0 per

100,000 PYs (Table 2). The incidence rates did not differ by HIV status(exact P � .58). Further, incidence rates did not differ between pre-HAART and HAART eras in the cohort as a whole (exact P � .81) orin the HIV-infected women.

Unadjusted lung cancer incidence rates were significantly associ-ated with older age (Table 3). Further, lung cancer incidence washighest among non-Hispanic blacks when compared with the com-bined nonblack groups (incidence rate ratio, 10.1; 95% CI, 1.5 to 431;Table 3). Black women were significantly more likely to be currentsmokers at baseline (59% v 45%; P � .001) but among current smok-ers, black women reported significantly lower pack-years compared tononblack women (median, 7.5 v 10.0 PYs; P � .008).

Comparison of WIHS to the US Population

Fourteen incident lung cancers were observed in WIHS, whilebetween four and five were expected based on population-based ageand race-specific rates from SEER (Table 4). Overall, the SIR for lungcancer in WIHS was 3.0 (95% CI, 1.7 to 5.1). The excess lung cancerburden did not vary by HIV status (exact P � .85), nor by pre-HAARTversus HAART eras (exact P � .96).

Because other recognized risk factors for lung cancer might ex-plain the excess incidence rate in WIHS, we compared the WIHScohort characteristics to those in the age- and race-adjusted US femalepopulation, using NHANES III data, reweighted to match the age andrace distributions of WIHS. Our adjustment yielded identical age andrace distributions in the two cohorts (data not shown). When com-pared with the NHANES III women, the WIHS participants hadsignificantly (P � .05) less education, lower annual household in-comes, were less likely to be employed, have medical insurance cover-age, or have a BMI higher than 30. A higher percentage of WIHSparticipants had consumed alcohol during the past 12 months(54.4% v 37.5%). A higher percentage of WIHS participants (bothHIV infected and uninfected) had history of smoking cigarettes(68.0% v 37.2%; P � .001). Among current smokers at enrollment inthe two studies, the cumulative exposure (pack-years) was more than50% higher in WIHS.

Table 2. Unadjusted Lung Cancer Incidence in the Women’s Interagency HIV Study

Parameter All Pre-HAART Era:1994-1996 HAART Era:1997-2003

HAART Era v Pre-HAART Era

Rate Ratio 95% CI

AllObserved No. with cancer 14 3 11PYs 25,000 4,059 20,941 0.71 0.19 to 3.97IR per 100,000 PYs 56.0 73.9 52.5

HIV positiveObserved No. with cancer 12 2 10PYs 18,825 3,221 15,604 1.03 0.22 to 9.69IR per 100,000 PYs 63.7 62.1 64.1

HIV negativeObserved No. with cancer 2 1 1PYs 6,175 838 5,337 0.16 0.002 to 12.3IR per 100,000 PYs 32.4 119.3 18.7

Rate ratio for HIV positive v HIV negative 1.97 0.52 3.4295% CI 0.44 to 18.1 0.03 to 30.7 0.49 to 148.4

Abbreviations: HAART, highly active antiretroviral therapy; PY, person-years; IR, incidence rate.

Levine et al

1516 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



Risk Factors for Lung Cancer

Among the characteristics that differed between the age- andrace-adjusted WIHS participants and US female population fromNHANES III, only smoking history and pack-years of smoking weresignificantly associated with lung cancer in WIHS. No lung cancersoccurred among WIHS women who had never smoked, and a dose-response relationship between pack-years and lung cancer incidencerate was clearly observed among both HIV-infected and uninfectedcurrent smokers, though the latter group did not reach statistical

significance (Table 3). When stratifying by pack-years, we also found asignificant dose-response relationship with lung cancer incidencerates. Among HIV-uninfected women, lung cancers were only ob-served among women with at least 20 pack-years while the majority oflung cancers in HIV-infected women occurred in those with history of10 to 20 pack-years of smoking.

The 14 WIHS participants with lung cancer had a median cumu-lative smoking exposure of 18.9 pack-years, significantly higher thanthe 9.7 pack-years among the women who smoked but did not de-velop lung cancer (P � .002). Pack-years of smoking did not differ byHIV status among lung cancer cases. There was no difference betweenage of onset of smoking for either HIV-infected (17.3 years) or HIV-uninfected current smokers (17.9 years), or for WIHS women with orwithout incident lung cancer.

History of previous injection drug use (IDU) was present in bothHIV-uninfected women and three of the 12 HIV-infected womenwith lung cancer, while three additional HIV infected women re-ported current IDU. The incidence rate for lung cancer among thosewith current or prior history of IDU was 96.5/100,000 PYs, versus36.1/100,000 PYs in those without IDU (incidence rate ratio, 2.67;95% CI, 0.81 to 9.35), and adjustment for age and pack-years did notstatistically alter this result.

Clinical Data Among the WIHS Women With

Lung Cancer

The median age at lung cancer diagnosis in the 12 HIV infectedwomen was 53.3 years (range, 36 to 64). All were non-Hispanic black,with a median of 15.5 pack-years smoking exposure (range, 10.0 to96.3 pack-years). Median CD4 cells and plasma HIV-1 RNA levels atthe WIHS visit before lung cancer diagnosis were 376/mm3 (range, 0to 893/mm3) and 3,400 copies/mL (range, 550 to 310,000 copies/mL).Prior AIDS defining conditions were present in eight (67%). At thevisit before diagnosis of lung cancer, two patients were taking HAART,three were on combination ART, and seven were taking no antiret-roviral therapy. Pathologic types of lung cancer included adenocar-cinoma, poorly differentiated nonsmall cell, and squamous cellcarcinoma, all equally distributed. Advanced cancer (stage IIIB or IV)was diagnosed in seven of 14 (50%), while stage I or II was present in

Table 3. Unadjusted Lung Cancer Incidence in WIHS by Age, Race,Smoking History, and HIV Status

ParameterNo. of Lung

Cancers PYsIR/100,000

PYs

Age (P � .0001)Younger than 30 0 3,242 030-39 1 9,444 10.640-49 4 9,247 43.350 and older 9 3,067 293.4

Race (P � .056)Non-Hispanic Black 13 14,047 92.5Non-Hispanic White 0 3,804 0Latina 1 6,408 15.6Other groups 0 741 0

Second race comparison (P � .007)Non-Hispanic Black 13 14,047 92.5All others 1 10,953 9.1

Cigarette smoking historyOverall (P � .003)

Never 0 7,419 0Former smoker 1 3,889 25.7Current smoker 13 13,576 95.8

HIV negative (P � .50)Never 0 1,770 0Former smoker 0 749 0Current smoker 2 3,626 55.2

HIV positive (P � .007)Never 0 5,648 0Former smoker 1 3,140 31.8Current smoker 11 9,951 110.5

Lifetime cigarette consumptionamong women who reportedbeing current cigarettesmokers at enrollment,pack-years�

Overall (P � .002)� 10 0 6,445 010-20 7 3,817 183.4� 20 6 3,315 181.0

HIV negative (P � .05)� 10 0 1,841 010-20 0 977 0� 20 2 807 247.8

HIV positive (P � .005)� 10 0 4,604 010-20 7 2,840 246.5� 20 4 2,508 159.5

Abbreviations: WIHS, Women’s Interagency HIV Study; PYs, person-years;IR, incidence rate.

�One incident lung cancer occurred in an HIV positive woman who hadstopped smoking prior to being enrolled in the WIHS, and she was excludedfrom this analysis that was restricted to women who were current smokersat enrollment.

Table 4. Standardized Incidence Ratios for Lung Cancer Incidence in theWomen’s Interagency HIV Study Compared With the Surveillance,

Epidemiology and End Results Program

Parameter

ObservedPerson-Years

No. of LungCancers Standardized

IncidenceRatio 95% CIObserved Expected

Overall 25,000 14 4.60 3.04 1.66 to 5.10HIV positive 18,825 12 3.65 3.28 1.70 to 5.74HIV negative 6,175 2 0.95 2.11 0.25 to 7.61

Pre-HAART era(1994-1996) 4,059 3 0.48 6.22 1.28 to 18.19

HIV positive 3,221 2 0.40 4.97 0.60 to 17.95HIV negative 838 1 0.08 12.57 0.32 to 70.05

HAART era(1997-2006) 20,941 11 4.12 2.67 1.33 to 4.78

HIV positive 15,604 10 3.25 3.08 1.47 to 5.66HIV negative 5,337 1 0.87 1.15 0.03 to 6.40

Abbreviation: HAART, highly active antiretroviral therapy.





two; staging information was unavailable in five. Median survivalfrom diagnosis of lung cancer was 14.1 months (range, 3.0 to 62months) with one women remaining alive, at 28 months.

The two HIV-uninfected WIHS women with incident lung can-cer were 46 and 56 years of age, with 25.0 and 30.9 PYs smokinghistory. One was non-Hispanic black while the other was Latina.Survival was 1.6 and 8 months from diagnosis.

DISCUSSION

We found a substantially increased risk of lung cancer amongboth HIV-infected and at-risk uninfected women compared withpopulation-based expectations. A possible explanation is the high rateof cigarette smoking in WIHS women, reported by approximatelytwo thirds, including all women diagnosed with incident lungcancer. Several prior reports have also documented a strong historyof tobacco exposure in their HIV-infected patients who developedlung cancer.6,8,9,11-13

As previously noted,23 we found that WIHS women were almosttwice as likely to smoke as age- and race-matched women, studied aspart of NHANES III.17-19 While multiple other behavioral and demo-graphic differences between WIHS and NHANES III women werefound, only smoking was significantly associated with incident lungcancer. Thus, when compared to population-based controls, any in-crease in the incidence of lung cancer among HIV-infected womencould be explained by differences in history of tobacco exposure.

When comparing lung cancer incidence rates between HIV-infected women in the WIHS and the internal group of HIV-uninfected women, no differences were apparent. Of importance, allwomen with lung cancer had strong histories of tobacco exposure,thus serving to explain the equivalent increase in lung cancer amongboth HIV-infected and uninfected women, when compared withpopulation-based expectations. Of note, both HIV-infected and-uninfected WIHS participants were statistically more likely to smokethan the NHANES III/US female population. Nonetheless, HIV-uninfected women with lung cancer had smoked for 25 and 30 PYs,while those infected with HIV had 10 to 20 PY smoking history. It ispossible that HIV may accelerate the development of lung cancer.

Several studies have shown a significant increase in lung canceramong HIV-infected patients after the introduction of HAART.6,8,9

The remarkable prolongation in survival due to HAART may haveallowed these individuals to live long enough to develop lung cancer.However, we found no difference in the incidence of lung canceramong HIV-infected women in the pre-HAART versus HAART eras.A recent study of 54,780 HIV-infected patients also failed to demon-strate an increase in lung cancer incidence in the HAART era,24 sug-gesting that the excess risk of lung cancer is not related to use ofantiretroviral therapy per se, but rather to other factors, such as pack-years of smoking, in an aging population.

A significant increase in the risk of death due to lung cancer wasreported among HIV-infected IDUs,8 studied as part of the AIDS Linkto the Intravenous Experience Study (ALIVE); 26 of 27 patients hadhistory of smoking. After adjusting for smoking status and othervariables, HIV infection was found to be independently associatedwith an increased risk of lung cancer death. Our data indicate thatHIV, per se, was not a risk factor for initial development of lungcancer. While it is plausible that HIV-infected patients with lung

cancer may be more likely to succumb to the malignancy than theirHIV-uninfected counterparts, still, this study, and that from ALIVEactually address different issues. It is also possible that lifestyle factorsrelated to IDU may have increased the risk of pre-existing pulmonarydisease, possibly predisposing to lung cancer. In this regard, the inci-dence rate for lung cancer among former or current IDUs in the WIHSwas more than twice that of participants without history of IDU,although this difference was not statistically significant.

Similar to this study, locally extensive or metastatic lung cancerhas been reported at diagnosis in both pre-HAART12 and HAARTeras,25 despite improvements in immunity associated with HAART.Delays in initial diagnosis of lung cancer among HIV-infected personsmay explain the disseminated nature of disease.25 Alternatively, fac-tors related to HIV itself, or to the abnormal immunologic milieuassociated with HIV may be operative.

Several studies have reported that adenocarcinomas occur morecommonly than expected in HIV-infected individuals,4,12,26-29 whileothers have not.6,13,30 Our data demonstrate an equivalent distribu-tion of pathologic types. Brock and colleagues25 noted a change in thepathologic spectrum of lung cancer among 92 HIV-infected patients,when comparing pre-HAART and HAART eras, with 48% of allcancers diagnosed as adenocarcinoma in both time periods, whilesquamous cell carcinoma increased from 10% to 21%.

The WIHS study followed a large cohort prospectively for up to12 years, and all cancer diagnoses were confirmed. However, details oftreatment or response were not available. Furthermore, despite ourlarge database of more than 3,500 women and 25,000 PYs of follow-up, the small number of incident lung cancers limited the statisticalpower. Nonetheless, a prospective comparison between HIV-infectedwomen, and HIV-uninfected women with similar lifestyles was possi-ble, augmenting the study design. Further, the careful documentationof tobacco exposure, and the ability to compare our data with behav-ioral data from age- and race-matched US women (NHANES III)allowed evaluation of the potential role of cigarette smoking as a causefor the increase in lung cancer among WIHS women.

We have demonstrated that WIHS participants, whether HIV-infected or at-risk but uninfected, have a significantly increased risk oflung cancer when compared with the rates expected in the generalpopulation, while no difference in lung cancer rates among HIV-infected versus uninfected women was seen. Of importance, bothHIV-infected and -uninfected WIHS participants were significantlymore likely to have smoked than the NHANES III/US female popula-tion. All WIHS women with lung cancer had history of smoking, andthe risk of cancer increased with increasing smoking exposure. Thedevelopment of lung cancer among HIV-infected women appearsvery strongly correlated with tobacco exposure. As such, the develop-ment and implementation of smoking cessation programs aimed atHIV-infected persons will be of increasing importance. The preciserole of HIV infection, per se, in terms of the development or progres-sion of lung cancer awaits further clarification.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

The author(s) indicated no potential conflicts of interest.

Levine et al

1518 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



AUTHOR CONTRIBUTIONS

Conception and design: Alexandra M. Levine, Eric C. Seaberg, Nancy A.Hessol, Susan Preston-Martin, Sylvia Silver, Kathryn Anastos,Jan OrensteinFinancial support: Alexandra M. Levine, Mardge H. Cohen, KathrynAnastos, Howard Minkoff, Geraldina Dominguez, D. Heather WattsAdministrative support: Alexandra M. LevineProvision of study materials or patients: Alexandra M. Levine, Nancy A.Hessol, Susan Preston-Martin, Mardge H. Cohen, Kathryn Anastos,Howard Minkoff

Collection and assembly of data: Alexandra M. Levine, Nancy A. Hessol,Mardge H. Cohen, Howard MinkoffData analysis and interpretation: Alexandra M. Levine, Eric C. Seaberg,Nancy A. Hessol, Susan Preston-Martin, Sylvia Silver, Mardge H. Cohen,Kathryn Anastos, D. Heather WattsManuscript writing: Alexandra M. Levine, Eric C. Seaberg, Nancy A.Hessol, Susan Preston-Martin, Sylvia Silver, Mardge H. Cohen,Kathryn Anastos, Howard Minkoff, Geraldina Dominguez,D. Heather WattsFinal approval of manuscript: Alexandra M. Levine, Eric C. Seaberg,Nancy A. Hessol, Sylvia Silver, Mardge H. Cohen, Kathryn Anastos,Howard Minkoff, Jan Orenstein, D. Heather Watts

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