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AUTHOR COMMENTARIES - From Special Topics

Human Papillomavirus - July 2008
Interview Date: August 2008
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Bosch Dr. Xavier Bosch
From the Special Topic of Human Papillomavirus
Human papillomavirus (HPV) is a virus that infects the deepest layer of the skin and mucosa, causing a spectrum of conditions from benign warts in the skin, the genital tract, or the oral cavity, to invasive cancer in the same locations. There are about 100 types of HPV, of which around 40 infect the genital area. Of these, at least 13 are known to cause cervical cancer, and two of these (types 16 and 18) cause over 70% of all cases. The realization that a virus is primarily the cause of cervical cancer has transformed not only the understanding of the disease but also its management.

A Special Topics analysis of papers on HPV spotlighted the research achievements of Xavier Bosch, whose specialty is improving the understanding of the role of HPV in the etiology of cervical cancer. In this analysis, Dr. Bosch's work ranks at #4 by total cites, and includes 41 qualifying papers cited a total of 4,155 times. In Essential Science IndicatorsSM from Clarivate Analytics, Dr. Bosch's record includes 108 papers, the majority of which are classified in the field of Clinical Medicine, cited a total of 6,290 times between January 1, 1998 and April 30, 2008. Dr Bosch is the Head of the Cancer Epidemiology Research Program and Chief of International Affairs at the Catalan Institute of Oncology (ICO) in Barcelona, Spain.

In the interview below, ScienceWatch.com correspondent Dr. Simon Mitton talks with Dr. Bosch about his highly cited HPV research.

  How did you become an oncologist?

I went to medical school first, and my specialization was in internal medicine and clinical oncology. At the time, oncology was a very difficult discipline in Spain; the number of jobs was rather limited. In fact, the very concept of oncology was just beginning. In the hospital, cancers were treated by a number of different specialists and only came to the oncology ward when the cancer was at such an advanced stage we could do very little by way of treatment.

Being interested in research, I wanted to learn about public health and epidemiology. To that end I went to the US for formal training in cancer epidemiology at UCLA, where I had the opportunity to view oncology from the preventive point of view as well as acquiring some skills in the methodology of epidemiology investigations.

  What developments influenced your interest in HPV as a risk factor in cervical cancer?

"Any preventative strategy that uses HPV as the guiding point (such as HPV screening or vaccination) should target all cases of cervical cancer."

I received an offer to join the International Agency for Research on Cancer (IARC), where we launched the cervical cancer program. We were a rather small group—just two people—Dr. Nubia Muñoz, who was the unit chief at the time, and myself. A firmly established research structure and an impressive network of collaborators worldwide aided us. The network remains active in conducting research on HPV and cancers other than those of the cervix.

We put together a study to investigate the sexual behavior of males and females as a critical risk factor for cervical cancer. Just as we got started, a research group in Heidelberg developed new technology for isolating and characterizing HPV DNA. Professors Zur Hausen and Lutz Gissmann noted that HPV DNA might be involved in the etiology of these cancers.

We then merged our epidemiological studies with a protocol for taking specimens and for trying novel biomarkers for HPV in cervical scrapes. This was one of the earliest molecular epidemiology studies done at IARC. The working hypothesis stated that there was some association between HPV DNA and cervical cancer. Subsequently, after examining and testing several tens of thousands of individuals worldwide we were able to prove that the association was indeed strong, and that it was universal. We found it in all countries surveyed.

  How prevalent is cervical cancer in developing countries?

Invasive cervical cancer in the majority of countries in the world is still the #1 or #2 cancer in women. Where there is screening activity—the Pap test—the fatalities have dropped significantly, and in these populations it’s typically the sixth or seventh most common cancer in women.

The number of cases worldwide is close to half a million, of which more than 80% occur in developing countries, where the lack of access to medical facilities inevitably leads to high mortality in a relatively young age group. The HPV infections that are at the origin of these cancers occur early after the onset of sexual activity, and the first serious cases are already seen in young women in their 20s and 30s.

  So, should screening be introduced in developing countries?

That has been repeatedly shown to be very difficult and highly improbable, I’m afraid to say. Cervical cancer prevention has been largely a failure in developing countries, because hundreds of millions of women must be regularly screened at vast expense. The conventional method for screening, the Pap smear, is relatively insensitive and has to be repeated rather often. Screening requires adequate diagnosis, treatment, and follow up of women, which is only a reality in well-developed societies or in minority social groups in developing countries. That scenario clearly opens the door for the introduction of new vaccines. HPV vaccines are expected in the long run to make a significant breakthrough in cancer prevention in developing countries.

  Next, I’d like to discuss the impact of your most-cited paper for the time span 1998-2008, "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide," (Walboomers JMM, et al., Journal of Pathology 189:12-19, 1999). It really establishes the relationship between HPV and cervical cancer worldwide.

The precedent for my #1 paper in the analysis is, however, our 1995 publication in the Journal of the National Cancer Institute, in which I was the lead author, "Prevalence of human papillomavirus in cervical-cancer—a worldwide perspective," (87[11]: 796-802, 7 June 1995). That paper is one of the most quoted in the field. It is a prevalence survey describing the HPV DNA profile of over 1,000 specimens from 33 countries. The breakthrough in that paper was to set the prevalence of HPV DNA in cervical cancer at the 93% level and to show the consistency internationally.

"The number of [HPV] cases worldwide is close to half a million, of which more than 80% occur in developing countries, where the lack of access to medical facilities inevitably leads to high mortality in a relatively young age group."

However, from the results we were still left with 7% of cases that were apparently unrelated to HPV. On a second step, we identified those 7%, retrieved the specimens, and sent them to the late Jan Walboomers, who at the time was the head of the HPV research laboratories at the Free University in Amsterdam. He and his colleagues had developed a slightly different technology for detecting and typing HPV DNA. In the 7% apparently HPV-negative samples where he could retrieve cancer cells amenable for proper HPV testing, he found HPV DNA in virtually all of them.

So Paper #1, in which Jan is the leading author, is highly cited because it expanded and completed the 1995 results to show that virtually 100% of cervical cancer had HPV DNA—the necessary cause. This paper is important because it was the first time in cancer epidemiology in which a necessary cause was declared.

  What are the implications of this universal cause?

In the absence of exposure to HPV there won’t be any disease. Any preventative strategy that uses HPV as the guiding point (such as HPV screening or vaccination) should target all cases of cervical cancer. That paper contributed to set the agenda for novel concepts and options of cancer prevention. The impressive follow up was that technologies were rapidly developed and tested. In less than a decade, we had firm evidence that HPV-based screening is indeed significantly better that the conventional Pap smear.

  The second paper I’d like to know more about is from 2003, on the epidemiologic classification of HPV types in terms of their risk to induce cervical cancer (Muñoz N, et al. "Epidemiologic classification of human papillomavirus types associated with cervical cancer," NEJM 348: 518-27, 2003).

This is the final contribution of the series of case control studies organized from the IARC by the group led by Dr. Muñoz. In 1992 the causal link was announced for the first time based on two case-control studies conducted in Spain and Colombia. By the end of the project we had 11 papers on case-control studies, several of which feature in the Special Topics rankings. The studies were of large enough samples to allow for a specific estimate of the risk by HPV type, which is something that few of the other studies were able to do. The type-specific risk estimates allowed for the empirical epidemiological classification of the HPV types, which was a critical contribution.

  Paper #3 is a review paper on the causal relation of HPV to cancer (Bosch FX, et al., "The causal relation between human papillomavirus and cervical cancer," Journal of Clinical Pathology 55: 244-65, 2002). This one addresses public health officials and regulatory bodies.

This paper was written because the first time the proposal to use HPV tests was submitted to regulatory bodies in the US it was turned down because reviewers claimed that the causal association had not been proven. So the rationale for HPV screening was in doubt.

Then I was invited to prepare a fairly academic paper discussing the points at issue. The exercise blew away my 2001 summer vacation! The review put together a significant fraction of the epidemiological literature at the time. It went back to the criteria of causality that historically had been used for human carcinogens, and then reviewed one by one to ascertain which were the best pieces of evidence that would support the hypothesis one way or the other.

This paper is written in a language that is relatively easy and accessible. We reached the people who had to make the decisions on HPV screening. The paper is a proper review backed up by the best literature, and that was highly desirable at the time. The writing of this paper included an extensive group of reviewers who were most of the best in the field. I integrated their feedback and the effort was duly acknowledged. The names backing up the paper were unchallengeable, and that’s probably one of the reasons why so much notice has been taken of the paper. At the next session of the regulatory hearings, the manuscript was used as sufficient to prove causality. Paper #3 is also being used extensively in teaching the way epidemiology tackles cancer causality issues.

Dr. F. Xavier Bosch BSc, M.D., Ph.D.
Cancer Epidemiology Research Program
Catalan Institute of Oncology
Barcelona, Spain

Dr. Xavier Bosch's most-cited paper with 1,468 cites to date:
Walboomers JMM, et al., "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide," J. Pathol. 189(1): 12-19, September 1999. Source: Essential Science Indicators from Thomson Reuters.

Keywords: human papillomavirus, HPV, epidemiology, cervical cancer, etiology, developing countries, screening, vaccine, public health, regulatory bodies.

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Special Topics : Human Papillomavirus : Xavier Bosch - Special Topic of Human Papillomavirus