Factors that dictate risk of developing primary or secondary cancer

Apr 18 2007

Every day, people make assumptions, educated and not, about their risk for developing cancer.

For many, the risk of developing a secondary cancer after an earlier illness rests uncomfortably in the backs of their minds. Researchers are continuing to understand the factors that might dictate an individual's risk of developing primary or secondary cancer. The risk of developing cancer depends on the subtle interplay of genetics, personal choice and the environment, according to several long-term studies presented at the 2007 Annual Meeting of the American Association for Cancer Research.

Research has shown there is a connection between reproductive factors—such as age at first birth, number of births, and breastfeeding—and a woman's risk of breast cancer. Yet to be established is how these factors interact, and whether they have differing effects on risk for breast cancers that are estrogen and progesterone receptor positive (ERPR-positive) versus those that are not (ERPR-negative).

A new study by a team of researchers in the U.S. and Australia suggests that breastfeeding may help protect women against both subtypes.

“Our previous research had shown differing effects of these reproductive factors on ERPR-positive and ERPR-negative breast cancers, and we wanted to understand them better,” said study co-author Giske Ursin, M.D., Ph.D., associate professor in the Department of Preventive Medicine at the University of Southern California's Keck School of Medicine. “Our most important finding here is that breastfeeding seems to modify the increased risk that comes from having children later in life.” The study looked at 995 women with invasive breast cancer (729 ERPR-positive, 267 ERPR-negative), and 1498 controls, aged 55 years or older who participated in the Women's Contraceptive and Reproductive Experiences Study, a multicenter study of breast cancer in white and African-American women. The researchers considered women's age at first birth, the number of births – referred to as parity – and whether or not they had ever breastfed.

Women with a first birth before age 25 had 41percent lower relative risk of developing ERPR-positive breast cancer than women with no births; this protective effect did not hold true for women who gave birth at or after 25. The latter group also had double the risk of developing ERPR-negative cancers. “What we find is that early age at first birth protects against ERPR-positive cancer, but not receptor-negative,” Ursin said.

More notable, researchers said, was their finding related to age at first birth and parity. Breastfeeding was protective for both subtypes, regardless of when a woman gave birth.

“The protective effect of parity on ERPR-positive cancers was seen only among women who breastfed, but not among those who never breastfed,” said Ursin. “And for women giving birth after age 25, parity was associated with increased risk for both types of breast cancer only in women who had never breastfed.”

The researchers concluded that breastfeeding may lessen the increased risk that comes from having children later in life. According to Ursin, breastfeeding may act through different hormonal mechanisms than early age at first birth and parity.

For now, the study suggests that women who delay childbearing should consider breastfeeding when they do have children. “We suspect that women can reduce the increased risk that comes with later childbearing by choosing to breastfeed,” Ursin said.

Women diagnosed with cervical cancer tend to have good long-term survival, but they often have specific risk factors for developing a cancer later in life: a history of smoking, infection with the human papillomavirus, and/or treatment with radiation therapy.

A study by researchers in the U.S., Denmark, Finland, Sweden, and Norway has documented cervical cancer survivors' significantly increased risk of developing a second primary cancer—a risk that lasts for several decades after their initial diagnosis of invasive cervical cancer. Using 13 population-based cancer registries in Denmark, Finland, Sweden, Norway, as well as the U.S. Surveillance, Epidemiology, and End Results program, the researchers studied 104,760 cervical cancer survivors starting one year after their diagnosis and continuing over the next 40 years or more. They found that these women had a 30 percent higher incidence of all second cancers compared to women in the general population.

“The unique aspect of this study is the long length of follow up,” said Anil Chaturvedi, Ph.D., MPH, a researcher at the Division of Cancer Epidemiology and Genetics, National Cancer Institute. “Previous studies had evaluated second cancer risk up to 30 years of follow up. With these registries, we were able to assess longer-term risk over 40 years or more.”

The researchers examined the women's risk for specific cancers associated with smoking and HPV infection – known causes of cervical cancer. “We did not have information on smoking in our study, but it has been well-documented that women with cervical cancer are more likely to have a history of smoking,” Chaturvedi said.

Compared to women in the general population, risks for HPV-related cancers (oropharynx, female genital sites, and anus) and smoking-related cancers (lung, pancreas, and urinary bladder) were significantly elevated.

The researchers also compared second cancer risk in women who had radiation treatment versus women in the general population. Women who underwent radiation were at increased risk for any second cancer and cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, female genital sites) beyond 40 years of follow up.

“What's most significant is that even as far out as 40 years after diagnosis, these women have an increased risk for second cancers,” Chaturvedi said. “These results suggest a need for close medical surveillance for second cancers.”

Thanks to treatment advances, the majority of people diagnosed with Hodgkin's disease – often in youth or early adulthood – can expect to survive long-term. However, about 10 percent of them will eventually develop another form of cancer in the decades after finishing treatment.

Researchers at The University of Texas M. D. Anderson Cancer Center have discovered that genetic instability may help predict which subset of patients is at greatest risk for second cancers—which, in turn, could pose important implications for their treatment and long-term follow-up.

“It is particularly devastating for young adults to be hit with Hodgkin's disease, do well, and then face another cancer ten to 20 years down the line,” said Rand El-Zein, M.D., Ph.D., an assistant professor of epidemiology at M. D. Anderson. “Cytogenetic and chromosomal abnormalities have already been validated as such as markers of cancer risk. We wanted to find out if there are genetic markers that can serve as predictors of second primary tumors.”

The study analyzed chromosomal aberrations in lymphocytes collected from 252 adult Hodgkin's disease patients before they began treatment between 1986 and 1992. Their analysis focused on the number of chromatid breaks during 100 complete cell metaphases. Researchers found a strong correlation between the number of breaks and the likelihood of developing a second cancer.

At a follow-up of approximately 13 years, 27 patients, or 11 percent, developed second primary cancers: five solid tumors, four leukemia, eleven skin cancers, and seven lymphomas. These patients had significantly higher levels of total breaks than patients who remained cancer-free. The 25 percent of patients with the highest number of breaks were almost two-and-a-half times more likely to develop second cancers.

“We believe that these chromosomal aberrations explain why some patients develop second primary cancers and some don't,” said El-Zein. She also noted that this information could potentially be useful in tailoring treatment regimens and follow-up surveillance.

“For a patient with a higher level of genetic instability, you might want to give them a less toxic regimen, or spread out the treatments more, or give them some kind of agent to boost their genetic repair mechanisms,” said El-Zein. “Or you might want to do closer surveillance in the years after treatment.”

The research team is now looking at other potential predictors of second cancer risk, such as polymorphisms in the DNA repair genes, and plans to analyze samples taken from the same patients over time. Information about each patient's treatment regimen also will help them determine if there is a correlation between genetic instability and toxicity from the treatment.

“Being able to predict the likelihood of a second cancer has great potential to be helpful not only for Hodgkin's disease survivors, but for survivors of any cancer that is associated with later risk of a secondary cancer,” El-Zein said.

A team of 19 researchers from Australia, Canada, Iceland, Singapore, and several European countries has completed what they call the “largest population-based study of absolute and relative risk of second malignant neoplasms (SMNs)” in childhood leukemia and lymphoma survivors. The study, which analyzed data from 13 cancer registries in several countries, found that these survivors have a higher-than-average risk of developing a different type of cancer later in life.

“Large-scale, long-term population studies are necessary to have a better understanding of the risk of second primaries among cancer patients,” said study coordinator Paolo Boffetta, M.D., MPH, of the International Agency for Research on Cancer. “Most of the second primary cancers after a childhood cancer are, fortunately, rare. One therefore needs large series of patients to precisely estimate risks.”

The registries used had been active for at least 25 years and covered different time periods between 1943 and 2000. Each provided individual data on leukemia, Hodgkin's lymphoma, and Non-Hodgkin's lymphoma, along with second cancers – new primaries, not recurrences or metastases – in children from infancy through age 14. The researchers' analysis found that the cumulative incidence of second cancers was 2.43 percent, 12.7 percent, and 2.5 percent within 30 years since leukemia, Hodgkin's lymphoma and Non-Hodgkin's lymphoma, respectively.

According to the researchers, this means that survivors of these childhood cancers are considered to be “high risk” for developing second cancers. This is especially true for Hodgkin's lymphoma survivors: one in eight was affected within 30 years from the initial diagnosis.

“This is probably due to the better survival of Hodgkin's lymphoma patients who received highly toxic chemotherapy, as compared to other groups of patients,” Boffetta said. “In other words, chemotherapy, possibly in combination with radiotherapy, increased the survival of Hodgkin's lymphoma patients but also their risk of developing a second cancer.”

In Hodgkin's lymphoma survivors, researchers observed an increased risk for brain, thyroid, breast, and nonmelanoma skin cancer, as well as leukemia.

The study could not assess whether risk of a second cancer varied among children who were treated in the 1940s, 50s, or 60s versus more recent decades, due to the limited follow-up time for the latter population. According to Boffetta, their risk estimates are based on patients who had past treatment regimens – those for whom they have enough follow-up to make proper estimates. Those estimates may not reflect the risk entailed by more recent, and presumably less toxic, regimens.

“The significance of these results for adult survivors of childhood cancers is that they provide a more precise estimate of their risk of developing a second primary cancer,” Boffetta said.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 25,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts over 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, diagnosis and treatment. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.