Causes of Breast Cancer
The causes of breast cancer and the reasons for its occurrence are not fully known yet, but, scientific research and epidemiological studies have revealed several factors that influence the chances that a particular individual will get afflicted. These breast cancer risk factors broadly belong to three categories, 1) genetic, 2) events related to a woman's reproductive biology, and, 3) certain life-style factors
Risk factors discovered by scientific research
By far the most significant scientific finding related to the etiology of breast cancer
is the discovery of two breast-cancer-susceptibility genes that have been labelled BRCA1
and BRCA2. Women with mutations in either of these genes have a lifetime risk of breast
cancer of 60 to 85 percent. However, BRCA1 and BRCA2 mutations are very rare in the
general population (excluding Ashkenazi jewish women), and account for only about 5
percent of all breast cancer cases.
Risk factors identified through epidemiological research
It appears that there are other, as yet unidentified, high penetrance genetic factors leading to breast cancers. This conclusion follows from epidemiological research on large databases of families having more than one member affected by breast cancer. These genetic risk factors show up through the occurrence of the disease more frequently among members of affected families than in the general population. Epidemiological studies have also enabled the identification of parameters related to a woman's reproductive biology, e.g., age at menarche, age at menopause, parity (number of child-births), etc., and others related to life-style, e.g., the Body Mass Index (BMI), alcohol consumption, etc., to be risk factors.
Breast cancer risk calculation models
A number of large scale epidemiological research projects have contributed to the above
knowledge and have even enabled a quantitative characterization of the effects of the
different risk factors through well-established risk calculation models.
Gail et al.
analyzed the Breast Cancer Detection Demonstration Project
(BCDDP) database
and found that the following parameters significantly correlated with the probability of
occurrence of the disease: 1) age at menarche, 2) age at first live birth, 3) the number
of first-degree relatives with breast cancer, and, 4) the number of breast biopsies.
Further, they expressed this observation quantitatively in terms of a model (now referred
to as the Gail model) that gives the risk of breast cancer for an individual as a
probability or likelihood that is a function of quantized values for the above parameters.
A Modified Gail Model
was developed by scientists working on the National Surgical Adjuvant Breast and Bowel
Project (NSABP) to determine eligibility of
candidates for inclusion in the Breast Cancer Prevention Trial (BCPT, also called
NSABP-P1). Apart from the parameters used by the original model, this modified Gail model
included the race, presence of atypical hyperplasia on breast biopsy, and 1987 population
rates of breast cancer and death from other causes from the Surveillance, Epidemiology,
and End Results
(SEER) database.
This modified Gail model became very popular and is widely used even today.
Claus et al. derived
another model to predict risk of occurrence of breast cancer that is
applicable to women who have at least one first- or second-degree relative with breast
cancer. In these cases it appears that certain inherited (genetic) factors play a
predominant role in comparison to the other personal factors included in the Gail model.
The Claus model was derived from analyzing the data of Cancer and Steroid Hormone
Study (CASH), a large, population-based, case-control study of breast cancer.
Assuming the prevalence of high-penetrance genes for susceptibility to breast cancer, the
Claus model establishes a relationship between the probability of occurrence of breast
cancer and the ages at diagnoses of breast cancer in first- and second- degree relatives.
Thus the Claus model incorporates more extensive information about family history
than the Gail model, but it does not consider any of the other risk factors.
BRCAPRO
model predicts the risk of a counselee carrying deleterious mutations in BRCA1
and/or BRCA2. For this calculation it uses detailed information pertaining to first and
second degree relatives of the counselee, namely, number of first degree relatives
affected, number of second degree relatives affected, age of onset of cancer in the
affected first and second degree relatives, bilateral breast cancer, ovarian cancer,
male breast cancer, and Ashkenazi Jewish ancestry.
LAMBDA
Calculates the probability that an Ashkenazi Jewish woman (the counselee) carries
an inherited deleterious mutation of the BRCA1 and BRCA2 breast cancer susceptibility
genes. The calculation is based on the individual’s family history of breast and ovarian
cancer in first and second degree relatives.
The Tyrer, Duffy, Cuzick model combines calculation of risk based on genetic factors manifested in family
history of disease with those from personal history of a woman and gives a single
personalized risk estimate combining all factors.
Colditz et al.
evaluated risk factors for breast cancers jointly classified by estrogen and progesterone
receptor statuses, i.e., separately for (ER+/PR+), (ER+/PR-), (ER-/PR+),and (ER-/PR+)
types of breast cancers. The model was derived from data on 2096 incident cases of breast
cancer for which information on ER/PR status was available among 1,029,414 person-years
of follow-up of 66,145 women participating in the NHS from 1980 through
2000. Colditz et al. made use of a log-incidence model of breast cancer and applied
polychotomous logistic regression to evaluate the relative contribution of different
risk factors to the total risk. They found that to accurately estimate breast cancer
risk, breast cancer cases should be divided according to the ER and PR status of the
tumor. Que sera evaluates risk using this model.
Risk Disk - is
is a software provided by the National Cancer Institute
(NCI)on CD-ROM for calculation of risk by the
modified Gail model.
NCI Breast Cancer Risk Prediction Online Tool -
is the same software presented as an online tool.
CancerGene
- is a computer program provided by UT Southwestern at Dallas for estimating the
likelihood that a family carries a mutation in one of the cancer predisposition genes.
The software uses detailed family history in the form of a pedigree tree including
second degree relatives and incidences with dates of occurrence of breast cancer,
bilateral breast cancer, ovarian cancer, and male breast cancer. CancerGene includes a
module to calculate the Modified Gail model risk also.
Your Disease Risk - is a Web site
hosted by Harvard Center for Cancer Prevention (HCCP). A visitor to this site can find
out his or her risk of developing Cancer, Diabetes, Heart Disease, Osteoporosis, and
Stroke. The 'Cancer' category includes calculation of risk of developing breast cancer.
Personalized tips for reducing the risk and preventing the diseases are provided. Risk
calculation is based on analysis of data gathered by HCCP over a number of years.
The Hall's Calculator -
A web based risk calculator created by Dr. stephen B. Halls, M.D. Uses Gail model and
supplements with additional risk factors like alcohol consumption, mammographic density,
etc.
HIP
NSABP -
The National Surgical Adjuvant Breast and Bowel Project is a clinical trials
cooperative group supported by the National Cancer Institute (NCI). In its more than
40-year history of designing and conducting clinical trials NSABP has influenced the
treatment and prevention of breast cancer in a major way.
NSABP enrolls eligible women and men in clinical trials in breast and colorectal cancer.
Headquartered in Pittsburgh, Pennsylvania NSABP has research sites at nearly 1000 major
medical centers, university hospitals, large oncology practice groups, and health
maintenance organizations in the United States, Canada, Puerto Rico, Australia, and
Ireland. At those sites and their satellites, more than 5000 physicians, nurses, and
other medical professionals conduct NSABP treatment and prevention trials.
The NSABP was one of the first organizations to undertake large-scale studies in the
prevention of breast cancer. BCPT, and STAR, described below are well-known trials
conducted by NSABP.
BCPT
STAR
The Gail model
Modified Gail model
The Claus model
The BRCAPRO model
The LAMBDA model
Tyrer, Duffy, Cuzick model
Colditz model
Risk assessment tools
The risk predicted by some of the above models, e.g., the Claus model and the Gail model
can be obtained from look-up tables prepared for different combinations of risk factors.
However, a number of interactive tools (computer programs) are available and using
these the risk for a given combination of factors can be estimated easily.
Public Health Projects Related to Breast Cancer
BCDDP
- The Breast Cancer Detection Demonstration Project was a breast cancer screening program conducted under the joint sponsorship of the National Cancer Institute (NCI) and the American Cancer Society (ACS). The project ran from 1973 through 1980 and enrolled 283222 women at 29 screening centers in 27 cities across the United States.
In 1979, the NCI established the BCDDP follow-up study cohort of 64182 participants from a subset of the women enrolled in the original BCDDP screening study. All 4275 women in the screening study with a diagnosis of primary breast cancer, all 25114 women who had undergone a breast biopsy that indicated a benign condition, and all 9628 women who had been recommended to have a biopsy or breast surgery performed but did not have a surgical procedure were included in the follow-up cohort. An additional 25165 women with no history of breast disease were matched to the subjects with breast cancer and to the subjects with benign breast disease for age, time of entry in the BCDDP study, ethnicity, screening center, and duration of participation in the BCDDP.
NHS -
The Nurses’ Health Study, cohort was established in 1976, when 121,701 female, U.S.
registered nurses between the ages of 30 and 55 years responded to a mailed questionnaire
that inquired about risk factors for cancer and heart disease, with a specific focus on
reproductive history, menopausal status, contraceptive practices, hormone use, cigarette
smoking, and use of permanent hair dyes. The details of the establishment of this cohort
have been reported
here.
Briefly, in 1976, women reported their age at first full-term pregnancy and
the number of pregnancies lasting 6 months or more. In 1978 this information was
updated, and the women were asked to record the ages of their living children. Every 2
years thereafter, follow-up questionnaires were mailed to the women to bring the
information about risk factors up to date and to ascertain whether major medical events
occurred in-between. Reproductive history was updated through 1984, and other breast
cancer risk factors were updated upto 1998. Deaths in the cohort were reported by family
members or identified through the postal service or by a search of the National Death
Index.
SEER - The Surveillance, Epidemiology, and End Results Program of the NCI is an authoritative source of information on cancer incidence and survival in the United States. SEER began collecting data on cases on January 1, 1973, in five states and a couple of metropolitan areas of the United States. The SEER coverage progressively increased over the years and it currently collects and publishes cancer incidence and survival data from 14 population-based cancer registries and three supplemental registries covering approximately 26 percent of the US population.
The SEER Program is considered the standard for quality among cancer registries around the world. Quality control has been an integral part of SEER since its inception. Every year, studies are conducted in SEER areas to evaluate the quality and completeness of the data being reported.
CASH - The Cancer and Steroid Hormone Study, a SEER Landmark Study, was a population-based, case-control study conducted by eight SEER registries during the 1980s to investigate the relationship between oral contraceptive (OC) use and breast, endometrial, and ovarian cancers among U.S. women.
Women's CARE -
The Women’s Contraceptive and Reproductive Experiences, another SEER Landmark Study,
corroborated the earlier findings that OC use does not appear to increase the risk
of breast cancer in women. This study included women, 35 to 64 years old, who had
invasive breast cancer initially diagnosed between 1994 and 1998. The SEER registries in
Atlanta, Detroit, Los Angeles, and Seattle provided support for this study.