- Email: [email protected]
Colorectal carcinoma in a patient with prior breast cancer: Is there a causal link?
Radiography (2008) 14, 2e7
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / r a d i
Colorectal carcinoma in a patient with prior breast cancer: Is there a causal link? Elaine Scarles a, Julie Nightingale b,* a
Blackpool Victoria Hospital, Blackpool, Lancashire FY3 8NR, UK Department of Radiography, School of Health Care Professions, University of Salford, Salford, Greater Manchester, M6 6PU, UK
b
Received 13 April 2006; accepted 11 August 2006 Available online 19 October 2006
KEYWORDS Risk factors; Colonic neoplasm; Breast neoplasm; Neoplasm, second primary; Early diagnosis; Epidemiology
Abstract A 70-year-old female patient with prior breast cancer was diagnosed with colorectal carcinoma six years following the original breast referral. The cancers were both discovered at an early stage enabling potentially curative surgery to be performed, with an associated good long-term prognosis. This article explores a range of cancer risk factors associated with lifestyle, genetics and medication to ascertain whether the two primary cancers were independent oncological events, or whether they were related. Factors such as smoking, alcohol consumption, genetic predisposition and the use of contraceptives and Tamoxifen may increase the relative risk for both cancers. Various studies have offered conflicting data regarding the relative risk for developing the second cancer, but long-term cohort studies will continue to add to the evidence base. It is possible that the outcomes of these studies may have implications for the follow up of breast cancer patients within the colorectal cancer screening service. Published by Elsevier Ltd on behalf of The College of Radiographers.
Introduction A 64-year-old female patient was diagnosed with a Grade 2 duct carcinoma in her left breast. She underwent a left mastectomy and axillary node clearance, and was prescribed Tamoxifen drug treatment. Five years later there was no evidence of recurrence so the Tamoxifen was discontinued and she was discharged to routine monitoring via the breast-screening programme.
* Corresponding author. Tel.: þ44 161 295 2158. E-mail address: [email protected] (J. Nightingale).
Six years following the diagnosis of breast cancer the patient was referred by her GP for urgent investigation of symptoms suggestive of colorectal carcinoma. A double contrast barium enema examination demonstrated an eight centimetre shouldered stricture in the transverse colon. This was confirmed by histology and computed tomography to be a moderately well differentiated adenocarcinoma of the colon (Dukes B, T3, N0, M0) (Table 1). Although the patient had a good prognosis, she had presented with two metachronous primary tumours in different anatomical sites within a relatively short timeframe. This article outlines the aetiology of breast cancer and colorectal cancer, and explores whether women with
1078-8174/$ - see front matter Published by Elsevier Ltd on behalf of The College of Radiographers. doi:10.1016/j.radi.2006.08.002
Colorectal carcinoma in a patient with prior breast cancer Table 1
Staging of colonic tumours
Stage Description (TNM) 0 I
II
III
IV
Modified Dukes’
Tis N0 T1, T2 N0
M0 Tumour in situ (mucosa) M0 A Tumour invades submucosa (T1) or muscularis propria (T2), no nodal spread or metastases T3, T4 N0 M0 B Tumour invades beyond muscularis (T3) or into adjacent organs (T4). No nodal spread Any T N1, N2 M0 C Tumour invades 1e3 local nodes (N1), 4 or more regional nodes involved (N2). No metastases Any T Any N M1 D Tumour metastasises to other organs (M1)
Traditionally colorectal tumours were staged using the Dukes’ system, but clinicians have now generally adapted the TNM staging system. T, tumour stage; N, lymph nodes affected; M, presence of metastases.
prior breast cancer are at increased risk for developing colorectal cancer.
Discussion Breast cancer and colorectal cancer are the two most common cancers to affect women in the United Kingdom,1 and at presentation she was in the high risk age bracket for developing both cancers.2 Research has investigated possible links between these cancers and whilst there may be a connection, factual proof seems tenuous. A proven link would have implications for the colorectal cancer screening services: should it be proven that women who have had breast cancer are more susceptible to colon cancer then they will need to be included in a regular colorectal monitoring programme.
3
Smoking and breast cancer Prior to the diagnosis of breast cancer, the patient had been a regular smoker. The link between smoking and breast cancer is complex, and is founded on 3 main theories: 1. carcinogens in tobacco may elevate the risk of breast cancer; 2. an anti-oestrogenic effect of smoking may actually protect women from breast cancer; and 3. smoking is associated with dietary patterns (such as alcohol intake) that may elevate breast cancer risk.7 Experimental evidence demonstrates that carcinogens in tobacco smoke induce neoplastic transformations in breast epithelial tissue;8 however, the likelihood of cancer induction appears to be related to the rate of differentiation and proliferation of epithelial cells. In other words, young nulliparous females are much more susceptible to the effects of smoking carcinogens on the breast than females following pregnancy and lactation (when the cells have differentiated) and after the menopause.8 With an increase in females smoking at an early age in the UK, it could be postulated that there is likely to be an associated increase in breast cancer in younger women. However, breast cancer is undoubtedly hormone dependent, and there is evidence to suggest that smoking may have an anti-oestrogenic effect in women.8 Therefore, to some extent there is a potentially protective effect of smoking at younger ages. One of the largest studies re-analysing worldwide data on 58,515 women with breast cancer found that smoking had little or no independent effect on the risk of the disease.9 However, they noted that smokers tend to drink more alcohol than non-smokers, and the risk of breast cancer is clearly linked to alcohol consumption. (The patient’s alcohol consumption was 14e21 units per week; 14 units is the maximum limit recommended for women.) Chaturvedi10 argues that in populations where smoking is highly prevalent, even a modest positive association would result in a substantial increase in the number of breast cancer cases.
Lifestyle Smoking and colon cancer The statistical chance of developing cancer can be influenced by lifestyle. For colorectal and breast cancers common risk factors are obesity and a sedentary lifestyle.3e5 The risk of colon cancer increases by an estimated 15% in overweight and 33% in obese people.6 Whereas little is known regarding the activity levels of the patient, she had a Body Mass Index of 22 so was not obese. Bowel cancer incidence is generally lower in populations with high fibre, low fat diets. However, prospective studies following people with high-fibre diets have reported variable results ranging from a lower risk of bowel adenomas and of carcinoma, to no association with colorectal cancer.6 An inverse relationship between fruit and vegetable intake and colorectal cancer has been noted in some studies, and a significant increase in colorectal cancer has been found in people with a high fat and a high red or processed meat consumption.3
Colorectal carcinoma is not normally considered to be a tobacco related cancer, although D’Avanzo et al.11 outline a number of clinical studies demonstrating a link between smoking and the development of colorectal adenomas (benign, but potentially malignant polyps). Experimental work has also identified that cigarette smoke extract promoted in-vitro angiogenesis in colon cancer growth, and adenoma formation in mice.12 The large case-control study by D’Avanzo et al. indicated that smoking was not a strong risk factor for colorectal cancer, even after a long induction period.11 They point out, however, that smokers tend to have a diet poor in fresh fruit and vegetables, and higher intakes of fats and alcohol, thus explaining an apparent association with smoking and colon cancer. This finding is also supported by Emmons et al. in their study of patients
4
E. Scarles, J. Nightingale
diagnosed with colorectal adenomas,3 but other studies have been unable to support a hypothesis of a common diet-related causal mechanism for both breast and colon cancer.7
Oral contraceptives and HRT Oral contraceptives and Hormone Replacement Therapy (HRT), used by many women at the time of the menopause, should be considered within the aetiology of colon cancer. Female hormones protect against colon cancer, possibly because of changes in bile synthesis and secretion, leading to a reduced concentration of bile acids in the colon. Previous studies suggest that the overall risk of colon cancer halves with 5e10 years of HRT use, and is reduced by 18% following the use of oral contraceptives at any time,6 although the effects significantly decrease after stopping treatment.13 Oestrogen-only HRT appears to have no effect on the risk of colon cancer, whereas combined oestrogeneprogestogen therapy HRT appears to reduce the risk.13,14 Kmet et al.,5 however, found that the risk for colon cancer is unrelated to prior HRT, or indeed menopausal status or hormone receptor status of breast cancer. It is not known if the patient in this case study had been prescribed HRT.
Tamoxifen treatment For post-menopausal women with oestrogen-receptive cancers and an absence of metastases, Tamoxifen (which blocks the effects of cancer-promoting oestrogen) has been shown to reduce recurrence by 40e50%.15 The patient was prescribed Tamoxifen for 5 years after her mastectomy, and its use has been implicated in increasing the risk of colorectal cancer. In 1995 a joint analysis of three major Scandinavian studies found that there was a significant increase (almost doubling) in the relative risk of developing colorectal cancer for patients undergoing Tamoxifen therapy.16 An American epidemiological cohort study by Newcomb et al.17 concluded that Tamoxifen therapy modestly increases the risk of colorectal cancer, but only after 5 years following initiation of therapy.17
Table 2
More recent research, however, seems to be contradicting these results. Various studies have found no additional colon cancer or second cancer risk following Tamoxifen use.18,19 Data collated from all Tamoxifenrelated randomised trials prior to 1990 (involving a total of 37,000 women from 55 randomised trials) found that Tamoxifen had no apparent effect on the incidence of colorectal cancer.20 These clinical findings have been opposed by experimental data, demonstrating that Tamoxifen and gonadal steroids can inhibit the growth of colon cancer cells.21 At the present time the research does not conclusively prove whether or not there is a possibility of the patient having increased susceptibility to colon cancer after Tamoxifen therapy, but whilst conflicting evidence still exists, clinicians need to be aware that any bowel symptoms should be viewed suspiciously.
Genetic links Three classes of genes have been implicated in carcinogenesis (oncogenes, tumour suppressor genes and DNA repair genes), with gene mutations leading to altered cellular growth and the potential induction of cancer (see Table 2). Specific gene mutations that follow a relatively consistent pattern have been identified in the development of colon cancer (Fig. 1).22 The evidence for specific genetic links for cancer is particularly strong when one considers familial breast and bowel cancers. Familial cancers are those that the patient has an inherited genetic susceptibility to developing. The genetics of familial colon cancer has been extensively investigated and genes linked to Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC) have been discovered. In the case of this patient, she did not have the numerous polyps associated with FAP, and her family history did not meet the criteria for HNPCC. It is therefore likely that her colorectal carcinoma was sporadic (random events). The hereditary breast cancer syndrome accounts for about 5e15% of all breast cancers, requiring a strong family history of breast cancer, particularly at a young age, with
Genes implicated in cancer development
Gene classification
Examples
Oncogenes
Tumour suppressor genes (TSGs)
p53 tumour suppressor gene; APC tumour suppressor gene
DNA repair genes
Mismatch repair gene, MMR
Role Mutated form of proto-oncogenes, which play an essential role in controlling cell proliferation and encoding growth and transcription factors Negative regulators of cell growth. Their inactivation results in loss of growth inhibition, hence the cell gains a growth advantage. Recessive genes so both copies must be inhibited for the malignant characteristics to occur. (50% of all tumours carry a p53 gene mutation) These genes repair DNA damage incurred due to numerous factors (such as spontaneous mutation and exposure to radiation). Mutations within DNA repair genes tend to result in a genetic instability leading to additional mutational events, such as inactivation of TSGs
Colorectal carcinoma in a patient with prior breast cancer
5 different types of cancers. Some studies suggest an underlying genetic predisposition linking breast cancer with some other cancers such as uterine serous cancer,24 but no links with colon cancer have yet been identified.
Normal Epithelium Inactivation of APC TSG Dysplastic DNA hypomethylation Early adenoma
Statistical chances of having a second cancer Activation of k-ras oncogene
Intermediate adenoma Inactivation of DCC TSG Late adenoma Inactivation of p53 TSG Carcinoma Rapid accumulation of mutations
Metastasis
Figure 1
Development of colorectal cancer (Cassidy et al.28).
bilateral cancers and multiple affected members.23 Again it appears that the patient did not fit into the hereditary category, more likely having a sporadic breast cancer. In sporadic cancers both copies of the genes involved need to undergo mutation, and as yet no definite genetic link between different sporadic cancers has been proven. The genetic role of cancer is beginning to be unravelled, and some genes have been found to be common to several
Table 3
Having considered some of the risk factors for both breast and colon cancer (Table 3), what are the chances of developing these two separate primary cancers? A study by Fowble et al.25 followed up 1253 women with early breast cancer who had received conservative treatment followed by radiation with or without adjuvant therapy. The 10year cumulative index of a second cancer was found to be 16%, with 167 women developing a second cancer at a median interval of 6.1 years from their initial breast cancer diagnosis.25 The patient in this case study also had an interval between her two cancers of 6 years. Excluding skin and contralateral breast cancer, the most common sites of second cancer were colorectal, endometrial and nonHodgkin’s lymphoma. The factors associated with a statistically significant increased cumulative incidence of a second non-breast cancer malignancy was age over 65 years, postmenopausal status, and the use of Tamoxifen as the only adjuvant therapy.25 Once again, this reflects closely with the patient in this case study. A German study by Ochsenku ¨hn et al.26 used colonoscopy to investigate the frequency of colorectal adenomas
Possible risk factors for breast and colorectal cancer
Risk factor
Breast cancer
Bowel cancer
Relevant to this patient?
Age over 65 Obesity/sedentary lifestyle High fat/red meat diet
[ [ e
[ [ [
Yes No ?
Low fruit/vegetable consumption Smoking
[ [
[ ?
? Yes
Alcohol
[
[
Yes
Oral contraceptives
e
Y
?
Combined oestrogeneprogesterone HRT
e
Y
?
Tamoxifen use
Y
[
Yes
FAP and HNPCC
e
[
No
Hereditary breast cancer syndrome
[
e
No
Comments
Some studies unable to support diet related hypothesis Menopausal women less susceptible to breast risks than young women. Some studies say smoking has little effect on breast. Smoking and colon cancer risk confounded by poor diet of some smokers Increased alcohol intake often associated with smoking Effects decrease significantly after stopping treatment Much debate surrounds effects of HRT on colon. Oestrogen only HRT less likely to have any effects Reduces recurrence of oestrogen receptive breast cancerdmost studies suggest small increase in colon cancer risk Familial colon cancer syndromes increase risk significantly
[, increased risk of cancer; Y, decreased risk of cancer; e, no evidence either way/not studied.
6 and carcinomas in women with breast cancer. Women with breast cancer were found to have a higher risk of adenomas than the age-matched controls, particularly in the 65e85 age group. Although colorectal carcinomas were found infrequently in both groups, the colonic adenomas do have a risk of malignant transformation.26 Ochsenku ¨hn et al. recommend that women with breast cancer should be encouraged to participate in colorectal cancer screening programmes. These are offered in most countries for average risk individuals over the age of 50,26 although there is an argument to suggest that they should be accessing more comprehensive high-risk programmes offered to some other client groups. However, a large retrospective cohort study based on 17,415 breast cancer women in the United Kingdom by Srinivasan et al. 2005 reported that women with prior breast cancer are not at an increased risk of colorectal cancer, and they recommend that they can follow average risk colorectal screening programmes.27
Conclusion Risk factors for the two primary cancers have been identified, and some of these (such as obesity, sedentary lifestyle, diet and alcohol intake) are common to both cancers. The evidence regarding tobacco smoking as a risk factor is debatable, with several studies suggesting that it is the associated alcohol consumption and poor diet of many smokers that is of greater significance. Many cancers are influenced to some degree by female hormones, and much controversy surrounds the potentially protective effect of HRT and contraceptive use on the colon, and the potentially harmful effect of Tamoxifen use. The genetics of cancer are only just beginning to be understood, and some genes are common to different cancer types. Although hereditary links have been associated with some types of breast and colon cancer, as yet no direct genetic link between sporadic breast and colon cancers has been shown. Large cohort studies following women diagnosed with breast cancer have offered variable results regarding the relative risk for developing colon cancer. Although a definite link between the two primary cancers has not been shown, all the research indicates that one must not be ruled out. Long-term follow-up studies of breast cancer patients continue to offer additional information regarding the risks, trends and patterns of second cancers, such that appropriate surveillance and screening strategies can be implemented. Evidence presented in this review is not conclusive in determining whether the probability of developing colon cancer was higher for the patient in the presented case history. Whilst two metachronous primary cancers developed within 6 years, it is possible that these cancers were sporadic (chance) events, as the patient did not meet the criteria for a hereditary cancer. She did, however, have a number of potential risk factors for the development of colorectal cancer (Table 3), including age over 65, postmenopausal status, smoking and alcohol use, and Tamoxifen treatment. Similar risk factors have been identified in breast cancer follow-up studies where patients have gone on to develop a second cancer,25 although a large
E. Scarles, J. Nightingale retrospective study suggested that there was no increased risk of colon cancer.27 With such contradictory evidence it is inappropriate to postulate that the probability of developing the second cancer was indeed raised for this patient.
References 1. Cancer Research UK. Fact sheets: Cancer statistics. http:// www.cancerresearchuk.org; 2006 [accessed on 06.04.06]. 2. Braunwald E, Fauci AS, Kasper DL, Hauser SL, Lango DL, Jameson LJ. Harrison’s principles of internal medicine, vol. 1. 15th ed. London: McGraw Hill Medical Publishing Division; 2001. 3. Emmons KM, McBride CM, Puleo E, Pollak KI, Marcus BH, Napolitano M, et al. Prevalance and predictors of multiple behavioural risk factors for colon cancer. Preventative Medicine 2005;40:527e34. 4. Cancer Research UK, Fact sheets: Breast cancer symptoms and treatment. http://www.cancerresearchuk.org; 2006 [accessed on 01.04.06]. 5. Kmet LM, Cook LS, Weiss NS, Schwartz SM, White E. Risk factors for colorectal cancer following breast cancer. Breast Cancer Research and Treatment 2003;79(2):143e7. 6. Cancer Research UK. Fact sheets: Bowel cancer statistics. http:// www.cancerresearchuk.org; 2006 [accessed on 06.04.06]. 7. Manjer J, Janzon L. Covariance of breast cancer incidence with smoking-, oestrogen- and diet-related cancers in pre- and postmenopausal women in Sweden. Medical Hypotheses 1999; 52(6):561e8. 8. Russo IH. Cigarette smoking and risk of breast cancer in women. The Lancet 2002;360:1033e4. 9. Collaborative Group on Hormonal Factors and Breast Cancer, Alcohol, tobacco, and breast cancer. Collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. British Journal of Cancer 2002;87:1234e45. 10. Chaturvedi P. Does smoking increase the risk of breast cancer? The Lancet Oncology 2003. p. 657e8. 11. D’Avanzo B, La Vecchia C, Franceschi S, Gallotti L, Talamini R. Cigarette smoking and colorectal cancer: A study of 1,584 cases and 2,879 controls. Preventative Medicine 1995;24:571e9. 12. Ye YN, Wu WKK, Shin VY, Cho CH. A mechanistic study of colon cancer growth promoted by cigarette smoke extract. European Journal of Pharmacology 2005;519:52e7. 13. Kenemans P, Verstraeten RA, Verheijen RHM. Postmenopausal hormone therapy and cancer risk. International Congress Series 2005;1279:133e40. 14. Olsson H, Bladstrom A, Ingvar C. Are smoking-associated cancers prevented or postponed in women using hormone replacement therapy? Obstetrics and Gynaecology 2003;102(3):565e70. 15. Breast Cancer Org. Five benefits of tamoxifen. http://www. breastcancer.org; 2004 [accessed on 04.04.06]. 16. Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N. Adjuvant Tamoxifen therapy for early stage breast cancer and second primary malignancies. Journal of the National Cancer Institute 1995;87(9):645e51. 17. Newcomb PA, Solomon C, White E. Tamoxifen and risk of large bowel cancer in women with breast cancer. Breast Cancer Research and Treatment 1999;53(3):271e7. 18. Cook LS, Weiss NS, Pharris CN, Schwartz SM, White E. Colorectal cancer following tamoxifen therapy for breast cancer. Cancer Causes and Control 2001;12(5):405e10. 19. Matsuyama Y, Tominaga T, Nomura Y, Koyama H, Kimura M, Sano M. Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan. Annals of Oncology 2000;11(12):1537e43. 20. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. The Lancet 1998;351:1451e67.
Colorectal carcinoma in a patient with prior breast cancer
7
21. Nakayama Y, Sakamoto H, Satoh K, Yamamoto T. Tamoxifen and gonadal steroids inhibit colon cancer growth in association with inhibition of thymidylate synthase, surviving and telomerase expression through estrogen receptor beta mediated system. Cancer Letters 2000;161:63e71. 22. Parham P. The immune system. London, England: Garland Publishing; 2000. 23. Fasching PA, Nestle-Kramling C, Brumm C, Djahansouzi S, Beckmann MW. Cancer in the family and implications for hormone replacement therapy. International Congress Series 2002;1229:157e61. 24. Gehrig PA, Bae-Jump VL, Boggess JF, Groben PA, Fowler WC, Van Le L. Association between uterine serous carcinoma and breast cancer. Gynecologic Oncology 2004;94:208e11.
25. Fowble B, Hanlon A, Freedman G, Nicolaou N, Anderson P. Second cancers after conservative surgery and radiation for stages I-II breast cancer: Identifying a subset of women at increased risk. International Journal of Radiation Oncology Biology Physics 2001;51(3):679e90. 26. Ochsenkuhn T, Bayerdorffer E, Meining A, Spath L, Mannes GA, Wiebecke B, et al. Increased prevalence of colorectal adenomas in women with breast cancer. Digestion 2005;72(2e3):150e5. 27. Srinivasan R, Yang Y, Rubin SC, Morgan MA, Lewis JD. Women with a prior diagnosis of breast cancer are not at an increased risk for subsequent colorectal cancer. American Journal of Gastroenterology 2005;100(12):2759e64. 28. Cassidy J, Bissett D, Spence RAJ. Oxford handbook of oncology. Oxford, UK: Oxford University Press; 2002.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / r a d i
Colorectal carcinoma in a patient with prior breast cancer: Is there a causal link? Elaine Scarles a, Julie Nightingale b,* a
Blackpool Victoria Hospital, Blackpool, Lancashire FY3 8NR, UK Department of Radiography, School of Health Care Professions, University of Salford, Salford, Greater Manchester, M6 6PU, UK
b
Received 13 April 2006; accepted 11 August 2006 Available online 19 October 2006
KEYWORDS Risk factors; Colonic neoplasm; Breast neoplasm; Neoplasm, second primary; Early diagnosis; Epidemiology
Abstract A 70-year-old female patient with prior breast cancer was diagnosed with colorectal carcinoma six years following the original breast referral. The cancers were both discovered at an early stage enabling potentially curative surgery to be performed, with an associated good long-term prognosis. This article explores a range of cancer risk factors associated with lifestyle, genetics and medication to ascertain whether the two primary cancers were independent oncological events, or whether they were related. Factors such as smoking, alcohol consumption, genetic predisposition and the use of contraceptives and Tamoxifen may increase the relative risk for both cancers. Various studies have offered conflicting data regarding the relative risk for developing the second cancer, but long-term cohort studies will continue to add to the evidence base. It is possible that the outcomes of these studies may have implications for the follow up of breast cancer patients within the colorectal cancer screening service. Published by Elsevier Ltd on behalf of The College of Radiographers.
Introduction A 64-year-old female patient was diagnosed with a Grade 2 duct carcinoma in her left breast. She underwent a left mastectomy and axillary node clearance, and was prescribed Tamoxifen drug treatment. Five years later there was no evidence of recurrence so the Tamoxifen was discontinued and she was discharged to routine monitoring via the breast-screening programme.
* Corresponding author. Tel.: þ44 161 295 2158. E-mail address: [email protected] (J. Nightingale).
Six years following the diagnosis of breast cancer the patient was referred by her GP for urgent investigation of symptoms suggestive of colorectal carcinoma. A double contrast barium enema examination demonstrated an eight centimetre shouldered stricture in the transverse colon. This was confirmed by histology and computed tomography to be a moderately well differentiated adenocarcinoma of the colon (Dukes B, T3, N0, M0) (Table 1). Although the patient had a good prognosis, she had presented with two metachronous primary tumours in different anatomical sites within a relatively short timeframe. This article outlines the aetiology of breast cancer and colorectal cancer, and explores whether women with
1078-8174/$ - see front matter Published by Elsevier Ltd on behalf of The College of Radiographers. doi:10.1016/j.radi.2006.08.002
Colorectal carcinoma in a patient with prior breast cancer Table 1
Staging of colonic tumours
Stage Description (TNM) 0 I
II
III
IV
Modified Dukes’
Tis N0 T1, T2 N0
M0 Tumour in situ (mucosa) M0 A Tumour invades submucosa (T1) or muscularis propria (T2), no nodal spread or metastases T3, T4 N0 M0 B Tumour invades beyond muscularis (T3) or into adjacent organs (T4). No nodal spread Any T N1, N2 M0 C Tumour invades 1e3 local nodes (N1), 4 or more regional nodes involved (N2). No metastases Any T Any N M1 D Tumour metastasises to other organs (M1)
Traditionally colorectal tumours were staged using the Dukes’ system, but clinicians have now generally adapted the TNM staging system. T, tumour stage; N, lymph nodes affected; M, presence of metastases.
prior breast cancer are at increased risk for developing colorectal cancer.
Discussion Breast cancer and colorectal cancer are the two most common cancers to affect women in the United Kingdom,1 and at presentation she was in the high risk age bracket for developing both cancers.2 Research has investigated possible links between these cancers and whilst there may be a connection, factual proof seems tenuous. A proven link would have implications for the colorectal cancer screening services: should it be proven that women who have had breast cancer are more susceptible to colon cancer then they will need to be included in a regular colorectal monitoring programme.
3
Smoking and breast cancer Prior to the diagnosis of breast cancer, the patient had been a regular smoker. The link between smoking and breast cancer is complex, and is founded on 3 main theories: 1. carcinogens in tobacco may elevate the risk of breast cancer; 2. an anti-oestrogenic effect of smoking may actually protect women from breast cancer; and 3. smoking is associated with dietary patterns (such as alcohol intake) that may elevate breast cancer risk.7 Experimental evidence demonstrates that carcinogens in tobacco smoke induce neoplastic transformations in breast epithelial tissue;8 however, the likelihood of cancer induction appears to be related to the rate of differentiation and proliferation of epithelial cells. In other words, young nulliparous females are much more susceptible to the effects of smoking carcinogens on the breast than females following pregnancy and lactation (when the cells have differentiated) and after the menopause.8 With an increase in females smoking at an early age in the UK, it could be postulated that there is likely to be an associated increase in breast cancer in younger women. However, breast cancer is undoubtedly hormone dependent, and there is evidence to suggest that smoking may have an anti-oestrogenic effect in women.8 Therefore, to some extent there is a potentially protective effect of smoking at younger ages. One of the largest studies re-analysing worldwide data on 58,515 women with breast cancer found that smoking had little or no independent effect on the risk of the disease.9 However, they noted that smokers tend to drink more alcohol than non-smokers, and the risk of breast cancer is clearly linked to alcohol consumption. (The patient’s alcohol consumption was 14e21 units per week; 14 units is the maximum limit recommended for women.) Chaturvedi10 argues that in populations where smoking is highly prevalent, even a modest positive association would result in a substantial increase in the number of breast cancer cases.
Lifestyle Smoking and colon cancer The statistical chance of developing cancer can be influenced by lifestyle. For colorectal and breast cancers common risk factors are obesity and a sedentary lifestyle.3e5 The risk of colon cancer increases by an estimated 15% in overweight and 33% in obese people.6 Whereas little is known regarding the activity levels of the patient, she had a Body Mass Index of 22 so was not obese. Bowel cancer incidence is generally lower in populations with high fibre, low fat diets. However, prospective studies following people with high-fibre diets have reported variable results ranging from a lower risk of bowel adenomas and of carcinoma, to no association with colorectal cancer.6 An inverse relationship between fruit and vegetable intake and colorectal cancer has been noted in some studies, and a significant increase in colorectal cancer has been found in people with a high fat and a high red or processed meat consumption.3
Colorectal carcinoma is not normally considered to be a tobacco related cancer, although D’Avanzo et al.11 outline a number of clinical studies demonstrating a link between smoking and the development of colorectal adenomas (benign, but potentially malignant polyps). Experimental work has also identified that cigarette smoke extract promoted in-vitro angiogenesis in colon cancer growth, and adenoma formation in mice.12 The large case-control study by D’Avanzo et al. indicated that smoking was not a strong risk factor for colorectal cancer, even after a long induction period.11 They point out, however, that smokers tend to have a diet poor in fresh fruit and vegetables, and higher intakes of fats and alcohol, thus explaining an apparent association with smoking and colon cancer. This finding is also supported by Emmons et al. in their study of patients
4
E. Scarles, J. Nightingale
diagnosed with colorectal adenomas,3 but other studies have been unable to support a hypothesis of a common diet-related causal mechanism for both breast and colon cancer.7
Oral contraceptives and HRT Oral contraceptives and Hormone Replacement Therapy (HRT), used by many women at the time of the menopause, should be considered within the aetiology of colon cancer. Female hormones protect against colon cancer, possibly because of changes in bile synthesis and secretion, leading to a reduced concentration of bile acids in the colon. Previous studies suggest that the overall risk of colon cancer halves with 5e10 years of HRT use, and is reduced by 18% following the use of oral contraceptives at any time,6 although the effects significantly decrease after stopping treatment.13 Oestrogen-only HRT appears to have no effect on the risk of colon cancer, whereas combined oestrogeneprogestogen therapy HRT appears to reduce the risk.13,14 Kmet et al.,5 however, found that the risk for colon cancer is unrelated to prior HRT, or indeed menopausal status or hormone receptor status of breast cancer. It is not known if the patient in this case study had been prescribed HRT.
Tamoxifen treatment For post-menopausal women with oestrogen-receptive cancers and an absence of metastases, Tamoxifen (which blocks the effects of cancer-promoting oestrogen) has been shown to reduce recurrence by 40e50%.15 The patient was prescribed Tamoxifen for 5 years after her mastectomy, and its use has been implicated in increasing the risk of colorectal cancer. In 1995 a joint analysis of three major Scandinavian studies found that there was a significant increase (almost doubling) in the relative risk of developing colorectal cancer for patients undergoing Tamoxifen therapy.16 An American epidemiological cohort study by Newcomb et al.17 concluded that Tamoxifen therapy modestly increases the risk of colorectal cancer, but only after 5 years following initiation of therapy.17
Table 2
More recent research, however, seems to be contradicting these results. Various studies have found no additional colon cancer or second cancer risk following Tamoxifen use.18,19 Data collated from all Tamoxifenrelated randomised trials prior to 1990 (involving a total of 37,000 women from 55 randomised trials) found that Tamoxifen had no apparent effect on the incidence of colorectal cancer.20 These clinical findings have been opposed by experimental data, demonstrating that Tamoxifen and gonadal steroids can inhibit the growth of colon cancer cells.21 At the present time the research does not conclusively prove whether or not there is a possibility of the patient having increased susceptibility to colon cancer after Tamoxifen therapy, but whilst conflicting evidence still exists, clinicians need to be aware that any bowel symptoms should be viewed suspiciously.
Genetic links Three classes of genes have been implicated in carcinogenesis (oncogenes, tumour suppressor genes and DNA repair genes), with gene mutations leading to altered cellular growth and the potential induction of cancer (see Table 2). Specific gene mutations that follow a relatively consistent pattern have been identified in the development of colon cancer (Fig. 1).22 The evidence for specific genetic links for cancer is particularly strong when one considers familial breast and bowel cancers. Familial cancers are those that the patient has an inherited genetic susceptibility to developing. The genetics of familial colon cancer has been extensively investigated and genes linked to Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC) have been discovered. In the case of this patient, she did not have the numerous polyps associated with FAP, and her family history did not meet the criteria for HNPCC. It is therefore likely that her colorectal carcinoma was sporadic (random events). The hereditary breast cancer syndrome accounts for about 5e15% of all breast cancers, requiring a strong family history of breast cancer, particularly at a young age, with
Genes implicated in cancer development
Gene classification
Examples
Oncogenes
Tumour suppressor genes (TSGs)
p53 tumour suppressor gene; APC tumour suppressor gene
DNA repair genes
Mismatch repair gene, MMR
Role Mutated form of proto-oncogenes, which play an essential role in controlling cell proliferation and encoding growth and transcription factors Negative regulators of cell growth. Their inactivation results in loss of growth inhibition, hence the cell gains a growth advantage. Recessive genes so both copies must be inhibited for the malignant characteristics to occur. (50% of all tumours carry a p53 gene mutation) These genes repair DNA damage incurred due to numerous factors (such as spontaneous mutation and exposure to radiation). Mutations within DNA repair genes tend to result in a genetic instability leading to additional mutational events, such as inactivation of TSGs
Colorectal carcinoma in a patient with prior breast cancer
5 different types of cancers. Some studies suggest an underlying genetic predisposition linking breast cancer with some other cancers such as uterine serous cancer,24 but no links with colon cancer have yet been identified.
Normal Epithelium Inactivation of APC TSG Dysplastic DNA hypomethylation Early adenoma
Statistical chances of having a second cancer Activation of k-ras oncogene
Intermediate adenoma Inactivation of DCC TSG Late adenoma Inactivation of p53 TSG Carcinoma Rapid accumulation of mutations
Metastasis
Figure 1
Development of colorectal cancer (Cassidy et al.28).
bilateral cancers and multiple affected members.23 Again it appears that the patient did not fit into the hereditary category, more likely having a sporadic breast cancer. In sporadic cancers both copies of the genes involved need to undergo mutation, and as yet no definite genetic link between different sporadic cancers has been proven. The genetic role of cancer is beginning to be unravelled, and some genes have been found to be common to several
Table 3
Having considered some of the risk factors for both breast and colon cancer (Table 3), what are the chances of developing these two separate primary cancers? A study by Fowble et al.25 followed up 1253 women with early breast cancer who had received conservative treatment followed by radiation with or without adjuvant therapy. The 10year cumulative index of a second cancer was found to be 16%, with 167 women developing a second cancer at a median interval of 6.1 years from their initial breast cancer diagnosis.25 The patient in this case study also had an interval between her two cancers of 6 years. Excluding skin and contralateral breast cancer, the most common sites of second cancer were colorectal, endometrial and nonHodgkin’s lymphoma. The factors associated with a statistically significant increased cumulative incidence of a second non-breast cancer malignancy was age over 65 years, postmenopausal status, and the use of Tamoxifen as the only adjuvant therapy.25 Once again, this reflects closely with the patient in this case study. A German study by Ochsenku ¨hn et al.26 used colonoscopy to investigate the frequency of colorectal adenomas
Possible risk factors for breast and colorectal cancer
Risk factor
Breast cancer
Bowel cancer
Relevant to this patient?
Age over 65 Obesity/sedentary lifestyle High fat/red meat diet
[ [ e
[ [ [
Yes No ?
Low fruit/vegetable consumption Smoking
[ [
[ ?
? Yes
Alcohol
[
[
Yes
Oral contraceptives
e
Y
?
Combined oestrogeneprogesterone HRT
e
Y
?
Tamoxifen use
Y
[
Yes
FAP and HNPCC
e
[
No
Hereditary breast cancer syndrome
[
e
No
Comments
Some studies unable to support diet related hypothesis Menopausal women less susceptible to breast risks than young women. Some studies say smoking has little effect on breast. Smoking and colon cancer risk confounded by poor diet of some smokers Increased alcohol intake often associated with smoking Effects decrease significantly after stopping treatment Much debate surrounds effects of HRT on colon. Oestrogen only HRT less likely to have any effects Reduces recurrence of oestrogen receptive breast cancerdmost studies suggest small increase in colon cancer risk Familial colon cancer syndromes increase risk significantly
[, increased risk of cancer; Y, decreased risk of cancer; e, no evidence either way/not studied.
6 and carcinomas in women with breast cancer. Women with breast cancer were found to have a higher risk of adenomas than the age-matched controls, particularly in the 65e85 age group. Although colorectal carcinomas were found infrequently in both groups, the colonic adenomas do have a risk of malignant transformation.26 Ochsenku ¨hn et al. recommend that women with breast cancer should be encouraged to participate in colorectal cancer screening programmes. These are offered in most countries for average risk individuals over the age of 50,26 although there is an argument to suggest that they should be accessing more comprehensive high-risk programmes offered to some other client groups. However, a large retrospective cohort study based on 17,415 breast cancer women in the United Kingdom by Srinivasan et al. 2005 reported that women with prior breast cancer are not at an increased risk of colorectal cancer, and they recommend that they can follow average risk colorectal screening programmes.27
Conclusion Risk factors for the two primary cancers have been identified, and some of these (such as obesity, sedentary lifestyle, diet and alcohol intake) are common to both cancers. The evidence regarding tobacco smoking as a risk factor is debatable, with several studies suggesting that it is the associated alcohol consumption and poor diet of many smokers that is of greater significance. Many cancers are influenced to some degree by female hormones, and much controversy surrounds the potentially protective effect of HRT and contraceptive use on the colon, and the potentially harmful effect of Tamoxifen use. The genetics of cancer are only just beginning to be understood, and some genes are common to different cancer types. Although hereditary links have been associated with some types of breast and colon cancer, as yet no direct genetic link between sporadic breast and colon cancers has been shown. Large cohort studies following women diagnosed with breast cancer have offered variable results regarding the relative risk for developing colon cancer. Although a definite link between the two primary cancers has not been shown, all the research indicates that one must not be ruled out. Long-term follow-up studies of breast cancer patients continue to offer additional information regarding the risks, trends and patterns of second cancers, such that appropriate surveillance and screening strategies can be implemented. Evidence presented in this review is not conclusive in determining whether the probability of developing colon cancer was higher for the patient in the presented case history. Whilst two metachronous primary cancers developed within 6 years, it is possible that these cancers were sporadic (chance) events, as the patient did not meet the criteria for a hereditary cancer. She did, however, have a number of potential risk factors for the development of colorectal cancer (Table 3), including age over 65, postmenopausal status, smoking and alcohol use, and Tamoxifen treatment. Similar risk factors have been identified in breast cancer follow-up studies where patients have gone on to develop a second cancer,25 although a large
E. Scarles, J. Nightingale retrospective study suggested that there was no increased risk of colon cancer.27 With such contradictory evidence it is inappropriate to postulate that the probability of developing the second cancer was indeed raised for this patient.
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