1. Reproduction III: Cancers of the Reproductive System
Nancy Long Sieber, Ph.D.
October 25, 2010

2. Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2007, there were 562,875 cancer deaths in the US.

3. Compared to the peak rate of 215
Compared to the peak rate of per 100,000 in 1991, the cancer death rate decreased 17% to in Rates for other major chronic diseases decreased substantially during this period.

4. Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that about 1.5 million new cases of cancer will be diagnosed in Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers in both men and in women.

5. Lung cancer is, by far, the most common fatal cancer in men (29%), followed by prostate (11%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (9%) are the leading sites of cancer death.

6. Cancer Risk Factors Age – Cancer risk increases with age
Genetics – accounts for only about 5% of cases
Environmental exposures can cause somatic mutations. Eg: chemicals, tobacco, dietary factors, UV radiation, hormones, radiation
Lifestyle Factors
Tobacco use
Obesity & inactivity
Infectious agents, eg: hepatitis B, human papilloma virus, HIV, Helobacter pylori - exposure related to behavioral activities, some can be controlled by antibiotics.
Skin cancer – sun exposure & sunscreen use.

7. Cancer risk increases with age

8. International Breast Cancer Statistics There is a 3 to 4-fold difference in breast cancer rates between Western countries and Asia. The difference does not appear to be genetic, since women of Japanese ancestry living in the US have breast cancer rates similar to other American women.
McPherson, K et al. BMJ 2000;321:

9. Breast cancer incidence among Japanese Americans approaches that of white Americans. Suggests environmental factor. Diet? Exercise? Something else?

10. Cancer Statistics
It is hard to get good numbers for the incidence of certain cancers. Eg: breast and prostate cancer.
Changes in death rates may reflect a reduced incidence, better screening (leading to earlier treatment) or more effective treatments.
What does it mean to be “cured” of cancer? It depends on the type of cancer.

11. Breast cancer incidence rose between 1976 and 2000, largely due to greater use of mammograms. Levels have declined recently, perhaps due to reduced use of hormone replacement therapy.
After increasing from 1994 to 1999, breast cancer incidence rates in women decreased by 2.0% per year from 1999 to 2006, likely due in part to a reduction in use of hormone replacement therapy and a slight decline in mammography utilization. However, close inspection of the data show that in the last 4 years, rates have remained relatively unchanged. Similarly, although incidence of lung cancer has increased slightly by 0.4% per year since 1991, rates in the most recent several years have plateaued. Colorectal cancer incidence rates have been decreasing rapidly by 2.2% per year since 1998.

12. Similarly, the incidence of prostate cancer rose with the use of PSA screening
Incidence rates of prostate cancer have changed substantially over the last 20 years: rapidly increasing from 1988 to 1992, declining sharply from 1992 to 1995, remaining stable from 1995 to 2000, and decreasing from 2000 to 2006, due, in part, to changes in prostate cancer screening with the prostate-specific antigen (PSA) blood testing. Incidence rates for both lung and colorectal cancers in men have declined in recent years.

13. Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing; this decrease has been estimated to account for about 40% of the overall decrease in cancer death rates in men. Stomach cancer mortality has decreased considerably since Death rates for prostate and colorectal cancers have also been declining.

14. Lung cancer death rates in women have leveled off after rapidly increasing for several decades. The gender difference in the pattern of lung cancer is because smoking rates peaked in women several decades later than in men. In comparison, breast cancer death rates changed little between 1930 and 1990, but decreased 29% between 1990 to The death rates for stomach and uterine cancers have decreased steadily since 1930; colorectal cancer death rates have been decreasing for more than 50 years.

15. What does it mean to be cured of cancer? 5 year survival? 10 year?
From  National Statistics: Cancer Trends in England and Wales : (The different colored lines are for different years of diagnosis and show improving survival rates over time.  These are UK figures for all stages (1-1V) of  the cancers.  US and Australian survival rates are somewhat higher but follow the pattern shown.)

16. What is cancer?

17. Acquired Capabilities of Cancer
From: Hanahan D. Weinberg RA. The hallmarks of cancer. Cell Jan 7;100(1):57-70

18. Cancer cells lose normal contact inhibition, and continue to divide despite bumping into other cells.

19. Abnormalities characteristic of pre-cancer and cancerous cells
Hyperplasia – Overgrowth of normal looking cells
Atypia – Abnormal looking cells.
Carcinoma in situ – neoplastic cells that have not spread

20. Tumor Development Occurs in Stages
Weinberg RA. How cancer arises. Sci Am Sep;275(3):62-70.

21. Tumor Development Occurs in Stages, cont.
Weinberg RA. How cancer arises. Sci Am Sep;275(3):62-70.

22. The Molecular Genetics of Cancer

23. Consider the cell cycle:

24. It takes an average of 3-7 independent random genetic changes for a cell to become cancerous.

25. The likelihood of mutation increases if certain key mutations have occurred.
Most important are mutations in genes that are involved in the “proofreading” of the DNA. These include adenomatous polyposis coli (APC) and p53 genes.
These lead to genomic instability, and make subsequent mutations more likely.

26. Genetic abnormalities in cancer cells
Oncogenes get activated or become expressed more than normal
Oncogene: a gene that, when mutated or dysregulated, participates in the onset and development of cancer. (Normal form is called a “proto-oncogene”).
The protein may be
expressed at a greater level (more protein in the cell)
become more active
lose its potential to be regulated
increase its stability (hang around in the cell longer)
These changes can cause the cell to be hyper-responsive to growth signals, grow in the absence of proper growth signals, evade apoptosis, etc.

27. Genetic abnormalities, cont.
Tumor suppressor genes stop working
Tumor suppressor gene: a gene that protects a cell from one step in the cancer pathogenesis process
The gene product may be a protein that maintains the normal cell cycle, inhibits an oncogene, inhibits cell division, etc.
When a tumor suppressor gene is mutated or dysregulated, the cell can progress to cancer if other aberrations are also present

28. Oncogenes promote unregulated cell division

29. This is how p53, a tumor suppressor gene, normally works:
When p53 is damaged, this normal repair and control does not take place.

30. (Normal form is called a “proto-oncogene”).
Gibbs WW. Untangling the roots of cancer. Sci Am Jul;289(1):56-65.

31. What Causes Mutation?
Infectious agents, especially viruses. Eg: papilloma viruses, HTLV-1, hepatitis B and C.
Chemical carcinogens – chemical changes in DNA, often after forming DNA adducts. May also alter RNA or protein (epigenetic changes)
Radiation – chromosome breaks and translocations

32. DNA adducts occur when a chemical binds to DNA
Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA43
Normal DNA

33. How does cancer spread from one site to another?

39. Cancer Treatments Chemotherapy Radiation Anti-angiogenic Factors
Targeted therapies Examples:
Hormonal therapy – block hormones that promote tumor growth
Monoclonal antibodies – target markers on the tumor with antibodies, immune system destroys them.
Why does cancer therapy sometimes fail?

40. Chemotherapy Effects and Side-effects

41. How do people die of cancer?
Compression of healthy tissues, especially in the brain.
Organ failure, as tumor compromises function of the organ of origin, or an organ where it has metastasized. Eg: Liver failure
Infection – chemotherapy compromises immune system. Eg: pneumonia

42. Is cancer painful?
Sometimes, especially if the cancer has spread to the bones.
Towards the end of life, people with cancer often experience difficulty breathing, and are given extra oxygen.
Hospice care provides morphine and other drugs to help with these kinds of discomfort during the last days.

43. Cancers of the Male Reproductive System
Examples:
Testicular Cancer
Prostate Cancer

44. Testicular Cancer Mostly in young men, median age 34 yrs.
Cause unknown, but risk factors include:
Congenital malformations of the testes
Possible role of environmental exposure to endocrine disruptors.

45. Prostate Cancer
Most common cancer in men. Diagnosed in 1 out of 6 men, and 1 in 36 die from it.
30% of men over 50 have it, 80% of men over 80 have it.
Widespread PSA testing has lead to an increase in diagnosis, but we are still unable to distinguish between indolent cases, which will probably never progress, and more aggressive ones.
“Watchful waiting” is the most common strategy if a man’s PSA levels are elevated, but he has no other symptoms.

46. Role of body weight and IGF-1 (insulin-like growth factor-1) in cancer development
Trends Endocrinol Metab Oct;17(8):328-36

47. T. vaginalis Parasitic protozoan
Infection affects 5-20% of U.S. young adults, typically asymptomatic in males
Causes inflammation and may induce anti-apoptosis genes
Preliminary data suggest that infection is linked to higher risk of aggressive prostate cancer

48. Cancers of the Female Reproductive System
Examples:
Breast Cancer
Cervical Cancer
Uterine (endometrial) cancer
Ovarian Cancer

49. Genes influence breast cancer risk but other factors are also involved

50. Breast Cancer Genes
from

51. BRCA genes and increased cancer risk
Type of Cancer
General Population That Will Develop Disease
Women With BRCA1 or BRCA2 Mutation Who Will Develop Disease
Breast
13.2%
36-85%
Ovarian
1.7% 
16-60%
BRCA2 is also associated with increased risk of prostate cancer,
male breast cancer, and pancreatic cancer.
Source: National Cancer Institute (

52. Odds of developing breast cancer:
by age out of 2,212
by age out of 235
by age out of 54
by age out of 23
by age out of 14
by age out of 10
Ever out of 8

54. Breast Cancer Staging Stage 0—Carcinoma in situ 5 year survival = 100%
Atypical cells have not spread outside of the ducts or lobules.
Stage I—Early stage invasive breast cancer year survival = 98%
The tumor is < 2 cm in diameter, and has not spread to surrounding lymph nodes or outside the breast.
Stage II A and B year survival = 92 and 81%
Tumor enlarging, beginning to spread to local lymph nodes
Stage III A and B year survival = 67 and 54%
Further enlargement, and spread to additional lymph nodes or the chest wall and other local structures.
Stage IV year survival = 27%
The cancer has spread to distant organs or tissues, such as the liver, lungs, brain, or bone

55. Receptors present on the tumor cells can be used to target therapy
Estrogen receptors – hormonal therapy (tamoxifen, an estrogen receptor blocker) as well as aromitase inhibitors (block estrogen production)
Progesterone receptors – usually present when estrogen receptors are present, usually use hormonal therapy
HER2 (human epidermal growth factor receptor 2) – responds to Herceptin
“Triple Negative” cancers, which lack all 3 receptors, are harder to treat.

56. HER2 and Herceptin

57. Cervical Cancer Risk Factors
Women who have sex at an early age,
Women with multiple partners or who have partners who have multiple partners are at high risk.
Cigarette smoking also increases risk (potentially through the affecting immune response or inducing genetic damage)

59. Uterine Cancer

60. Ovarian cancer has often spread to other organs before it is diagnosed.

61. July 17, 2009