Sunday, March 6, 2011

Breast Cancer Energetics

Breast Cancer afflicts over a million women worldwide and just over 200,000 women in the US.  About 40,000 deaths are directly attributed to this disease.

From 2003-2007, the median age at diagnosis for cancer of the breast was 61 years of age3. Approximately 0.0% were diagnosed under age 20; 1.9% between 20 and 34; 10.5% between 35 and 44; 22.6% between 45 and 54; 24.1% between 55 and 64; 19.5% between 65 and 74; 15.8% between 75 and 84; and 5.6% 85+ years of age. The age-adjusted incidence rate was 122.9 per 100,000 women per year. These rates are based on cases diagnosed in 2003-2007 from 17 SEER geographic areas.


The incidence has recently stabilized after a prolonged increase for several years. The thinking is that the hormone replacement therapy used widely in the past may have contributed to that rise. The Join-point analyses shows the following trend based on the SEER data a rising rate of 0.4 through 1975-1990 and a drop -2.2 from 1990-2007. These numbers are of significant value in terms of long-term trends.
Other factors that contributed include worldwide awareness and early diagnosis, self-examination and the use of mammography for early detection. Early detection may have helped the lead-time-bias to diagnose the disease earlier, thus migrating patients into an earlier stage-time. The benefits of early detection have been significant.

Incidence of Breast Cancer

Over the past 30 years, the distribution of breast cancer stages has changed. The diagnosis of ductal carcinoma in situ (DCIS) and very early stage breast cancer (stage I) has increased. Diagnosis of DCIS alone has increased by more than 350%in white women over 50 and more than 400% in African American women over the age of 50 Large increases have been seen in diagnosis of DCIS and stage I breast cancer in women under 50 as well. These changes suggest that higher screening rates and better screening tools allow more breast cancer cases to be caught in early stages when they are most treatable.
Breast Cancer Stage migration over decades

Migrating the diagnosis to an earlier time also leads to down-staged (or found at an earlier stage) disease. Finding the disease in early stage without spread leads to better cure rates. That pattern of falling incidence seems to be moderating now since those patterns of care have been factored in already.

Stage Distribution and 5-year Relative Survival by Stage at Diagnosis for
1999-2006, All Races, Females
Localized (confined to primary site)
5 Yr Survival 98.0%
Regional (spread to regional lymph nodes)
5 Yr Survival 83.6%
Distant (cancer has metastasized)
5 Yr Survival 23.4%
Unknown (un-staged)
5 Yr Survival 57.9%

We concentrate for this discussion on genes as they relate to breast cancer.

It is well known that a strong family history of both vertical (mother to child) and horizontal (sister and sister) transmission of the genetic effect can have an impact on elevating the risks of this disease. Additionally if the disease has occurred in younger family members there is a higher level of suspicion that genetics may be involved in the initiation and promotional processes of the disease. (By initiation is meant the denovo cause of the disease specifically due to genetic mutation and promotion means that the inherent cause may still be undetermined but subsequent genetic mutation, such as, from environmental factors may have caused the disease to blossom).

BRCA gene mutation:
Mary-Claire King PhD

Mary-Claire King, PhD who discovered that humans and chimpanzees share 99% of the genome also discovered the BRCA1 and BRCA2 suppressor genes found on Chromosome 17 as a root cause for about 8-14% of all breast cancers in white women. These two genes are a normal part of the human genome. These two genes are involved in day-to-day regulation of the human genome, picking off any abnormality such as an uncalled for genetic mutation. That is why they are called tumor suppressor genes. They suppress any genetically malfunctioned cellular growth activity. Dr. King found that there were cohorts of individuals in various communities who had a predisposition to dysregulation of these two genes. These individuals were predominantly from the Ashkenazi Jewish background and lived in Long Island, NY and Peru. The genetic malfunction seemed to be within pockets of communities. Further testing has expanded the relative occurrence of these gene malfunctions in the Dutch and Icelandic populations also.

BRCA gene function:

 The BRCA 1 gene functions to repair the double stranded DNA breaks that occur due to damage. It is a part of a protein complex that works its reparative magic when the DNA is wrapped around the histone in the cell’s nucleus. Research has identified hundreds of mutations of the BRCA gene complex that are associated with the breast cancer risk.
BRCA 1 gene coded protein

Women with an mutated BRCA1 or BRCA2 gene have up to an 60% (6 of 10) risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations

BRCA1 and BRCA 2 gene mutations are associated with a 5 times higher risk of breast cancer then the general population. (60% versus 12%). Women with BRCA 1 gene mutation also have higher risks of ovarian cancers and to a lesser extent cervical, and uterine. Those with BRCA 2 gene mutation have higher risk of pancreatic cancer, stomach, gallbladder, bile duct cancer (Interestingly these four cancer arise in close proximity to each other) and melanoma. Men who carry BRCA 1 mutation have a higher risk for male breast cancer, pancreatic cancer, testicular cancer and prostate cancer.

It is important to know that not every individual with the BRCA 1 and 2 mutation will develop breast, ovarian or any other cancer. In addition those individuals with the BRCA mutation with SNPs (single nucleotide polymorphisms) called “snips” may increase the inherent risk further and potentially cause more aggressive types of cancer (The more mutations the DNA uncurs the more aggressive the behavior of that cancer cell).

Other genes that show mutations in hereditary breast and ovarian cancer include TP53 (considered the guardian of the genome and implicated with Li Fraumeni syndrome), PTEN (cell regulatory gene), STK11/LKB1, CDH1(associated with lobular cancer of the breast and stomach cancer), CHEK2 (tumor suppressor gene which limits wayward cell proliferation), ATM (DNA repair gene), MLH1, and MSH2.

Breast Cancer Risk Monitoring is necessary for the following individuals:

1. Two first-degree relatives or three or more first or second-degree family members with breast cancer before age 50.
2. Both breast and ovarian cancer exist in the first or second-degree relative.
3. Women in the family have breast cancer.
4. Ashkenazi Jewish heritage especially with family member with breast or ovarian cancer.
5. A male member in the family with breast cancer. (Male breast cancer is 1% of the total breast cancer prevalence.
6. A first-degree relative with bilateral breast cancer.
7. Individuals with dense breasts have a six-times higher risk.
8. Radiation therapy for Hodgkin or Non-Hodgkin Lymphoma before age 30.
9. Full term pregnancy after age 30
10. Long Menstrual history.

Options that exist for individuals with known BRCA gene mutations:


1. Monthly self-examination
2. Breast examination by medical professional

3. Mammography
Digital (left) vs Analog Mammography (right)

4. MRI of the breasts

MRI scan of the breast

5. Ultrasonography of the breasts as a supplemental test.
6. Prophylactic Bilateral Mastectomy (removal of both breasts) and Salpingo-oopherectomy Removal of ovaries and the fallopian tubes). 

Risk avoidance:
Avoid the following things:

1. Fatty diet
2. Obesity
3. Smoking
4. Alcohol
5. Hormone replacement therapy
6. Birth Control Pills
7. Sedentary habits


The large P1 study determined that use of Tamoxifen (a Serum Estrogen Modulator) in high-risk individuals for breast cancer had a 50% reduction of that risk by taking the SERM. Physicians will generally assess the risk factors related to a specific patient and determine the need for this preventative measure. The balance between the protective effect and the potential side effects of the medication must always be taken into account and should be discussed with the physician.

Oncotype DX:

Genetics have also helped in decision-making regarding patient care. A DNA micro-array chip of 21 mutated genes (Oncotype DX) can determine the nature of the malignancy, whether it is aggressive or not and thus determine the need for chemotherapy. 
MammaPrint (70 coded genes) vs OncoType DX (21 coded genes)

The assay is indicated in a select group of patients with Stage I and II, lymph node negative and Estrogen Receptor positive disease state. It defines a 10 year projected risk of recurrence and thus tailors treatment for the individual patient. The Oncotype DX has benefited many patients over the past several years and modifications of the same, will further define individualized therapy.


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