Breast Cancer, Early Disease, and Prevention

Question 1

Describe the normal physiology of the breast.

Answer 1

• The breast is a modified eccrine gland and embryologically related to the skin
• Development of the breast begins at puberty under the influences of the hormones estrogen and progesterone
  
  • Estrogen is responsible for ductal elongation, and progesterone for lobular development
• Terminal differentiation of the mammary gland does not occur until a term pregnancy, and the florid proliferation that occurs during pregnancy regresses after weaning through a process of involution

Question 2

What are the major risk factors of breast cancer?

Answer 2

• Risk factors for breast cancer are related to hormonal exposure and to genetics
• Hormonal factors increase risk by a relatively modest amount (2-fold or less); they include:
  
  • early menarche
  • later first term pregnancy
  • late menopause
  • use of exogenous hormones (small risk for contraceptive use and larger risk for postmenopausal hormones)
• Other hormonally mediated risk factors include postmenopausal obesity and moderate to heavy alcohol use
• Like other solid tumors, breast cancer is a disease of aging and 2/3 of breast cancers occur in premenopausal women
• When breast cancer occurs early in life, particularly if there is a family history of breast cancer, an inherited genetic susceptibility may be responsible
  
  • The major source of this lies with mutations in the BRCA1 and BRCA2 genes, which are inherited in an autosomal dominant fashion, but other genetic syndromes also apply
• These highly penetrant gene mutations increase risk by 15-fold or more
  
  • Other weak genetic influences also exist, and much of the breast cancer seen in families may be related to a confluence of multiple low penetrance genes

Question 3

What are proliferative epithelial lesions of the breast?

Answer 3

• These two major sources of breast cancer risk (hormonal exposure and genetics) converge in the causation of proliferative epithelial lesions in the breast which indicate increased breast cancer risk
  
  • If hyperplasia without atypia is present, the risk is increased by about 2-fold
  • The presence of atypical hyperplasia increases risk by about 4-fold
  • Lobular carcinoma in situ (LCIS) is also a risk marker and implies an 8-10 fold increased risk.
• These epithelial lesions are usually found on screening mammography and diagnosed by image-guided core needle biopsy
• Women with atypical hyperplasia or LCIS are particularly likely to benefit from medication for breast cancer prevention

Question 4

What are the prevention options for breast cancer?

Answer 4

• Life-style measures for breast cancer prevention should be offered to all women regardless of risk status
  
  • healthy diet
  • regular physical activity
  • maintaining a close to ideal body weight
  • moderation in alcohol use
  • lactation for at least 2 years (lifetime) for women planning to be pregnant
• Medication for breast cancer prevention has been tested in randomized trials of women who were judged to be at high risk, as calculated using a logistic regression model that includes a number of risk factors
  
  • These medicines are endocrine agents that work through estrogen deprivation
  • One group, the selective estrogen receptor modulators (SERMs) blocks estrogen through competing for the estrogen receptor, and the other group, aromatase inhibitors, decrease estrogen production by inhibiting conversion of estradiol precursors to estradiol
• Both groups decrease breast cancer risk by about one-half, and are prescribed for 5 years
  
  • Acceptance of these medications by high risk women has been low due to concern about side effects (uterine cancer and thromboembolism for SERMs and bone loss/arthralgia for AIs)
• The final preventive option is **bilateral prophylactic mastectomy, **generally reserved for women with cancer-causing mutations such as BRCA1/2
• This drastic intervention is however, very effective and reduces risk of breast cancer by more than 90% (e.g. for a woman with a starting lifetime risk of 70%, the residual risk would be 3.5%)

Question 5

What is involved in the diagnosis and staging of breast cancer?

Answer 5

• Most breast cancer presents as either a mammographic abnormality or as a palpable lump
• Diagnosis is generally made by core needle biopsy which may or may not require imaging guidance
  
  • The biopsy provides information about histological features that can be assessed on routine (hematoxylin and eosin) staining such as the pattern (ductal, lobular, other), the grade (how far the microscopic appearance has drifted from normal), and the presence of tumor cells in blood or lymph channels
• Once a diagnosis is made, a clinical stage can be assigned, based on the tumor size (by imaging or palpation), the presence of enlarged/abnormal lymph nodes, and any indication of metastases (spread to other organs)
  
  • Like other solid tumors, these features are summarized in the TNM (Tumor, Nodes, Metastasis) Staging system
• In general, tumors that are confined to the breast and are small are Stage 1, tumors that appear to involve the lymph nodes are Stage II (if small) or III (if large)
  
  • Tumors that have spread to distant organs are Stage IV
• This initial clinical staging exercise helps to design the treatment plan in that women whose tumors have metastasized are not generally advised to receive specific therapy to the breast, and their treatment consists of medications by mouth (endocrine agents) or chemotherapy which is usually given by vein
• If there is no reason to suspect metastases, the initial steps in treatment are generally directed to the breast, although with large tumors, or those that have invaded into the skin or chest wall
  
  • An initial period of medical therapy (neoadjuvant therapy) may be used to shrink the tumor prior to surgery

Question 6

What are the methods of local treatment of the primary breast tumor?

Answer 6

• The classical treatment for the primary breast cancer was mastectomy
  
  • In the 1960s, Dr Bernard Fisher and colleagues articulated a hypothesis that breast cancer is a systemic disease at outset, and therefore breast conserving resection of the tumor (popularly called “lumpectomy”) would provide equivalent survival compared to mastectomy
  • In a landmark clinical trial (NSABP B06), they tested this hypothesis; women with Stage I-II breast cancer were randomly assigned to treatment with wide excision of the tumor vs. wide excision with breast radiotherapy versus mastectomy
  • All participants received axillary dissection (removal of axillary lymph nodes), and all women with tumor-involved lymph nodes received chemotherapy
• On long-term follow-up (upto 20 years) no difference was observed in the overall survival of these three groups
• The two wide-excision groups did as well as the mastectomy group, but the frequency of in-breast tumor recurrence was 40% in the wide excision alone group, compared to 14% in the wide excision plus radiotherapy group
  
  • Thus survival and local control are equally good for women who receive wide excision with tumor-free margins and radiotherapy as it is for women who are treated with mastectomy

Question 7

What are some important molecular markers involved in the classification and treatment of breast cancer?

Answer 7

• Classically, breast cancers were categorized by stage, grade, and histology
• The first biologic classifier ever defined was the presence of the estrogen receptor (ER) protein, discovered by Geoffrey Greene at the University of Chicago in the 1960s
  
  • This discovery explained the fact that some breast cancers respond to endocrine strategies and some do not (the first-ever example was the use of oophorectomy by Beatson in the 1890s)
• The presence of the estrogen receptor protein in about 2/3 of breast tumors allows an opportunity to use drugs that either occupy the receptor and competitively inhibit the growth-promoting influence of endogenous estradiol, or deplete the body of estradiol
• It was subsequently noted that there is a correlation between classical classifiers and ER positivity in that ER+ tumors tended to be better differentiated (lower grade), and most lobular cancers were ER+
• The next step in the biological definition of breast cancer came with the discovery that the HER2-neu gene was amplified in about 20% of breast cancers, leading to massive overexpression of the HER2 protein, and associations with high grade, rapidly proliferating and aggressive tumors

Question 8

How do molecular tools contribute to the diagnosis and treatment of breast cancer?

Answer 8

• Molecular tools such as expression arrays were applied to the study of breast cancer biology, and it became clear that gene expression patterns of breast cancer associated with these known prognostic and predictive markers, and further refinement of biological classification became possible
• Currently, there are several biological classifiers that have been validated prospectively, in studies that demonstrate superior prognostic value when compared to the classical parameters of stage, grade, and histology
• The major biological categories are:
  
  • Luminal A (ER/PR positive, HER2 negative, low proliferation)
  • Luminal B (ER/PR positive, high proliferation
  • HER2 positive
• These gene-expression-based tests also provide predictive information as to which treatment is likely to be successful
  
  • The most widely used of these is the Onctotype-Dx Recurrence Score, which is used in women with ER positive and node negative tumors, and predicts whether or not chemotherapy will be useful in addition to endocrine therapy

Question 9

What are the goals of local and systemic therapy for breast cancer?

Answer 9

• Local therapy consists of measures that affect the specific region where they are directed (surgery and radiation), and is intended to ablate/destroy the local tumor, and to maintain control over the long term
• In breast cancer therapy, this means removal of the tumor with surgery, followed by consolidation of this with radiotherapy
  
  • ​Success is measured in terms of the loco-regional area (breast/chest wall/regional lymph nodes) remaining free of recurrence
  • Systemic therapy is delivered orally or by vein (endocrine, cytotoxic, or biologic) and in the setting of primary disease, has the goal of killing tumor cell deposits which may be present in other organs
• If successful, it will reduce the chances of tumor recurrence in other organs (i.e. metastatic disease) in the future and will increase cure rates
• Systemic therapy is the mainstay of therapy in women who relapse after initial treatment, with appearance of tumor growths at distant sites (most commonly bones, lung, and liver)
  
  • It is also the main form of treatment in women who have detectable distant disease when their tumor is first diagnosed (de novo Stage IV breast cancer)
• There is of course some interaction between local and systemic therapy in that good local control promotes survival and effective systemic therapy aids both local and distant control of tumor