ESPAÑOLA, Mayreen M ñ Medical Therapeutics3A 23 July 2010

BREAST CANCER

INTRODUCTION

Carcinoma of the breast is the most common non-skin malignancy in women. A woman who lives to age 90 has a one in eight chance of developing breast cancer. Needless to say, it is the leading cause of cancer death among women.

Over the last two decades, breast cancer research has led to extraordinary progress in our understanding of the disease, resulting in more efficient and less toxic treatments. Increased public awareness and improved screening have led to earlier diagnosis at stages amenable to complete surgical resection and curative therapies. Consequently, survival rates for breast cancer have improved significantly, particularly in younger women.

Breast cancer incidence rates have risen globally, with the highest rates occurring in the westernized countries. Reasons for this trend include change in reproductive patterns, increased screening, dietary changes, and decreased activity. Although breast cancer incidence is on the rise globally, breast cancer mortality has been decreasing, especially in industrialized countries. Nevertheless, as the demographic bulge of the baby boomers continues to grow older, the number of women with breast cancer is expected to increase by a third over the next 20 years.

The lifetime risk of acquiring breast cancer in all women, regardless of race, location, and age, is approximately 12.7%. Asian and Pacific Islander women have an incidence rate which increases at 1.5% per year or 89 out of 100 000 yearly. In the Philippines, 26 females out of 100 females and 1 male for every 105 males may be diagnosed with breast cancer. Since the 1980s, breast cancer ranks first among the top leading cancers afflicting women in the Philippines and ranks second to lung cancer if both sexes are considered. Its incidence starts to peak at the age of 30 in women. In 2004, breast cancer cases in the Philippines exceeded lung cancer by 685 cases for both sexes.

Recently, more women are presenting with a bilateral disease at an early age of 30-40. Generally, the disease is still being diagnosed late in its course. Hence, the survival rate of breast cancer in the Philippines is below 50%. Making the situation more difficult, an estimated 70% of breast cancer patients in the Philippines are indigents. In addition, the Philippines has the highest prevalence of breast cancer in all of Asia. Although the trend may seem progressively alarming, the incidence rate is still relatively lower than the incidence rate among female Westerners.

Since 1990, breast cancer death rates have steadily decreased. Approximately 40,610 breast cancer deaths (40,170 women, 440 men) were projected in 2009. The largest decrease in mortality has

been seen in women younger than 50 years (3.3% per year) versus those aged 50 years and older (2.0% per year). This particular trend of breast cancer death rates is perceived as a representation of the progress in both early detection and improved treatment modalities.

Risk factors which are highly sensationalized whenever dealing with carcinoma are, of course, important points of discussion. In the case of carcinoma of the breast, the most important risk is gender. Only 1% of breast cancer cases occur in men. Breast cancer is a predominantly female disease and will continue to challenge women health care systems around the globe for the coming decades.

The Breast Cancer Risk Assessment Tool incorporates additional risk factors which can enable physicians in accurately gauging the absolute risk of an individual woman developing invasive cancer within the next 5 years or over a lifetime:

Age. The incidence rises throughout a woman’s lifetime, peaking at the age of 75-80 years, and then, declining from thereafter. Sixty-one is the average age at diagnosis for white women, 56 for Hispanic women, and 46 for African American women. In the Philippines, many breast cancers are found among 35-50-year-old women. Breast cancer is very rare before the age of 25.

Age at Menarche. Women who reached menarche younger than 11 years have a 20% increased risk of having this type of cancer compared with those who reached menarche older than 14 years. Late menopause increases risk as well.

Age at First Live Birth. Women who experience a first full-term pregnancy at ages younger than 20 years have half the risk of nulliparous women or those who have had their first live birth at age 35. This is supported by a hypothesis which explains that pregnancy enables terminal differentiation of milk-producing luminal cells, eradicating their potential to be included in a possible pool of cancer precursors.

Atypical Hyperplasia. Women who have had previous breast biopsies especially if there is evident atypical hyperplasia are at risk for having these histological changes as precursors for the development of an invasive carcinoma.

First-Degree Relative with Breast Cancer. The number of affected first-degree relatives like a mother, a sister, or a daughter is in direct proportion with the risk of breast cancer. This is especially true in cases wherein the cancer occurred at a very young age. This is not a particularly strong risk factor since only 13% of women with breast cancer have one affected relative and only 1% have two. Over 87% of women with a family history will not get afflicted with breast cancer.

Estrogen Exposure. Postmenopausal hormone replacement therapy increases the risk of breast cancer 1.2-1.7 fold. This increases even further upon the addition of progesterone. Reducing endogenous estrogens via oophorectomy decreases the risk of acquiring breast cancer by up to 75%. Drugs which block estrogenic effects as well as those which block estrogen formation offer lowered risks for developing estrogen receptor (ER)-positive breast carcinoma.

Other risk factors include: breast density, radiation exposure, carcinoma of the contralateral breast or endometrium, geographic location, diet, obesity, exercise, environmental toxins, and tobacco.

Breastfeeding offers a reduction of breast cancer risk when prolonged. Lactation suppresses ovulation and may trigger terminal differentiation of luminal cells. With this, breastfeeding should be highly recommended to women of lactating age. It should be emphasized repeatedly that breastfeeding benefits not only the infant but the nursing mother just as well.

Risk Factor EstimatedRelative Risk

Advanced Age >4Family History

Two or more relatives (mother, sister)One first-degree relativeFamily history of ovarian cancer in women <50y

>5>2>2

Personal HistoryPersonal HistoryPositive BRCA1/BRCA2 mutationBreast biopsy with atypical hyperplasiaBreast biopsy with LCIS or DCIS

3-4>44-5

8-10Reproductive History

Early age at menarche (<12y)Late age at menopauseLate age at first-term pregnancy (>30y)/nulliparity

21.5-2

2Use of combined estrogen/progesterone HRT 1.5-2Current or recent use of oral contraceptives 1.25Lifestyle Factors

Adult weight gainSedentary lifestyleAlcohol consumption

1.5-21.3-1.5

1.5

ETIOLOGY AND PATHOGENESIS

Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast. It has been widely accepted for some time that breast cancer is a heterogeneous disease with a wide array of histologic appearances. It has been confirmed that there are many types of cancer but also show that most carcinomas cluster into several major groups with important biologic and clinical differences. The majority of carcinomas are ER-positive and are characterized by a gene signature dominated by the dozens of genes under the control of estrogen. Among the ER-negative tumors, many fall into a distinctive basal-like group. The basal-like group has the characteristic of notable absence of

estrogen and progesterone recepters and lack of overexpression of HER2/neu protein. Indeed, ER-positive and ER-negative carcinomas have always shown striking differences with regard to patient characteristics, pathologic features, treatment response, and outcome.

Hormonal and genetic factors are the major risks for the development of breast cancer. Those related with hormonal factors may be classified as sporadic cases while those related with genetic factors may be classified as hereditary cases.

Hereditary Breast Cancer

Approximately 12% of breast cancer cases are caused by inheritance of some form of susceptible gene/s. Mutations in BRCA1 and BRCA2 account for the majority of cancers attributable to single mutations and about 3% of all breast cancers. Mutations in BRCA1 markedly increase the risk of developing ovarian carcinoma in addition to breast cancer while BRCA2 mutations confers a smaller risk for ovarian carcinoma but is most frequently related with male breast cancer.

BRCA1-associated breast cancers are commonly poorly differentiated, have a syncytial growth pattern with pushing margins, have a lymphocytic response, and do not express hormone receptors or overexpress them resulting in the so-called triple negative phenotype. This phenotype simply means that there are breast cancers which do not express estrogen and progesterone receptors, and lack overexpression of the HER2/neu protein. They are categorized as basal-like. These cancers are also related with loss of the inactive X chromosome and reduplication of the active X which renders the Barr body absent.

BRCA2-associated breast cancers are relatively poorly differentiated as well. Only, this type of breast cancers more often expresses hormone receptors.

Other gene mutations associated with breast cancer are germline mutations in p53 (Li-Fraumeni syndrome), germline mutations in CHEK2 (Li-Fraumeni variant syndrome), PTEN (Cowden syndrome), LKBI/STK11 (Peutz-Jeghers syndrome), and ATM (ataxia telangiactasia). Germline mutations in p53 are the most common mutations among sporadic cases. CHEK2 mutations, on the other hand, may increase risk for breast cancer after radiation exporsure. These are all tumor suppressor genes which, along the progress of carcinogenesis, have lost their normal function.

Sporadic Breast Cancer

Hormone exposure is the major risk factor for sporadic breast cancer cases. This is in relation with several patient aspects: age, gender, age at menarche and menopause, reproductive history, breastfeeding, and exogenous estrogens. Most of this type of breast cancer are ER-positive and occur postmenopausally.

Hormonal exposure increases the number of potential target cells by stimulating breast growth during puberty, menstrual cycles, and pregnancy. It exposes cells for DNA damage via driving cycles of proliferation. It can nourish premalignant or malignant cells once they appear. They can disrupt growth of normal epithelium and stromal cells and allow for tumor development instead.

Carcinogenesis

Populations of cells that harbour some of the genetic and epigenetic changes required for carcinogenesis give rise to morphologically recognizable breast lesions. These lesions are usually proliferative changes which may be caused by loss of growth-inhibiting signals, aberrant changes in pro-growth signals, or decreased apoptosis. Most early lesions express increased expression of hormone receptors and abnormal proliferation regulation. Loss of heterozygosity is almost universally present in carcinoma in situ. Profound DNA instability as represented by aneuploidy manifesting as nuclear enlargement, irregularity, and hyperchromasia is seen only in high-grade ductal carcinoma in situ and some invasive types. Malignant clones can sometimes achieve immortality and promote neo-angiogenesis.

The stem cell hypothesis is a credible start in knowing how to determine the cell of origin of breast cancer. This hypothesis reveals that malignant changes occur in a stem cell population that has unique properties which define them from more differentiated cells. Although majority of tumor cells would consist of non-stem cell progeny, only the malignant stem cells would contribute to tumor progression or recurrence.

The ER-expressing luminal cell is the most likely type of cell origin for most carcinomas since most are ER-positive. ER-negative cancers, on the other hand, may arise from ER-negative myoepithelial cells and not luminal cells.

The transition of carcinoma in situ into an invasive one marks the final procedure for carcinogenesis. It is the most crucial step yet it is not fully understood. Genetic markers specific for invasive types have never been unearthed. The normal development of the breast in the human lifetime is of special interest in the onset of carcinogenesis. Luminal, myoepithelial, and stromal cells are in a complex interplay to render normal structure and function of the breast. Events involved in normal formation of new ductal branch points and lobules during puberty and pregnancy are the events actually repeated during carcinogenesis. These events include abrogation of the basement membrane, increased proliferation, escape form growth inhibition, angiogenesis, and stromal invasion. In the case of pregnancy, remodelling of the breast during and shortly after pregnancy involves inflammatory and wound healing-like tissue reactions which give rise to an opportunity for the development of cancer. Such changes could facilitate this final part of carcinogenesis.

THE CASE

General Data

The patient is A.M., a 48-year-old Filipino female residing in Batangas City, Batangas. She is a Roman Catholic and is presently an employee of the Batangas City government.

Chief Complaint

Right breast lump

History of Present Illness

Five years prior to admission, the patient first noticed changes in the contour of her right breast. She had lumpectomy which revealed fibrocystic change in the right breast but no malignancy was noted.

Four years PTA, the patient followed up on unspecified breast exams and results reveal no recurrence of the condition or malignancy. She had another unspecified breast exam, 2 years PTA, and this revealed no recurrence of the condition or malignancy.

Ten months PTA, the patient noticed a thickening and hardness in her right breast. She described it as bumpy and irregularly-shaped beneath the areola. Breast ultrasound was done and revealed multiple cystic masses of varying sizes noted in the retroareolar, periareolar, and inner zones with the largest mass measuring 3.38 cm x 2.55 cm x 2.14 cm (LxWxAP). A fine-needle aspiration biopsy (FNAB) was done but the specimen was too bloody that malignancy cannot be identified.

A month PTA, the patient described the mass as firm and growing and went to get advice regarding options for operation. FNAB confirmed the diagnosis.

Past Medical History

Adult Illness. Medical: The patient already had urinary tract infection. Surgical: NoneHealth Maintenance. The patient regularly takes Moriami Forte, Fern Cee, Vitamin E 400 IU, and

Calcium.

Obstetrics-Gynecological History

The patient is G3P3 (3-0-0-3). All sons were delivered normally and were born in the hospital. There were no complications in all pregnancies. She had her first live-birth delivery at the age of 23.

Menarche was at the age of 11 while Menopause was at 48 y/o with LMP during the second cycle of her chemotherapy on 04 September 2008. The patient recalled using at least 3 napkins per day. Menstrual period lasted for 7 days without accompanying signs and symptoms.

DOB Place Age Sex Attendant1. 24 June 1983 Hospital 27 M MD2. 25 April 1988 Hospital 22 M MD3. 05 January 1995

Hospital 15 M MD

Family History

The patient’s father has a heart disease while her mother and her brother both have diabetes. There are no first-degree relatives who have breast cancer or any other type of cancer for that matter.

Personal and Social History

The patient is a local government employee. She is married and has three sons. She never smokes. She does not take any alcoholic beverages. She has no history of illicit drug abuse.

Physical Examination

Head & Neck: HEENT normal. No palpable nodes or thyroid. Trachea is in the midline. Respiratory: Clear to percussion and auscultation in all fields. Cardiovascular: Normal PMI. S1 & S2 are normal. No murmurs or extra sounds. Peripheral pulses are present and equal bilaterally Breasts: There is a firm, non-tender mass on the lower medial quadrant of the right breast. It has a measurement of 7 cm x 7 cm. There is no gross inflammatory response. There is no nipple discharge. Left breast is normal. There are no axillary or supraclavicular nodes palpable bilaterally. Abdomen: Scaphoid, soft. No liver, spleen, or kidneys palpable. No masses or tenderness. Bowel sounds normoactive. Pelvic Exam: Normal. CNS: Grossly normal. Deep tendon reflexes present and equal bilaterally.

Course in the Wards

Fasting blood sugar, creatinine, sodium, and potassium were examined. The following results were obtained:

TEST RESULT NORMAL RANGEFasting Blood Sugar 6.05 3.60-5.80 mmol/LCreatinine 61.88 62.00-106.00 mmol/LSodium 139.00 137.00-145.00 mmol/LPotassium 4.20 3.60-5.00 mmol/L

Complete blood count was also done with the following results:

TEST RESULT NORMAL RANGECBC

White Blood Cells 6.90 5-11 x 103/uLRed Blood CellsHemoglobinHematocritMCVMCHMCHCPlatelet

3.7710.332.385.727.331.9

256.0

4.2-5.4 x 106/uL12.0-16.0 g/dL

38-47%80-100 fL27-33 pg

31-36 g/dL150-400 x 103/uL

Differential Count:NeutrophilLymphocyteMonocyteEosinophilsBasophilsBlastBand/Stabs

56.033.05.06.00.0

55-77%27-33%0-12%0-7%1-5%

Diagnosis

Correct staging of breast cancer patients is of extraordinary importance. It permits accurate prognosis, and in many cases, is the basis of therapeutic decision-making. The TNM classification should be used in accordance with the histologic classification in order to come up with a tailored management for a particular cancer patient.

The TNM Classification

PRIMARY TUMOR (T)T0 No evidence of primary tumorTIS Carcinoma in situT1 Tumor ≤2cmT2 Tumor >2cm but ≤5cmT3 Tumor >5cmT4 Extension to chest wall, inflammation,

satellite lesions, ulcerations

REGIONAL LYMPH NODES (N)N0

No regional lymph nodes

N1

Metastasis to movable ipsilateral nodes

N2

Metastasis to matted or fixed ipsilateral nodes

N3

Metastasis to ipsilateral internal mammary nodes

TREATMENT

The diagnosis of invasive ductal carcinoma Stage 1, Grade 3 calls for immediate surgery of the tumor. Breast-conserving treatments results in a survival that is as good as that after extensive procedure like mastectomy or modified radical mastectomy with or without further irradiation. While it is associated with a possibility of recurrence of the breast, 10-year survival is, at least, as good as that after more radical surgery. Nevertheless, a great many women still undergo mastectomy who could safely avoid this procedure. This could be because they fall under certain exclusions from breast-conserving surgery: (1) it is not suitable for tumors >5 cm, (2) it is not suitable for tumor involving the nipple areola complex, (3) it is not for tumors with extensive intraductal disease involving multiple breast quadrants (4) it is not for women with history of collagen-vascular disease, and (4) it is not for women who do not have motivation for breast conservation or do not have access to radiation therapy.

The patient in this case has an invasive ductal carcinoma which largely involves the nipple areola complex. This is why, as primary treatment, she chose to undergo modified radical mastectomy of the right breast. Radiation therapy may be indicated postmastectomy. But it is more regularly employed after a breast-conservation surgery. In fact, for women with node-negative disease who have undergone mastectomy like the patient, there was not a statistically significant reduction in 15-year breast cancer mortality if further irradiation were to follow.

Adjuvant systemic therapy can be immediately administered postmastectomy. This form of therapy improves survival. However, estrogen receptor status of the carcinoma must be determined first. Tamoxifen, a steroid hormonal chemotherapeutic drug, for example, is restricted to women with ER-positive or ER-unknown breast tumors. The patient is ER-negative which is why Tamoxifen was no longer administered. In addition, it is not effective in a high-risk node-negative disease like the case.

Risk Categories for Women with Node-Negative Breast CancerLow risk

(has all listed factors)Intermediate risk

(risk classified between the other categories)

High risk(has at least one listed

factor)Tumor size ≤1 cm 1-2 cm >2 comER- or PR- status + + -Tumor grade Grade 1 Grade 1-2 Grade 2-3

Aromatase inhibitors like Anastrozole and Letrozole, can also be prescribed for survival advantage. These have become first-line adjuvant therapy for postmenopausal women. However, tamoxifen remains a more reasonable alternative. And since the use of aromatase inhibitors requires

hormone-receptor positive cancers, it is still not applicable to the patient. The same is true with microtubule inhibitors which are essentially cytotoxic to cancer cells. Microtubule inhibitors like Paclitaxel and Docitaxel both require hormone-receptor positive cancers. Both aromatase and microtubule inhibitors are for metastatic cases which was not appreciated in the case. Monoclonal antibodies like Trastuzumab, on the other hand, require overexpression of HER2/neu protein which was also absent from the cancer discussed in the case.

The most plausible next step for the patient after having modified radical mastectomy is chemotherapy. In women below age 50, chemotherapy, particularly polychemotherapy or multidrug therapy may reduce the annual risk of disease relapse and death from breast cancer by 37% and 30%, respectively. The 2005 Early Breast Cancer Trialists Collaborative Group has made numerous clinical trials which attempt to determine which is superior between anthracycline-based regimens and cyclophosphamide, methotrexate, fluorouracil (CMF)-type regimen alone. The usual anthracycline-based regimens are mostly 6 months of fluorouracil, doxorubicin, cyclophosphamide (FAC) or fluorouracil, epirubicin, cyclophosphamide (FEC). Compared to CMF, anthracycline-based regimens were associated with a modest but a statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. The absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years. For the case, anthracycline-based regimens are hardly applicable. FAC as well as FEC regimens are directed at cancers which overexpress the protein HER2/neu. The patient is negative for HER2/neu overexpression as revealed by her immunohistochemistry report.

The CMF-type regimens, on the other hand, are more tailored in addressing the cancer of the patient. CMF or the Bonadonna regimen can be used in both metastatic and non-metastatic cancer. And when it comes to node-negative breast cancer with an immunohistochemistry reading of negative estrogen and progesterone receptors as well as absence of HER2/neu amplification, CMF regimen leads the pack.

CMF Regimen

Cyclophosphamide is an alkylating agent which directs its action towards the DNA. It does not discriminate between the cycling and resting cells and is actually most toxic for rapidly dividing cells. It is mutagenic and carcinogenic. It is biotransformed by P450 cytochrome in the liver. Cyclophosphamide actually has the strongest tendency to cause relative myelosuppression compared to the other drugs included in the regimen. Other adverse reactions include: nausea, vomiting, alopecia, hemorrhagic cystitis, sterility, and immunosuppression. Cyclophosphamide needs an assurance of adequate hydration and diuresis during therapy. It is contraindicated for those with severe bone marrow depression, and pregnancy and lactation.

Methotrexate is an antimetabolite which interferes with the availability of normal thymidine nucleotide precursors. It is S-phase specific. It deprives cells of folate coenzymes needed for biosynthesis. Although nucleotides adenine and guanine and amino acids methionine and serine

depend on folate coenzymes needed for their synthesis, the most prominent effect is on thymidine. It becomes depressed which would result in depressed DNA, RNA, and protein synthesis. Administration of leucovorin which bypasses the blocked enzyme replenishes the folate pool. Adverse reactions include hematolic and GI effects, dermatologic reactions, renal dysfunction, allergic reactions, and ocular side effects. It is contraindicated for those with serious anemia, leukopenia, thrombocytopenia, renal or hepatic impairment, and pregnancy and lactation.

Fluorouracil is another antimetabolite which induces thymidine-less cell death among rapidly dividing cells. Its anticancer effect takes place in S phase of the cell cycle. It is employed primarily in the treatment of slowly growing solid tumors. It has to be administered intravenously because it is severely toxic to the GI tract. Other adverse reactions are: hematotoxicity, leukopenia, thrombocytopenia, stomatitis, anorexia, nausea, vomiting, diarrhea, maculopapular rash, alopecia, cerebellar dysfunction, eye toxicity, and ECG changes. It is contraindicated for those with depressed bone marrow function, poor nutritional state, pregnancy and lactation.

Safety Affordability Necessity EfficacyCyclophosphamide

++ ++ ++++ ++

Methotrexate +++ + ++++ ++5-Fluorouracil +++ +++ ++++ ++

Methotrexate and 5-fluorouracil are safer drugs than cyclophosphamide because the latter has the higher tendency to cause bone marrow depression compared to the former drugs. When it comes to affordability, methotrexate emerges as the most expensive with a patient having to spend P5220.00 for the duration of the 6 cycles. All drugs are essential part of the combination therapy which give all rate of 4 +’s. Efficacy of each drug may not be optimal if each would be used as a monotherapy.

Multidrug Therapy

When it comes to an invasive breast tumor with no involvement of axillary nodes and no distant metastasis, breast-conserving surgery with consequent irradiation or mastectomy is considered the primary treatment. After these procedures, it is most appropriate to follow up with chemotherapy for a better survival and mortality rate for the patient. There are a lot of polychemotherapy which targets this stage of invasive carcinoma (Stage I). But the most applicable are regimens which are anthracycline-based and those which are of CMF-type. Anthracycline-based regimens highly depend on the overamplification of HER2/neu protein. This specificity is not one with the case since the patient is HER2/neu negative. Simply put, CMF-type regimen is the most appropriate.

Clinical trials show that CMF-type regimens are most applicable for Stage I breast carcinoma which are estrogen-receptor and progesterone-receptor negative as well as p53 negative. Overamplification of HER2/neu, which is absent from the case, is much needed to be able to utilize an anthracycline-based therapy.

A clinical study involves the comparison of CMF regimen and a simple MF regimen among female breast cancer patients with no axillary node involvement and no estrogen receptors. CMF regimen gave recurrence-free survival benefit and most especially, overall survival benefit. Febrile neutropenia was more frequent among CMF-treated patients. Menopausal women experience more toxic effects in using the CMF regimen. Thus, methrotrexate followed by 5-fluoruracil is a reasonable substitute for CMF for older women.

Safety Affordability Necessity EfficacyCMF ++ ++ ++++ ++++MF +++ ++++ +++ +++

The MF regimen seems safer because it does not include cyclophosphamide which has the highest tendency among the 3 drugs to cause myelosuppression. Also, as shown in the previous study, febrile neutropenia developed among CMF-treated patients. The MF regimen is more affordable because of the absence of cyclophosphamide. For the 6 cycles, Ledoxan would cost P3787.80. Use of the MF regimen requires no spending of such additional amount. The previous study revealed that CMF has recurrence-free survival benefit as well as overall survival benefit. This means that although CMF can be considered a regimen with risks, it is still the one that can render survival advantage and prolong survival postmastectomy or after breast-conserving energy. The CMF regimen is chosen as the drug of choice while the MF regimen is chosen as an alternative.

PRESCRIPTIONS

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