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02-Breast ca_2016.pdf yes opvvhsjvdjbdbd

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The document provides an introduction to breast cancer, including risk factors, clinical presentation, staging, and treatment approaches. It discusses that breast cancer develops through pre-invasive and invasive phases. The most common types are invasive ductal carcinoma and invasive lobular carcinoma. Treatment depends on stage, with surgery, radiation, chemotherapy, and hormonal therapy used for early and locally advanced breast cancer. Systemic adjuvant therapy after local treatment can help cure early stage disease. Commonly used chemotherapy regimens are described.

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Fekede B. (M.Pharm, RPh) Mobile: +251911758845 Email: fekedeb@gmail.com Institutional Email: fekede.bekele@ju.edu.et Breast Cancer
Introduction  Breast cancer is a malignant tumor that originates from epithelial cells of breast tissue.  The development of malignancy is a multistep process with pre-invasive (or noninvasive) and invasive phases.  Non-invasive cancers stay within the milk ducts or lobules in the breast.  do not grow into or invade normal tissues within or beyond the breast.  sometimes called carcinoma in situ (“in the same place”) or pre- cancers or pre-invasive breast cancer. 2
Introduction….  Most breast cancers are invasive, but there are different types of invasive breast cancer.  The two most common: invasive ductal carcinoma and invasive lobular carcinoma.  Invasive cancers do grow and spread into normal, healthy breast tissues  Most breast carcinomas are adenocarcinomas and are classified as ductal or lobular based on the basis of their microscopic appearance. 3
Introduction….  It can be categorized into …  Breast Ca at early stages …. potentially curable  Metastatic breast cancer (MBC) …. usually incurable. 4
Introduction….  Breast ca …. the top cancer in women  both in the developed and the developing countries  Incidence of breast ca is increasing in developing world ….  increase life expectancy  increase urbanization  adoption of western lifestyles 5
Introduction….  Mammography screening ….  the only Breast ca screening method that has proved effectiveness  very costly  cost-effective & feasible in countries with good health infrastructure  Clinical breast examination, could be implemented in limited resource settings  low-cost screening approaches 6 Early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control. 
Introduction ….  Breast ca ….. the most common cancer, followed by lung, colon and rectum and prostate cancers.  The most common in 2020 (in terms of new cases of ca):  breast, lung, colon and rectum, prostate, …  The most common causes of cancer death in 2020:  Lung, colon and rectum, liver, stomach, breast, …  In females, breast cancer …. next to lung ca … the most common cause of cancer-related deaths 7 https://www.who.int/news-room/fact-sheets/detail/cancer
Introduction….  Female breast cancer incidence rates vary considerably across racial and ethnic groups.  Incidence rates of breast Ca …..  higher in whites ……….. vs. African Americans  Death rate is higher among African American women than white women despite the lower incidence. 8
Introduction….  High death rate and low incidence rate among African American women than whites  Possible reasons: differences in ….  reproductive and lifestyle factors  access to and use of screening  access to care  socioeconomic status, cultural differences  higher stage at diagnosis, etc 9
Risk Factors  Several endocrine, genetic, environmental, and lifestyle factors are associated with the development of breast cancer to varying degrees.  Some factors are modifiable, but others are not.  The impact of individual risk factors may vary depending on other confounding variables such as ….  age, family history, estrogen use, menopausal status 10
Risk Factors ….  Gender and age (advancing age)  1 in 8 women will develop breast ca during her lifetime.  this is a cumulative lifetime risk of developing the disease from birth to death.  the risk of developing BCA before age of 40… about 1 in 203  more than half the risk occurs after age 60 years. 11
Risk Factors ….  Risk of developing BCA in women of all races 12
Risk Factors ….  Personal history of BCA in the contralateral breast,  Family history of BCA (10%),  first degree relatives …increases risk by 1.5  3 fold  risk increases with increasing numbers of affected 1st-degree relatives  BRCA gene mutations (either BRCA1 or BRCA2 genes) 13
Risk Factors ….  Early menarche (menstruation beginning before age 12),  Late age of natural menopause (55 or later),  Nulliparity  Late age at first birth (≥30)  Long term use of exogenous estrogens  safety and benefits of low-dose oral contraceptives currently outweigh the potential risks  The use of postmenopausal HRT in women with a history of breast cancer is generally contraindicated. 14
Risk Factors ….  Alcohol consumption ……advice to use in moderation.  High fat diet, obesity  Heterocyclic amines (known carcinogens) found commonly in cooked red meat or processed meat.  Studies of red meat ingestion and BCA incidence are inconsistent  Radiation to the breast tissue 15
Risk Factors ….  International differences in the incidence of breast cancer;  differences in age of menarche,  age difference at menopause,  childbearing age differences 16
Clinical Presentation 17  The patient may not have any symptoms, as breast cancer may be detected in asymptomatic patients though routine screening mammography.  Local signs and symptoms  painless, palpable lump ….most common  Less common: pain; nipple discharge, retraction or dimpling; skin edema, redness or warmth.  Palpable local–regional lymph nodes may be present.
Clinical Presentation…. 18  Signs & symptoms of systemic metastases  Depends on the site of metastases,  may include…. bone pain, difficulty breathing, abdominal pain or enlargement, jaundice, mental status changes.  Note: the most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.
Clinical Presentation…. 19  Laboratory tests  Tumor markers may be elevated  such as cancer antigen (CA 27.29) or carcinoembryonic antigen (CEA).  Alkaline phosphatase or LFTs may be elevated in metastatic Dz.  Other diagnostic tests  Mammogram …..once every 1 to 2 years for age 40-49 yrs  annual mammogram for age ≥ 50  Ultrasound
Clinical Presentation…. 20  Breast biopsy….  for pathology review and determination of tumor estrogen/ progesterone receptor (ER/PR) status and HER2 status.  Breast exam….. either performed by patient or provider,  Breast self-examinations ….. monthly  Annual examination for breast cancer performed by a health care provider is recommended for all women >40 yrs  Women with a positive family history often are instructed to begin screening at an early age. HER2: human epidermal growth factor receptor-2
Staging  Stage is based on ….  the size of the primary tumor (T1–4)  presence and extent of lymph node involvement (N1–3)  presence or absence of distant metastases (M0–1)  These stages may be represented as:  Early BCA  Locally advanced BCA  Advanced or metastatic BCA 21
Staging…. 22  Early breast cancer  Stage 0: Carcinoma in situ or disease that has not invaded the basement membrane.  Stage I: Small primary tumor without lymph node involvement.  Stage II: Involvement of regional lymph nodes.
Staging….  Stage I  Early stage breast cancer  Tumor is small  Has not spread to lymph nodes 23
24 Stage II-A Stage II-B Staging….
Staging….  Locally advanced breast cancer [Stage III]  Usually a large tumor with extensive nodal involvement in which node or tumor is fixed to the chest wall,  also includes inflammatory breast cancer, which is rapidly progressive. 25
Staging…. 26 Stage III-A Stage III-B
Staging….  Advanced or metastatic breast cancer [Stage IV]  Metastases in organs distant from the primary tumor. 27
TNM staging for BCA  Stage 0: Tis, No, Mo  Stage I:  T (To, T1), N (No, N1), Mo  Stage II:  T (To, T1, T2, T3), N (No, N1), Mo  Stage III:  T (To, T1, T2, T3, T4, any T), N (No, N1, N2, N3), Mo  Stage IV: any T, any N, M1 28
 Goal of therapy ….depends on stage of BCA  Early and locally advanced BCA ….. cure  Metastatic BCA ….  to improve symptoms  to improve quality of life  to prolong survival Treatment of BCA
Stage I & II Treatment of early BCA
Local–regional therapy  Surgery alone can cure ….  most patients with in situ cancers, and approximately one-half of those with stage II cancers  Breast-conserving therapy (BCT) ….  It consists of lumpectomy (excision of primary tumor & adjacent breast tissue) followed by radiation therapy to prevent local recurrence.  is appropriate primary therapy for most women with stage I & II  it produces equivalent survival rates with cosmetically superior results compared with the modified radical mastectomy. 31
Local–regional therapy….  Radiation therapy is administered to the entire breast over 4 to 6 weeks to eradicate residual disease after BCT.  minor complications associated with radiation therapy ….  reddening and erythema of the breast tissue  shrinkage of total breast mass  Mastectomy involves removal of the entire breast without dissection of underlying muscle or axillary nodes.  used for carcinoma in situ where the incidence of axillary node involvement is only 1%. 32
Lumpectomy vs. Mastectomy 33
Systemic adjuvant therapy 34  Systemic adjuvant therapy is the administration of systemic therapy following definitive local therapy (surgery, radiation, or both) when there is no evidence of metastatic disease but a high likelihood of disease recurrence.  The goal of such therapy is cure.  Chemotherapy, hormonal therapy, or both result in improved disease-free survival and/or overall survival for all treated patients.
Adjuvant chemotherapy…. 35  Early administration of effective combination chemotherapy at time of low tumor burden …..  increase the likelihood of cure  minimize emergence of drug-resistant tumor cell clones  Combination regimens have historically been more effective than single agent chemotherapy.
Adjuvant chemotherapy….  Commonly used cytotoxic drugs as adjuvant therapy in BCA …  Anthracyclines (doxorubicin, epirubicin)  Alkylating agents such as cyclophosphamide  Antimetabolites (methotrexate, fluorouracil)  Paclitaxel, docetaxel, vinorelbine, vincristine  Prednisone 36
Adjuvant chemotherapy…. 37  Anthracycline-containing regimens …..  significantly reduce the rate of recurrence and improve overall survival as compared with regimens that contain cyclophosphamide, methotrexate, and fluorouracil.  Both node-negative and node-positive patients benefit from anthracycline-containing regimens.  addition of taxanes to adjuvant regimens ….improve disease- free survival and overall survival in node-positive BCA patients.
Adjuvant chemotherapy…. 38  Although the optimal duration of adjuvant chemotherapy administration is unknown, it appears to be on the order of 12 to 24 weeks and depends on the regimen being used.  Chemotherapy should be initiated within 12 weeks of surgical removal of the primary tumor.
Adjuvant chemotherapy…. 39  Dose intensity and dose density …..  critical factors in achieving optimal outcomes in adjuvant breast cancer therapy.  Dose intensity is defined as the amount of drug administered per unit of time and is typically reported as mg/m2/week.  Increasing dose, decreasing time between doses, or both can increase dose intensity.
Adjuvant chemotherapy…. 40  Dose density is one way of achieving dose intensity by decreasing the time between treatment cycles.  Increasing doses in standard regimens ….  not beneficial but may be harmful.  Decreasing doses in standard regimens ….  should be avoided unless necessitated by severe toxicity.
Adjuvant chemotherapy…. 41  The short-term toxic effects of chemotherapy used in the adjuvant setting are generally well tolerated.  Supportive therapy is important in patients receiving systemic adjuvant chemo such as anthracycline-containing regimen.  Antiemetics  Colony-stimulating factors
Adjuvant chemotherapy…. 42  Antiemetics to assist in managing chemotherapy-induced nausea and vomiting,  serotonin-antagonist with substance P/neurokinin 1-antagonist such as aprepitant and dexamethasone  Colony-stimulating factors …..  to prevent febrile neutropenia, particularly in elderly patients or patients receiving dose-dense chemotherapy regimens.
Adjuvant chemotherapy…. 43  Other side effects common with chemo regimens used for treatment of early stage BCA  alopecia, weight gain, and fatigue  cessation of menses that may not return; accompanied by signs and symptoms of menopause.  DVT in combination chemotherapy regimens.  Leukemia and other hematologic disorders …associated with the alkylating agents (e.g., cyclophosphamide) and the anthracyclines (e.g., doxorubicin and epirubicin).
Adjuvant chemotherapy…. 44  Survival benefit for adjuvant chemotherapy in stage I and II breast cancer is modest.  Absolute reduction in mortality at 10 years …..  5% in patients with negative axillary lymph nodes vs. 10% in node-positive disease  Addition of a taxane to an anthracycline-based chemo….  standard of care for women with node-positive BCA.  controversial in patients with node-negative disease
Commonly used adjuvant chemo regimens  AC  Doxorubicin 60 mg/m2 IV, day 1 plus cyclophosphamide 600 mg/m2 IV, day 1, repeat cycles every 21 days for 4 cycles.  AC  Paclitaxel  Doxorubicin 60 mg/m2 IV, day 1 plus cyclophosphamide 600 mg/m2 IV, day 1, repeat cycles every 21 days for 4 cycles.  Followed by: Paclitaxel 80 mg/m2 IV weekly, repeat cycles every 7 days for 12 cycles 45
Commonly used adjuvant chemo regimens… 46  FAC  Fluorouracil 500 mg/m2 IV, days 1 and 4  Doxorubicin 50 mg/m2 IV continuous infusion over 72 hours  Cyclophosphamide 500 mg/m2 IV, day 1  Repeat cycles every 21–28 days for 6 cycles  CMF  Cyclophosphamide 100 mg/m2 per day orally, days 1–14  Methotrexate 40 mg/m2 IV, days 1 and 8  Fluorouracil 600 mg/m2 IV, days 1 and 8  Repeat cycles every 28 days for 6 cycles
Commonly used adjuvant chemo regimens… 47  Dose-dense AC Paclitaxel  Doxorubicin 60 mg/m2 IV bolus, day 1  Cyclophosphamide 600 mg/m2 IV, day 1  Repeat cycles every 14 days for 4 cycles  Followed by:  Paclitaxel 175 mg/m2 IV over 3 hours  Repeat cycles every 14 days for 4 cycles
Adjuvant biologic therapy  Trastuzumab is a monoclonal antibody targeted against the HER2-receptor protein.  Trastuzumab in combination with adjuvant chemotherapy…  indicated in patients with early stage, HER2-positive BCA  risk of recurrence was reduced up to 50% in clinical trials  Optimal duration of trastuzumab therapy is unknown.  Trastuzumab in combination with docetaxel and carboplatin followed by trastuzumab (for a total of 1year) …FDA approved.  Alone for 1year following anthracycline-based chemo 48
Treatment of patients with breast cancers larger than 1 cm or with positive lymph nodes 49 (HR: hormone receptor; HER2: human epidermal growth factor receptor-2)
Adjuvant endocrine therapy 50  Hormonal therapies studied in the treatment of early stage BCA include….  Tamoxifen, aromatase inhibitors  Choice of agent(s) depends on …  menopausal status
Adjuvant endocrine therapy…. 51  Tamoxifen ….. the gold standard for adjuvant endocrine therapy.  Tamoxifen ….. is antiestrogenic in breast cancer cells, but estrogenic in other tissues and organs.  It is generally the adjuvant hormonal therapy of choice for premenopausal women although can also be used for postmenopausal woman.
Adjuvant endocrine therapy…. 52  The current recommended dose for tamoxifen in the adjuvant, metastatic, and preventive settings is……… 20 mg/day.  Adjuvant tamoxifen therapy …..  generally initiated after surgery or as soon as pathology results are known and the decision to administer tamoxifen as adjuvant therapy is made.  should be given after chemotherapy is completed, and continuing for 5 years.  Reduces the risk of recurrence and mortality.
Adjuvant endocrine therapy….  Tamoxifen ….. usually well tolerated.  Associated with hot flashes and vaginal discharge  increases the risks of stroke, pulmonary embolism, DVT, and endometrial cancer, particularly in women age 50 years or older. 53
Adjuvant endocrine therapy….  In postmenopausal women, aromatase inhibitors (AI) are recommended to be incorporated into adjuvant hormonal therapy; with the following options…  An aromatase inhibitor for 5 years, or  Tamoxifen for 2 to 3 years, followed by an aromatase inhibitor (for a total of 5 years of endocrine therapy), or  Tamoxifen for 5 years, followed by an aromatase inhibitor for another 5 years (total of 10 years). 54
Adjuvant endocrine therapy….  Available aromatase inhibitors (anastrozole, letrozole, exemestane)  have similar antitumor efficacy & toxicity profiles  generally well tolerated  Adverse effects of AIs include ….  osteoporosis, hot flashes, myalgia or arthralgia, vaginal dryness or atrophy, mild headaches, diarrhea.  Bisphosphonates are coadministered with the AI in many patients in the metastatic setting and may also be beneficial in the adjuvant setting. 55
Stage III BCA Treatment of locally advanced BCA
Treatment of Stage III BCA  Stage III BCA ….locally advanced breast cancer  refers to breast carcinomas with significant primary tumor and nodal disease, but in which distant metastases cannot be documented.  also includes inflammatory BCA, which is rapidly progressive.  Because of its aggressive nature, a delay in diagnosis can be fatal. 57
Treatment of Stage III BCA ….  Inflammatory BCA:  rare, rapidly developing cancer that makes the breast red, swollen and tender.  The rapid onset of symptoms within weeks to months, including erythema of the skin with or without a detectable underlying breast mass .......  the hallmark of inflammatory BCA  Patients with inflammatory BCA …..often inappropriately treated for cellulitis with antibiotics. 58
Treatment of Stage III BCA …. 59  Cure is the primary goal of therapy for most patients with stage III disease.  Neoadjuvant chemotherapy …..the initial treatment of choice…  renders inoperable tumors resectable  for patients with inoperable breast cancer, including inflammatory BCA  Primary chemotherapy with an anthracycline-containing regimen with/without a taxane is recommended.
Treatment of Stage III BCA …. 60  For patients with HER2-positive tumors ….  trastuzumab with chemotherapy is appropriate  Surgery followed by chemotherapy and adjuvant radiotherapy should be administered…….  to minimize local recurrence
Stage IV BCA Treatment of metastatic BCA
Treatment of metastatic BCA (Stage IV)  Beyond advanced local-regional disease, BCA is incurable.  Goal of treatment should be…  to improve symptoms and QOL,  to extend survival.  The choice of therapy for MBC is based on the site of disease involvement and presence or absence of certain characteristics,  Involves: endocrine therapy, chemotherapy, and biologic therapy 62
Endocrine therapy  The pharmacologic goal of endocrine therapy for BCA ….  decrease circulating levels of estrogen, or  prevent the effects of estrogen at the BCA cell (targeted therapy) by blocking the hormone receptors or down regulating the presence of these receptors.  The most important factor predicting response to endocrine therapy is the presence of estrogen and progesterone receptors in the primary tumor tissue. 63
Endocrine therapy….  Endocrine therapy is the treatment of choice for patients …  who have hormone receptor-positive metastases  The choice of a particular endocrine therapy is based primarily on ….  mechanism of action, toxicity, and patient preference.  Tamoxifen is the antiestrogen of choice in premenopausal women whose tumors are hormone-receptor positive,  maximal beneficial effects do not occur for at least 2 months. 64
Endocrine therapy…. 65  Aromatase inhibitors (anastrozole, letrozole, exemestane) ….  reduce circulating and target organ estrogens  generally used in advanced BCA in postmanopausal women, followed by other endocrine therapies upon progression.  similar response rate and longer time to progression as well as lower incidence of thromboembolic events and vaginal bleeding, compared with tamoxifen.
Endocrine therapy…. 66  Aromatase inhibitors  Anastrozole 1 mg orally daily  Letrozole 2.5 mg orally daily  Exemestane 25 mg orally daily  Antiestrogens  Tamoxifen 20 mg orally daily  Patients are sequentially treated with endocrine therapy until their tumors cease to respond, at which time chemotherapy can be given.
Chemotherapy  The goal of chemotherapy in the metastatic setting is palliative.  Chemotherapy is used as initial therapy for women…  with hormone receptor-negative tumors  after failure of endocrine therapy  Agents used previously as adjuvant therapy can be repeated unless the cancer recurred within 1 year. 67
Chemotherapy…..  Single agents are associated with lower response rates than combination therapy.  Single agents are better tolerated, an important consideration in the palliative metastatic setting.  Treatment with sequential single agents is recommended over combination regimens….. unless the patient has rapidly progressive disease, life-threatening visceral disease, or the need for rapid symptom control.  Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-line therapy for MBC. 68
Metastatic Single-Agent Chemo 69  Paclitaxel 175 mg/m2 IV over 3 hrs. Repeat cycles q21d, OR  Paclitaxel 80 mg/m2 per week IV over 1hr. Repeat dose q 7d  Vinorelbine 30 mg/m2 IV, days 1 and 8. Repeat cycles q21d, OR  Vinorelbine 30 mg/m2 per week IV. Repeat cycles q7 d (adjust dose based on absolute neutrophil count)  Docetaxel 60–100 mg/m2 IV over 1 hr. Repeat cycles q21d, OR  Docetaxel 30–35 mg/m2 per week IV over 30 min. Repeat dose q7d  Capecitabine 2,000–2,500 mg/m2 per day orally, divided twice daily for 14 days. Repeat cycles q21d
Metastatic Combination Chemo Regimens 70  Docetaxel + capecitabine  Docetaxel 75 mg/m2 IV over 1 hr, day 1  Capecitabine 2,000–2,500 mg/m2 per day orally divided twice daily for 14 days  Repeat cycles q21d  Paclitaxel + Gemcitabine  Paclitaxel 175 mg/m2 IV over 3 hrs, day 1  Gemcitabine 1,250 mg/m2 IV days 1 and 8  Repeat cycles q21d
Biologic therapy  Trastuzumab, a monoclonal antibody that binds to HER2,  produces response rates of 15% to 20% when used as a single agent  increases response rates, time to progression when combined with chemotherapy.  as doublet (taxane-trastuzumab; vinorelbine-trastuzumab)  as triplet (trastuzumab-taxane-platinum) combinations  Trastuzumab is well tolerated,  But, the risk of cardiotoxicity is 5% to the single-agent and unacceptably high in combination with an anthracycline. 71
Radiation therapy 72  Radiation is commonly used to treat painful bone metastases or other localized sites of disease.  Pain relief is seen in approximately 90% of patients who receive RT.
Prevention of breast cancer  Tamoxifen therapy  Tamoxifen reduce the rates of invasive BCA in women at high risk for developing the disease.  At 20 mg/day for 5 years, a decreased risk for invasive and noninvasive cancer of 50% was seen.  Caution when using tamoxifen  Increased risk for endometrial cancer  Increased risk for life-threatening thromboembolic events 73
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02-Breast ca_2016.pdf yes opvvhsjvdjbdbd

  • 1. Fekede B. (M.Pharm, RPh) Mobile: +251911758845 Email: fekedeb@gmail.com Institutional Email: fekede.bekele@ju.edu.et Breast Cancer
  • 2. Introduction  Breast cancer is a malignant tumor that originates from epithelial cells of breast tissue.  The development of malignancy is a multistep process with pre-invasive (or noninvasive) and invasive phases.  Non-invasive cancers stay within the milk ducts or lobules in the breast.  do not grow into or invade normal tissues within or beyond the breast.  sometimes called carcinoma in situ (“in the same place”) or pre- cancers or pre-invasive breast cancer. 2
  • 3. Introduction….  Most breast cancers are invasive, but there are different types of invasive breast cancer.  The two most common: invasive ductal carcinoma and invasive lobular carcinoma.  Invasive cancers do grow and spread into normal, healthy breast tissues  Most breast carcinomas are adenocarcinomas and are classified as ductal or lobular based on the basis of their microscopic appearance. 3
  • 4. Introduction….  It can be categorized into …  Breast Ca at early stages …. potentially curable  Metastatic breast cancer (MBC) …. usually incurable. 4
  • 5. Introduction….  Breast ca …. the top cancer in women  both in the developed and the developing countries  Incidence of breast ca is increasing in developing world ….  increase life expectancy  increase urbanization  adoption of western lifestyles 5
  • 6. Introduction….  Mammography screening ….  the only Breast ca screening method that has proved effectiveness  very costly  cost-effective & feasible in countries with good health infrastructure  Clinical breast examination, could be implemented in limited resource settings  low-cost screening approaches 6 Early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control. 
  • 7. Introduction ….  Breast ca ….. the most common cancer, followed by lung, colon and rectum and prostate cancers.  The most common in 2020 (in terms of new cases of ca):  breast, lung, colon and rectum, prostate, …  The most common causes of cancer death in 2020:  Lung, colon and rectum, liver, stomach, breast, …  In females, breast cancer …. next to lung ca … the most common cause of cancer-related deaths 7 https://www.who.int/news-room/fact-sheets/detail/cancer
  • 8. Introduction….  Female breast cancer incidence rates vary considerably across racial and ethnic groups.  Incidence rates of breast Ca …..  higher in whites ……….. vs. African Americans  Death rate is higher among African American women than white women despite the lower incidence. 8
  • 9. Introduction….  High death rate and low incidence rate among African American women than whites  Possible reasons: differences in ….  reproductive and lifestyle factors  access to and use of screening  access to care  socioeconomic status, cultural differences  higher stage at diagnosis, etc 9
  • 10. Risk Factors  Several endocrine, genetic, environmental, and lifestyle factors are associated with the development of breast cancer to varying degrees.  Some factors are modifiable, but others are not.  The impact of individual risk factors may vary depending on other confounding variables such as ….  age, family history, estrogen use, menopausal status 10
  • 11. Risk Factors ….  Gender and age (advancing age)  1 in 8 women will develop breast ca during her lifetime.  this is a cumulative lifetime risk of developing the disease from birth to death.  the risk of developing BCA before age of 40… about 1 in 203  more than half the risk occurs after age 60 years. 11
  • 12. Risk Factors ….  Risk of developing BCA in women of all races 12
  • 13. Risk Factors ….  Personal history of BCA in the contralateral breast,  Family history of BCA (10%),  first degree relatives …increases risk by 1.5  3 fold  risk increases with increasing numbers of affected 1st-degree relatives  BRCA gene mutations (either BRCA1 or BRCA2 genes) 13
  • 14. Risk Factors ….  Early menarche (menstruation beginning before age 12),  Late age of natural menopause (55 or later),  Nulliparity  Late age at first birth (≥30)  Long term use of exogenous estrogens  safety and benefits of low-dose oral contraceptives currently outweigh the potential risks  The use of postmenopausal HRT in women with a history of breast cancer is generally contraindicated. 14
  • 15. Risk Factors ….  Alcohol consumption ……advice to use in moderation.  High fat diet, obesity  Heterocyclic amines (known carcinogens) found commonly in cooked red meat or processed meat.  Studies of red meat ingestion and BCA incidence are inconsistent  Radiation to the breast tissue 15
  • 16. Risk Factors ….  International differences in the incidence of breast cancer;  differences in age of menarche,  age difference at menopause,  childbearing age differences 16
  • 17. Clinical Presentation 17  The patient may not have any symptoms, as breast cancer may be detected in asymptomatic patients though routine screening mammography.  Local signs and symptoms  painless, palpable lump ….most common  Less common: pain; nipple discharge, retraction or dimpling; skin edema, redness or warmth.  Palpable local–regional lymph nodes may be present.
  • 18. Clinical Presentation…. 18  Signs & symptoms of systemic metastases  Depends on the site of metastases,  may include…. bone pain, difficulty breathing, abdominal pain or enlargement, jaundice, mental status changes.  Note: the most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.
  • 19. Clinical Presentation…. 19  Laboratory tests  Tumor markers may be elevated  such as cancer antigen (CA 27.29) or carcinoembryonic antigen (CEA).  Alkaline phosphatase or LFTs may be elevated in metastatic Dz.  Other diagnostic tests  Mammogram …..once every 1 to 2 years for age 40-49 yrs  annual mammogram for age ≥ 50  Ultrasound
  • 20. Clinical Presentation…. 20  Breast biopsy….  for pathology review and determination of tumor estrogen/ progesterone receptor (ER/PR) status and HER2 status.  Breast exam….. either performed by patient or provider,  Breast self-examinations ….. monthly  Annual examination for breast cancer performed by a health care provider is recommended for all women >40 yrs  Women with a positive family history often are instructed to begin screening at an early age. HER2: human epidermal growth factor receptor-2
  • 21. Staging  Stage is based on ….  the size of the primary tumor (T1–4)  presence and extent of lymph node involvement (N1–3)  presence or absence of distant metastases (M0–1)  These stages may be represented as:  Early BCA  Locally advanced BCA  Advanced or metastatic BCA 21
  • 22. Staging…. 22  Early breast cancer  Stage 0: Carcinoma in situ or disease that has not invaded the basement membrane.  Stage I: Small primary tumor without lymph node involvement.  Stage II: Involvement of regional lymph nodes.
  • 23. Staging….  Stage I  Early stage breast cancer  Tumor is small  Has not spread to lymph nodes 23
  • 24. 24 Stage II-A Stage II-B Staging….
  • 25. Staging….  Locally advanced breast cancer [Stage III]  Usually a large tumor with extensive nodal involvement in which node or tumor is fixed to the chest wall,  also includes inflammatory breast cancer, which is rapidly progressive. 25
  • 27. Staging….  Advanced or metastatic breast cancer [Stage IV]  Metastases in organs distant from the primary tumor. 27
  • 28. TNM staging for BCA  Stage 0: Tis, No, Mo  Stage I:  T (To, T1), N (No, N1), Mo  Stage II:  T (To, T1, T2, T3), N (No, N1), Mo  Stage III:  T (To, T1, T2, T3, T4, any T), N (No, N1, N2, N3), Mo  Stage IV: any T, any N, M1 28
  • 29.  Goal of therapy ….depends on stage of BCA  Early and locally advanced BCA ….. cure  Metastatic BCA ….  to improve symptoms  to improve quality of life  to prolong survival Treatment of BCA
  • 30. Stage I & II Treatment of early BCA
  • 31. Local–regional therapy  Surgery alone can cure ….  most patients with in situ cancers, and approximately one-half of those with stage II cancers  Breast-conserving therapy (BCT) ….  It consists of lumpectomy (excision of primary tumor & adjacent breast tissue) followed by radiation therapy to prevent local recurrence.  is appropriate primary therapy for most women with stage I & II  it produces equivalent survival rates with cosmetically superior results compared with the modified radical mastectomy. 31
  • 32. Local–regional therapy….  Radiation therapy is administered to the entire breast over 4 to 6 weeks to eradicate residual disease after BCT.  minor complications associated with radiation therapy ….  reddening and erythema of the breast tissue  shrinkage of total breast mass  Mastectomy involves removal of the entire breast without dissection of underlying muscle or axillary nodes.  used for carcinoma in situ where the incidence of axillary node involvement is only 1%. 32
  • 34. Systemic adjuvant therapy 34  Systemic adjuvant therapy is the administration of systemic therapy following definitive local therapy (surgery, radiation, or both) when there is no evidence of metastatic disease but a high likelihood of disease recurrence.  The goal of such therapy is cure.  Chemotherapy, hormonal therapy, or both result in improved disease-free survival and/or overall survival for all treated patients.
  • 35. Adjuvant chemotherapy…. 35  Early administration of effective combination chemotherapy at time of low tumor burden …..  increase the likelihood of cure  minimize emergence of drug-resistant tumor cell clones  Combination regimens have historically been more effective than single agent chemotherapy.
  • 36. Adjuvant chemotherapy….  Commonly used cytotoxic drugs as adjuvant therapy in BCA …  Anthracyclines (doxorubicin, epirubicin)  Alkylating agents such as cyclophosphamide  Antimetabolites (methotrexate, fluorouracil)  Paclitaxel, docetaxel, vinorelbine, vincristine  Prednisone 36
  • 37. Adjuvant chemotherapy…. 37  Anthracycline-containing regimens …..  significantly reduce the rate of recurrence and improve overall survival as compared with regimens that contain cyclophosphamide, methotrexate, and fluorouracil.  Both node-negative and node-positive patients benefit from anthracycline-containing regimens.  addition of taxanes to adjuvant regimens ….improve disease- free survival and overall survival in node-positive BCA patients.
  • 38. Adjuvant chemotherapy…. 38  Although the optimal duration of adjuvant chemotherapy administration is unknown, it appears to be on the order of 12 to 24 weeks and depends on the regimen being used.  Chemotherapy should be initiated within 12 weeks of surgical removal of the primary tumor.
  • 39. Adjuvant chemotherapy…. 39  Dose intensity and dose density …..  critical factors in achieving optimal outcomes in adjuvant breast cancer therapy.  Dose intensity is defined as the amount of drug administered per unit of time and is typically reported as mg/m2/week.  Increasing dose, decreasing time between doses, or both can increase dose intensity.
  • 40. Adjuvant chemotherapy…. 40  Dose density is one way of achieving dose intensity by decreasing the time between treatment cycles.  Increasing doses in standard regimens ….  not beneficial but may be harmful.  Decreasing doses in standard regimens ….  should be avoided unless necessitated by severe toxicity.
  • 41. Adjuvant chemotherapy…. 41  The short-term toxic effects of chemotherapy used in the adjuvant setting are generally well tolerated.  Supportive therapy is important in patients receiving systemic adjuvant chemo such as anthracycline-containing regimen.  Antiemetics  Colony-stimulating factors
  • 42. Adjuvant chemotherapy…. 42  Antiemetics to assist in managing chemotherapy-induced nausea and vomiting,  serotonin-antagonist with substance P/neurokinin 1-antagonist such as aprepitant and dexamethasone  Colony-stimulating factors …..  to prevent febrile neutropenia, particularly in elderly patients or patients receiving dose-dense chemotherapy regimens.
  • 43. Adjuvant chemotherapy…. 43  Other side effects common with chemo regimens used for treatment of early stage BCA  alopecia, weight gain, and fatigue  cessation of menses that may not return; accompanied by signs and symptoms of menopause.  DVT in combination chemotherapy regimens.  Leukemia and other hematologic disorders …associated with the alkylating agents (e.g., cyclophosphamide) and the anthracyclines (e.g., doxorubicin and epirubicin).
  • 44. Adjuvant chemotherapy…. 44  Survival benefit for adjuvant chemotherapy in stage I and II breast cancer is modest.  Absolute reduction in mortality at 10 years …..  5% in patients with negative axillary lymph nodes vs. 10% in node-positive disease  Addition of a taxane to an anthracycline-based chemo….  standard of care for women with node-positive BCA.  controversial in patients with node-negative disease
  • 45. Commonly used adjuvant chemo regimens  AC  Doxorubicin 60 mg/m2 IV, day 1 plus cyclophosphamide 600 mg/m2 IV, day 1, repeat cycles every 21 days for 4 cycles.  AC  Paclitaxel  Doxorubicin 60 mg/m2 IV, day 1 plus cyclophosphamide 600 mg/m2 IV, day 1, repeat cycles every 21 days for 4 cycles.  Followed by: Paclitaxel 80 mg/m2 IV weekly, repeat cycles every 7 days for 12 cycles 45
  • 46. Commonly used adjuvant chemo regimens… 46  FAC  Fluorouracil 500 mg/m2 IV, days 1 and 4  Doxorubicin 50 mg/m2 IV continuous infusion over 72 hours  Cyclophosphamide 500 mg/m2 IV, day 1  Repeat cycles every 21–28 days for 6 cycles  CMF  Cyclophosphamide 100 mg/m2 per day orally, days 1–14  Methotrexate 40 mg/m2 IV, days 1 and 8  Fluorouracil 600 mg/m2 IV, days 1 and 8  Repeat cycles every 28 days for 6 cycles
  • 47. Commonly used adjuvant chemo regimens… 47  Dose-dense AC Paclitaxel  Doxorubicin 60 mg/m2 IV bolus, day 1  Cyclophosphamide 600 mg/m2 IV, day 1  Repeat cycles every 14 days for 4 cycles  Followed by:  Paclitaxel 175 mg/m2 IV over 3 hours  Repeat cycles every 14 days for 4 cycles
  • 48. Adjuvant biologic therapy  Trastuzumab is a monoclonal antibody targeted against the HER2-receptor protein.  Trastuzumab in combination with adjuvant chemotherapy…  indicated in patients with early stage, HER2-positive BCA  risk of recurrence was reduced up to 50% in clinical trials  Optimal duration of trastuzumab therapy is unknown.  Trastuzumab in combination with docetaxel and carboplatin followed by trastuzumab (for a total of 1year) …FDA approved.  Alone for 1year following anthracycline-based chemo 48
  • 49. Treatment of patients with breast cancers larger than 1 cm or with positive lymph nodes 49 (HR: hormone receptor; HER2: human epidermal growth factor receptor-2)
  • 50. Adjuvant endocrine therapy 50  Hormonal therapies studied in the treatment of early stage BCA include….  Tamoxifen, aromatase inhibitors  Choice of agent(s) depends on …  menopausal status
  • 51. Adjuvant endocrine therapy…. 51  Tamoxifen ….. the gold standard for adjuvant endocrine therapy.  Tamoxifen ….. is antiestrogenic in breast cancer cells, but estrogenic in other tissues and organs.  It is generally the adjuvant hormonal therapy of choice for premenopausal women although can also be used for postmenopausal woman.
  • 52. Adjuvant endocrine therapy…. 52  The current recommended dose for tamoxifen in the adjuvant, metastatic, and preventive settings is……… 20 mg/day.  Adjuvant tamoxifen therapy …..  generally initiated after surgery or as soon as pathology results are known and the decision to administer tamoxifen as adjuvant therapy is made.  should be given after chemotherapy is completed, and continuing for 5 years.  Reduces the risk of recurrence and mortality.
  • 53. Adjuvant endocrine therapy….  Tamoxifen ….. usually well tolerated.  Associated with hot flashes and vaginal discharge  increases the risks of stroke, pulmonary embolism, DVT, and endometrial cancer, particularly in women age 50 years or older. 53
  • 54. Adjuvant endocrine therapy….  In postmenopausal women, aromatase inhibitors (AI) are recommended to be incorporated into adjuvant hormonal therapy; with the following options…  An aromatase inhibitor for 5 years, or  Tamoxifen for 2 to 3 years, followed by an aromatase inhibitor (for a total of 5 years of endocrine therapy), or  Tamoxifen for 5 years, followed by an aromatase inhibitor for another 5 years (total of 10 years). 54
  • 55. Adjuvant endocrine therapy….  Available aromatase inhibitors (anastrozole, letrozole, exemestane)  have similar antitumor efficacy & toxicity profiles  generally well tolerated  Adverse effects of AIs include ….  osteoporosis, hot flashes, myalgia or arthralgia, vaginal dryness or atrophy, mild headaches, diarrhea.  Bisphosphonates are coadministered with the AI in many patients in the metastatic setting and may also be beneficial in the adjuvant setting. 55
  • 56. Stage III BCA Treatment of locally advanced BCA
  • 57. Treatment of Stage III BCA  Stage III BCA ….locally advanced breast cancer  refers to breast carcinomas with significant primary tumor and nodal disease, but in which distant metastases cannot be documented.  also includes inflammatory BCA, which is rapidly progressive.  Because of its aggressive nature, a delay in diagnosis can be fatal. 57
  • 58. Treatment of Stage III BCA ….  Inflammatory BCA:  rare, rapidly developing cancer that makes the breast red, swollen and tender.  The rapid onset of symptoms within weeks to months, including erythema of the skin with or without a detectable underlying breast mass .......  the hallmark of inflammatory BCA  Patients with inflammatory BCA …..often inappropriately treated for cellulitis with antibiotics. 58
  • 59. Treatment of Stage III BCA …. 59  Cure is the primary goal of therapy for most patients with stage III disease.  Neoadjuvant chemotherapy …..the initial treatment of choice…  renders inoperable tumors resectable  for patients with inoperable breast cancer, including inflammatory BCA  Primary chemotherapy with an anthracycline-containing regimen with/without a taxane is recommended.
  • 60. Treatment of Stage III BCA …. 60  For patients with HER2-positive tumors ….  trastuzumab with chemotherapy is appropriate  Surgery followed by chemotherapy and adjuvant radiotherapy should be administered…….  to minimize local recurrence
  • 61. Stage IV BCA Treatment of metastatic BCA
  • 62. Treatment of metastatic BCA (Stage IV)  Beyond advanced local-regional disease, BCA is incurable.  Goal of treatment should be…  to improve symptoms and QOL,  to extend survival.  The choice of therapy for MBC is based on the site of disease involvement and presence or absence of certain characteristics,  Involves: endocrine therapy, chemotherapy, and biologic therapy 62
  • 63. Endocrine therapy  The pharmacologic goal of endocrine therapy for BCA ….  decrease circulating levels of estrogen, or  prevent the effects of estrogen at the BCA cell (targeted therapy) by blocking the hormone receptors or down regulating the presence of these receptors.  The most important factor predicting response to endocrine therapy is the presence of estrogen and progesterone receptors in the primary tumor tissue. 63
  • 64. Endocrine therapy….  Endocrine therapy is the treatment of choice for patients …  who have hormone receptor-positive metastases  The choice of a particular endocrine therapy is based primarily on ….  mechanism of action, toxicity, and patient preference.  Tamoxifen is the antiestrogen of choice in premenopausal women whose tumors are hormone-receptor positive,  maximal beneficial effects do not occur for at least 2 months. 64
  • 65. Endocrine therapy…. 65  Aromatase inhibitors (anastrozole, letrozole, exemestane) ….  reduce circulating and target organ estrogens  generally used in advanced BCA in postmanopausal women, followed by other endocrine therapies upon progression.  similar response rate and longer time to progression as well as lower incidence of thromboembolic events and vaginal bleeding, compared with tamoxifen.
  • 66. Endocrine therapy…. 66  Aromatase inhibitors  Anastrozole 1 mg orally daily  Letrozole 2.5 mg orally daily  Exemestane 25 mg orally daily  Antiestrogens  Tamoxifen 20 mg orally daily  Patients are sequentially treated with endocrine therapy until their tumors cease to respond, at which time chemotherapy can be given.
  • 67. Chemotherapy  The goal of chemotherapy in the metastatic setting is palliative.  Chemotherapy is used as initial therapy for women…  with hormone receptor-negative tumors  after failure of endocrine therapy  Agents used previously as adjuvant therapy can be repeated unless the cancer recurred within 1 year. 67
  • 68. Chemotherapy…..  Single agents are associated with lower response rates than combination therapy.  Single agents are better tolerated, an important consideration in the palliative metastatic setting.  Treatment with sequential single agents is recommended over combination regimens….. unless the patient has rapidly progressive disease, life-threatening visceral disease, or the need for rapid symptom control.  Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-line therapy for MBC. 68
  • 69. Metastatic Single-Agent Chemo 69  Paclitaxel 175 mg/m2 IV over 3 hrs. Repeat cycles q21d, OR  Paclitaxel 80 mg/m2 per week IV over 1hr. Repeat dose q 7d  Vinorelbine 30 mg/m2 IV, days 1 and 8. Repeat cycles q21d, OR  Vinorelbine 30 mg/m2 per week IV. Repeat cycles q7 d (adjust dose based on absolute neutrophil count)  Docetaxel 60–100 mg/m2 IV over 1 hr. Repeat cycles q21d, OR  Docetaxel 30–35 mg/m2 per week IV over 30 min. Repeat dose q7d  Capecitabine 2,000–2,500 mg/m2 per day orally, divided twice daily for 14 days. Repeat cycles q21d
  • 70. Metastatic Combination Chemo Regimens 70  Docetaxel + capecitabine  Docetaxel 75 mg/m2 IV over 1 hr, day 1  Capecitabine 2,000–2,500 mg/m2 per day orally divided twice daily for 14 days  Repeat cycles q21d  Paclitaxel + Gemcitabine  Paclitaxel 175 mg/m2 IV over 3 hrs, day 1  Gemcitabine 1,250 mg/m2 IV days 1 and 8  Repeat cycles q21d
  • 71. Biologic therapy  Trastuzumab, a monoclonal antibody that binds to HER2,  produces response rates of 15% to 20% when used as a single agent  increases response rates, time to progression when combined with chemotherapy.  as doublet (taxane-trastuzumab; vinorelbine-trastuzumab)  as triplet (trastuzumab-taxane-platinum) combinations  Trastuzumab is well tolerated,  But, the risk of cardiotoxicity is 5% to the single-agent and unacceptably high in combination with an anthracycline. 71
  • 72. Radiation therapy 72  Radiation is commonly used to treat painful bone metastases or other localized sites of disease.  Pain relief is seen in approximately 90% of patients who receive RT.
  • 73. Prevention of breast cancer  Tamoxifen therapy  Tamoxifen reduce the rates of invasive BCA in women at high risk for developing the disease.  At 20 mg/day for 5 years, a decreased risk for invasive and noninvasive cancer of 50% was seen.  Caution when using tamoxifen  Increased risk for endometrial cancer  Increased risk for life-threatening thromboembolic events 73