BREAST CANCER

Incidence and Mortality

•Breast cancer is the most common malignancy diagnosed in women in the U.S.

•The second most common cause of cancer death in women, surpassed only by lung cancer.

•Approximately 213000 new cases of breast cancer are expected to be diagnosed in the U.S. during 2006 •An estimated 41,000 people are expected to die with breast cancer at 2006

Etiology

•The etiology of breast cancer is unknown

•But several predisposing factors for the disease have been determined.

•These factors can be divided into three major categories:

–Genetic or familial factors

–Endocrine factors

– Environmental factors

Risk factors for breast cancer development

•Personal history of breast cancer

•Family history of breast cancer in first-degree relatives

•Proliferative benign breast disease

•Early menarche, late menopause

•Nulliparity

•First pregnancy after age 35

•Exogenous estrogens (postmenopausal hormone replacement therapy, oral contraceptives)

•Obesity (menopausal weight gain, fat distribution)

•Dietary factors (alcohol, high fat diet)

•Radiation

Pathophysiology

Breast anatomy

•Human breast tissue is composed primarily of connective tissue and fat.

•There is also an elaborate duct system within the breasts that is used during lactation.

•Breast tissue has an abundant blood supply and an extensive lymphatic network.

•Lymphatic drainage of the mammary tissues flows into the axillary, interpectoral, and internal mammary lymph nodes

Lymph node areas adjacent to breast area.A pectoralis major muscleB axillary lymph nodes: levels IC axillary lymph nodes: levels IID axillary lymph nodes: levels IIIE supraclavicular lymph nodesF internal mammary lymph nodes

•A woman’s breast tissue and glands begin to develop around the time of puberty (limited) and the majority occurs during the first pregnancy.

•The large amounts of estrogen and progesterone produced by the ovaries during pregnancy stimulate rapid growth and terminal differentiation of immature breast tissue.

Tumor development

•Breast cancer occurs when breast cells lose their normal differentiation and proliferation controls

•The proliferation of these abnormal cells, or tumor cells, is influenced by various hormones, oncogenes, and growth factors.

•There is strong evidence to suggest that estrogen directly and indirectly stimulates the growth of tumor cells.

•Also, numerous growth factors, secreted by the breast cancer themselves, play a role in tumor development.

Growth factors can be classified as either:

•Autocrine (if they stimulate their own growth), such as:

– Transforming Growth Factor Alpha (TGF-α)

– Insulin-like Growth Factors I and II (IGF-I and IGF-II)

•Paracrine (if they have an effect on other cells) such as:

– Transforming Growth Factor Beta (TGF-β)

– Platelet-Derived Growth Factor (PDGF)

– Procathepsin D (52K protein)

•The mechanism of action of several hormonal agents used for the treatment of breast cancer involves the alteration of the growth factors involved in tumor development

•Trastuzumab is a monoclonal antibody binds specifically to growth factor receptors on the malignant cell surface

Clinical Presentation And Diagnosis

Sign and Symptoms

Breast cancer mass tend to be:•Painless•Solitary•Unilateral•Hard•Irregular, •Nonmobile

Patients may also have:•Skin changes•Nipple discharge or •Axillary lymphadenopathy.

Detection and Diagnosis•Early detection of breast cancer is critical because patients with early stages have a better prognosis.

•Three complementary screening techniques have been shown to be effective for detection:–Breast self examination (BSE)–Physical examination by a physician–Mammography

•On presentation, any women with suspected benign or malignant breast disease should have a mammography

•Any breast mass that is suggestive of malignancy by mammography or on physical examination should be biopsied for final diagnosis and staging

Breast Cancer Staging

•The TNM classification system is the most commonly accepted staging system for breast cancer

•Tumor size (T) is described on a scale of 0 to 4 based on characteristics of the primary tumor

•Extent of lymph node involvement (N) based on location and palpability

•Involvement of ipsilateral axillary, internal mammary and pectoral nodes are all considered regional spread of the disease

•The presence or absence of distance metastases (M) is also included in the system

•Involvement of any other lymph nodes, including the supracalvicular, cervical, or contralateral internal lymph nodes, is considered distant metastases

T1 2 cmT2 > 2 cm 5 cmT3 > 5 cmT4 Direct extension to chest wall or skin

N1 Metastasis to movable ipsilateral axillary lymph nodes(s) N2 Metastasis to ipsilateral axillary lymph nodes(s) fixed to one another or to other structure N3 Metastasis to ipsilateral internal mammary lymph nodes

M0 No distant metastasis M1 Distant metastasis {includes metastasis to ipsilateral supraclavicular lymph node(s)}

I T1 N0 M0

II T1 N1 M0 / T2 N0 M0 / T2 N1 M0 / T3 N0 M0

III T0-2 N2 M0 / T3 N1-2 M0 / T4 N0-3 M0 / T1-4 N3 M0

IV T1-4 N0-3 M1

Therapeutic Plan

•The goal of treatment in breast cancer varies by the stage of disease at diagnosis and patient-specific prognostic factors

•Most breast cancer disease (excluding metastatic disease) is treated for cure

•Some patients with isolated metastases that can be resected may also be treated for cure

•When cure is not possible (such if the disease recurs), the goals of treatment are to prolong survival and palliate symptoms (palliative goal of treatment)

Noninvasive Breast Cancer

Lobular Carcinoma In Situ (LCIS) not consider a malignancy, but may develop breast cancer in the future

Breast profile:A ductsB lobulesC dilated section of duct to hold milkD nippleE fatF pectoralis major muscleG chest wall/rib cage Enlargement:A normal cellsB lobular cancer cells breaking through the basement membraneC basement membrane

•Standard treatment: excisional biopsy and close observation of the patient

•Tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women

Ductal Carcinoma In Situ (DCIS)

Breast profile:A ductsB lobulesC dilated section of duct to hold milkD nippleE fatF pectoralis major muscleG chest wall/rib cage Enlargement:A normal duct cellsB ductal cancer cellsC basement membraneD lumen (centre of duct)

•Lumpectomy + radiation is sufficient treatment for patients with DCIS (with or without tamoxifen)

Early-stage Breast Cancer

•Lumpectomy + radiation is appropriate therapy for patients with early stage breast cancer.

•The decision to treat node-negative breast cancer particularly tumors less than 1 cm with adjuvant therapy must be made on an individual basis.

•Factors influence the physician’s final judgment concerning adjuvant therapy:–The presence or absence of prognostic factors –Patient’s desire to receive treatment

•Adjuvant therapy is chemotherapy or hormonal therapy that is administered in an attempt to treat the residual micrometastatic disease that remains after surgery

•The CAF marginally superior to CMF

•The addition of tamoxifen to the chemotherapy regimens was beneficial only in patients who were (ER+)

•In management of stage II breast cancer (tumor <5 cm with positive nodal involvement) studies indicate that systemic adjuvant therapy can prolong disease-free and overall survival

•Combination is more effective than single-agent regimens

•Clinicians should avoid chemotherapy dose reductions in the adjuvant settings to achieve the maximal benefit of therapy

•The availability of G-CSF and other supportive care measures may make this more feasible

•The optimal combination regimen has not been determined

•The combination of cyclophosphamide, methotrexate, and fluorouracil has been studied most extensively

•Doxorubicin (Adriamycin) has demonstrated significant activity as single-agent therapy

•It has produced increased response rates when used in combination chemotherapy

•CAF showed margin superiority to CMF, but the toxicities where also increased with CAF

•Some clinicians choose to restrict the doxorubicin-containing regimens to the metastatic disease setting because doxorubicin-refractory patients are very difficult to treat

•The approval of new agents, such as the taxanes and capecitabin for refractory disease setting change this practice

•The taxanes have demonstrated the best single-agent activity of any drug tested to date in the refractory disease setting

•Studies showed that the use of adjuvant tamoxifen for about 5 years produces a substantially greater delay in disease recurrence as compared with 1 or 2 years use

Combination chemotherapy regimens used in the treatment of breast cancer

Regimen Drug Dose CMF Repeat every 28 days

Cyclophosphamide Methotrexate Fluorouracil

100 mg/m2/day PO days 1-14 or 600 mg/ m2/day IV D1 40 mg/m2/day IV D1 and 8 600 mg/m2/day IV D1 and 8

TAC Repeat every 21-28 days

Docetaxel Doxorubicin Cyclophosphamide

75 mg/m2/day IV D1 50 mg/m2/day IV D1 600 mg/m2/day IV D1

AC Repeat every 21 days

Doxorubicin Cyclophosphamide

60 mg/m2/day IV D1 600 mg/m2/day IV D1

FAC or CAF Repeat every 21-28 days

Fluorouracil Doxorubicin Cyclophosphamide

500 mg/m2/day IV D1 and 8 50 mg/m2/day IV D1 600 mg/m2/day IV D1

CFM Repeat every 21 days

Cyclophosphamide Fluorouracil Mitoxantrone

500-600 mg/m2/day IV D1 500-600 mg/m2/day IV D1 10-12 mg/m2/day IV D1

Locally Advanced Breast Cancer

•Patients diagnosed with locally advanced breast cancer (stage III) have tumors larger than 5 cm or direct involvement of the skin or underlying chest wall

•These patients also have extensive lymph node involvement.

•Radiation, systemic chemotherapy and surgery have all been used in various regimens in clinical trials

•Neoadjuvant therapy involves the use of chemotherapy before surgery to decrease the size of tumor and improve resectability

•Other advantages of neoajuvant chemotherapy include:

–Earlier treatment of micrometastatic disease

–Intact tumor vasculature resulting in improved drug delivery

–The ability to determine tumor responsiveness to chemotherapy in vivo

–The ability to customize postsurgical systemic therapy based on this response

•After neoadjuvant chemotherapy patients will receive radiation therapy and surgery

•When all three modalities are combined, more than 90% of patients with locally advanced breast cancer are disease free after treatment and many remain disease free for 3-5 years

Metastatic Breast Cancer

•“Cure” is not the primary goal of therapy at this point

•The easiest, least toxic treatment that can provide the best possible response is generally preferred to palliate the patient and possibly prolong survival

•Breast cancer can metastasize to any site, but the most common sites include bone, lung, pleura, liver, soft tissue, and the CNS

•The choice of therapy for metastatic disease is based on the site of disease involvement and the presence or absence of certain patient characteristics

For example, patients who–Experience a longer disease-free survival (2 years or longer)–Have disease that is primarily located on bone or soft tissue–Have responded to primary endocrine therapy–Are late premenopausal or postmenopausal

•Will most likely respond to endocrine therapy

•The most important factor predicting response to hormonal therapy is the presence of estrogen receptors (ER) and progesterone receptors (PR) on tumor tissues

•In premenopausal women, LHRH analogues are to be used

•In postmenopausal women, tamoxifen therapy is the first-line treatment of choice because of ease of administration and lack of serious side effects

•Chemotherapeutic drugs are most commonly used as palliative therapy in patients who

-Would not be expected to respond to hormonal therapy (i.e. patients with rapidly progressive lung, liver, or bone marrow disease)

-Or who have failed to respond to initial endocrine therapy

•Radiation therapy is primarily used in brain and spinal cord metastases

•Progestins, aromatase inhibitors, and androgens are second line hormonal choices

•Due to comparable response rates between agents, the choice is currently based on toxicity, cost and ease of administration

•Patients with rapidly progressive disease or who do not fulfill the criteria or fail to respond for endocrine therapy should receive chemotherapy initially

Class Drug Dose Side Effects

LHRH (GnRH) (Premenopausal)

Goserelin Leuprorelin Buserelin

3.6/10.8 mg SC 4/12 weekly

3.75/11.25 mg SC 4/12 weekly

6.3 mg SC 8 weekly

Ammenorrhea, hot flushes, occasional nausea

Antiestrogen Tamoxifen Toremifene Fulvestrant

20-30 mg PO daily 60 mg PO daily 250 mg IM 4weekly

Disease flare, hot flushes, nausea, vomiting edema, vaginal discharge,

Progestins Medroxypro-gesterone Megestrol

500-1000 mg PO daily 160 mg PO daily

Weight gain, hot flashes, vaginal bleeding

Aromatase inhibitors

Anastrozole Letrozole Exemestane

1 mg PO daily 2.5 mg PO daily 25 mg PO daily

Letheargy, dizziness, nausea, hot fluches , skin rash, headache

Endocrine therapies used for metastatic breast cancer

•Some of the newer single agents have produced responses equivalent to those obtained with combination regimens, particularly in the anthracycline-refractory disease setting

•Paclitaxel (175 mg/m2 IV 3 weekly) are used for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy

•Similarly, docetaxel (60-100 mg/m2 IV 3 weekly) was approved for patients with locally advanced or metastatic breast cancer who have progressed during prior chemotherapy or relapsed during anthracycline-based adjuvant therapy

•Capecitabine is a prodrug that is converted to fluorouracil after oral administration

•This drug has been approved for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and anthracycline therapy or is not indicated

•The recommended starting dose is 2500 mg/m2 /day administered twice daily with food for 2 consecutive weeks followed by 1 week of rest (21-day cycles)

•Doxorubicin has demonstrated significant activity in the adjuvant treatment of breast cancer and in the treatment of metastatic disease

•Doxorubicin dosing is limited by the development of cardiomyopathy, which occurs with cumulative lifetime doses of greater than 400 mg/ m2

•Trastuzumab, which binds to the human epidermal growth factor receptor 2 (HER2), was approved for the treatment of:

Patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease

•Trastuzumab is also indicated in combination with docetaxel for the treatment of:

•Patients with metastatic breast cancer whose tumors overexpress HER2 and who have not received chemotherapy for their metastatic disease

Lapatinib is an oral tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor.

It has shown activity in combination with capecitabine in patients who have HER2-positive metastatic breast ca. that progressed after treatment with trastuzumab.

Toxicities of commonly used antineoplastic agents

Drug Toxicity Cyclophosphamide Myelosuppression, nausea/vomiting, alopecia, hemorrhagic cystitis, stomatitis

Methotrexate Myelosuppression, mucositis, diarrhea, nausea/vomiting, hepatic dysfunction, nephrotoxicity

Fluorouracil/ capecitabine

Myelosuppression, mucositis, alopecia, nausea/vomiting, diarrhea, skin hyperpigmentation/photosensitivity, cerebellar ataxia (FU only)

Vinblastine/ vinorelbine

Neurotoxicity, constipation, alopecia, myelosuppression, injection site reactions, skin necrosis after extravasation

Doxorubicin Myelosuppression, nausea/vomiting, alopecia, stomatitis, radiation recall, skin necrosis after extravasation, cardiotoxicity

Mitoxantrone Myelosuppression, nausea/vomiting, alopecia, mucositis, urine discoloration, cardiotoxicity

Paclitaxel/ docetaxel

Myelosuppression, hypersensitivity reactions, paresthesia/neuropathy, myalgias, and arthralgias, nausea,vomiting, diarrhea, alopecia, fluid retention (docetaxel), cutaneous reactions (docetaxel)

Trastuzumab Fever, chills, diarrhea, cardiac dysfunction