Tuesday, March 16, 2010

Breast cancer Pathology,Breast cancer Staging and prognostic factors,Breast cancer Treatment

Posted by sans at 4:45 AM

Doubling time

Doubling times for primary breast cancer ranged from 44 to more than 1,800 days, with a mean of 212 days. Metastatic lesions may have a slightly faster average rate of growth than primary tumors.

Classification

The World Health Organization classification of breast tumors organizes both benign and malignant lesions by histologic pattern. Epithelial tumors comprise the largest group, including intraductal papilloma, adenomas, intraductal and lobular carcinoma in situ, invasive (ductal and lobular) carcinoma, and Paget disease of the nipple. Invasive ductal carcinoma is by far the most common type.

The relative frequency of malignant breast cancers are:

  • Ductal carcinoma:78%
  • Lobular carcinoma: 9%
    Alveolar & mixed types are bilateral. Solid & signet ring have worse prognosis than IDC with high tendency to metastasize.
  • Comedocarcinoma: 5%
  • Medullary: 4%.
  • Inflammatory: worst prognosis
  • Paget's: unilateral eczema of the nipple.
  • Other
The pathological classification of breast cancer is based on on the anatomic or structural units
present in the female breast. These units consist of large, medium, and small ducts from which a variety of tumor types arise.

1. Large ducts

Noninvasive cancer

Tumors arising from duct epithelium may be found only within the lumen of the ducts of origin;
that is, the carcinomas are intraductal and do not penetrate the basement membrane or invade surrounding stroma. Most frequently, such tumors arise from large ducts and may present as several types.

Ductal carcinoma in situ (DCIS)

The noninvasive variety of ductal carcinoma, referred to as intraductal carcinoma or ductal
carcinoma in situ (DCIS), is a proliferation of a subgroup of epithelial cells confined to the mammary ducts without light microscopic evidence of invasion through the basement membrane into the stroma.
DCIS, like invasive ductal carcinoma, occurs more frequently in women, although it accounts for approximately 5% of all male breast cancers. The average age at diagnosis of DCIS is 54-56 years, which is approximately a decade later than the age at presentation for LCIS.
The clinical signs of DCIS include a mass, breast pain, or bloody nipple discharge. On mammography, the disease most often appears as microcalcifications.
The risk of developing an invasive carcinoma following a biopsy-proven diagnosis of DCIS is between 25% and 50%. Virtually all invasive cancers that follow DCIS are ductal and ipsilateral and generally present in the same quadrant within 10 years of the diagnosis of DCIS. DCIS is less likely than LCIS to be bilateral and has approximately a 30% incidence of multicentricity. DCIS is considered a more ominous lesion than LCIS and appears to be a more direct precursor of invasive cancer.
A variety of histologic patterns of DCIS have been recognized. The most frequently encountered are:
  • Comedo
  • Cribriform
  • Solid
  • Papillary
  • Micropapillary
The different histologic patterns have been associated with differences in biologic behavior. Some researchers have divided DCIS into two subgroups: comedo and noncomedo types. As compared with the noncomedo subtypes, the comedo variant has a higher proliferative rate, overexpression of HER-2/neu, and a higher incidence of local recurrence and microinvasion.The role of assays for estrogen and progesterone receptors (ER and PR) in DCIS has not been established.
Comedocarcinoma: is characterized by ducts that are dilated and filled with carcinoma cells. These are necrotic and can be expressed as semisolid necrotic plugs. Such cancers are not usually regarded as a separate cell type but rather represent a descriptive variant of intraductal carcinoma. Patients whose DCIS exhibits comedo features have been shown to have increased rates of local recurrence and may progress more rapidly to invasive breast cancer compared to other types.
Papillary carcinoma: If they grow into the ducts with a papillary configuration, they are recognized as papillary carcinomas. Such lesions are rare, accounting for about 1% of breast cancers. Histologically, pleomorphic duct epithelial cells with disturbed polarity can be demonstrated, as can their �heaping up� into papillae. Difficulty may be encountered in differentiating a papillary carcinoma from a benign atypical papilloma.
Papillary carcinomas rarely invade the surrounding stroma. A survival rate approaching
100% may be anticipated upon complete excision of such tumors. When these tumors do invade surrounding tissue, they grow rather slowly and attain considerable bulk. Skin and fascial attachments are unusual, and axillary node involvement is a late feature. Clinically, noninvasive tumors are found to be movable, circumscribed lesions that have a soft consistency not unlike that of fibroadenomas.

Invasive cancer

1. IDC NOS

Infiltrating duct carcinomas in which no special type of histologic structure is recognized are designated �not otherwise specified� (NOS) and are the most common duct tumors, accounting for almost 80% of breast cancers. They are characterized clinically by their stony hardness to palpation. When they are transected, a gritty resistance is encountered, and the tumor retracts below the cut surface. Yellowish, chalky streaks that represent necrotic foci are observed. Histologically, varying degrees of fibrotic response are present. As a rule, they do not become large. They frequently metastasize to axillary lymph nodes, and their prognosis is the poorest of the various tumor types. More than half (52.6%) of breast cancers are pure infiltrating duct lesions (NOS).

Special types of IDC

Medullary carcinoma

Medullary carcinoma, composing 5 to 7% of all mammary carcinomas, often attains large dimensions. This tumor is formed by cells of relatively high nuclear grade, and usually exhibits
an extensive infiltration of the tumor by small lymphocytes. Medullary carcinomas have a relatively well-circumscribed border, sometimes described as a �pushing� border, in contrast to
the NOS tumors in which small nests of cells tend to infiltrate the adjacent stroma more extensively. A study of medullary cancer using 336 typical and 273 atypical medullary breast
cancers from 6,404 patients enrolled in various Stage I and Stage II National Surgical Adjuvant Breast Project (NSABP) trials indicated that the survival of patients with typical medullary cancers was better than that for patients with NOS invasive ductal carcinomas. Survival was comparable for those with atypical medullary and NOS types.

Tubular carcinoma

Tubular carcinoma is an invasive carcinoma in which tubule formation is highly prominent. This tumor has a low nuclear grade with some cell polarity. Its prognosis is favorable, and, when combined with small size, it is a highly curable tumor.

Mucinous carcinoma

Mucinous or colloid carcinoma, which composes about 3% of all mammary carcinomas, is characterized on microscopy by its nests and strands of epithelial cells floating in a mucinous matrix. It usually grows slowly and can reach bulky proportions. When the tumor is predominantly mucinous, the prognosis tends to be good. Two entities represent special manifestations of mammary carcinoma.

Papillary carcinoma: See above.

2. Small ducts

Noninvasive cancer

Lobular carcinoma in situ

With the increased use of mammography, a much higher proportion of noninvasive cancers is being detected. Lobular CIS consists of a neoplastic proliferation of cells in the terminal breast ducts and acini. It is characterized by small and round cells of low nuclear grade that fill and expand lobules without penetration of the basement membrane. Though these lesions are low grade, there is a 15-30% risk for development of invasive carcinoma in the same or the opposite breast. This risk is greatest within 10-15 years after the diagnosis is established. Whereas DCIS often accompanies invasive ductal carcinoma, and may well be its usual precursor, LCIS may be followed by invasive ductal or invasive lobular carcinomas in either breast. LCIS thus is more a systemic marker than a local precursor. Recent investigations suggest that LCIS is heterogeneous, and there is biologic variability. Therefore, there may be certain subtypes of LCIS that are more likely to progress to invasion.
There is no mass lesion or mammographic abnormality associated with this disease. The pathologist is the only physician who makes this diagnosis. LCIS is found in 0.5-3.8% of otherwise benign breast biopsies. The true incidence of lobular carcinomas is uncertain. It has been emphasized that noninvasive mammary carcinomas make up almost 5% of all neoplastic lesions of the female breast and that LCIS accounts for about 50% of these, or 2.5 to 2.8% of all tumors. The incidence of LCIS has doubled over the past 25 years and is now 2.8 per 100,000 women. In the past, the peak incidence of LCIS was in women in their 40s. Over the past 3 decades, the peak incidence has increased to the 50s. The incidence of LCIS decreases in women who are in their 60s-80s. This may be related to the use of hormone replacement therapy (HRT).
Pathology: Most commonly in both breasts in multifocal and multicentric. If LCIS is found in a breast, >50% will have residual LCIS in the ipsilateral breast and >1/3 will have LCIS in the contralateral breast. Classically, involved acini are filled and distended by a uniform population of cells. At least half of the acini are involved within the lobular unit (this distinguishes it from atypical lobular hyperplasia in which fewer than half of the acini are expanded or distorted by a uniform population of lobular cells.

Lobular carcinoma

Lobular carcinoma arises from the small end ducts of the breast.
Invasive lobular carcinoma is similar to LCIS but the lesion extends beyond the boundary of the lobule or terminal duct from which it arises. Often the small cells interdigitate between collagen bundles in a single line, so-called �Indian file.� At other times, lobular carcinoma may be nearly indistinguishable from the conventional infiltrating duct carcinoma. The increase in invasive lobular carcinoma peaks in women in their 70s. It is associated with both synchronous and metachronous contralateral primary tumors in 30% of the cases.

Inflammatory breast cancer

Inflammatory breast cancer, or �dermal lymphatic carcinomatosis�, is an uncommon form of rapidly advancing breast cancer that usually accounts for approximately 1% to 3% of all breast cancer diagnoses. Inflammatory breast cancer causes the breast to appear swollen and inflamed. This appearance is often caused when cancer cells block the lymphatic vessels in the skin of the breast, preventing the normal flow of lymph fluid and leading to reddened, swollen and infect-looking breast skin�hence the designation "inflammatory" breast cancer. It can easily be confused with mastitis an infection of the breast ducts. To increase the confusion with infection, resulting in treatment with antibiotics, and sometimes, but not always, the antiobiotic treatment changes the appearance of clinical symptoms.  The reason for an apparent response to antibiotics when IBC is present is not known, and may delay the diagnosis of IBC.
With inflammatory breast cancer, the breast skin has a thick, pitted appearance that is classically described as peau d�orange (resembling an orange peel). Sometimes the skin develops ridges and small bumps that resemble hives. These features may be present at the time of primary diagnosis or as part of the clinical picture of recurrent breast cancer.
Biopsies of the erythematous areas and adjacent normal-appearing skin reveal poorly differentiated cancer cells filling and obstructing the subdermal lymphatics. Inflammatory cells are rarely present. Patients typically have signs of advanced cancer, including palpable axillary nodes, supraclavicular nodes, and/or distant metastases.

Paget's disease of the nipple

This disease presents as a persistent dermatitis of the nipple. Clinically, the patient presents with a relatively long history of eczematoid changes in the nipple, with itching, burning, oozing, and/or bleeding which is often unresponsive to topical steroid and antibiotics. The nipple changes are associated with an underlying carcinoma in the breast that can be palpated in about two-thirds of the patients. The alert physician may biopsy the nipple revealing the characteristic changes. Clinically impalpable and radiologically undetectable disease is present in about 40% of the patients. Most commonly, this is an infiltrating ductal carcinoma but occasionally a ductal carcinoma in situ (DCIS) may be present. Overall, this cancer is rare, comprising 1-4% of all patients with breast carcinoma.
Under the microscope, there is a proliferation of malignant epithelial cells scattered throughout the epidermis. The cells have abundant pale staining cytoplasm surrounding a hyperchromatic nucleus with prominent nucleoli.

Other histological types

Several other histologic types of mammary carcinomas have been described but are rarely encountered. Adenocystic carcinoma, carcinosarcomas, pure squamous cell carcinoma, metaplastic carcinomas (carcinoma with osseous or cartilaginous stroma), basal cell carcinomas, and so-called lipid-rich carcinomas have been observed. Because of their rarity, clinical correlates are practically nonexistent.

Breast cancer
Staging and prognostic factors

Staging techniques -
Bone metastasis
(80%)

1. Bone scan

The bone scan can detect an abnormality prior to the radiograph becoming abnormal. Abnormal areas of accumulation are seen related to osteoblastic activity. Purely lytic lesions such as multiple myeloma may be missed on the bone scan.

Benefits

  • Bone scans are quite sensitive (70%) for the detection of metastatic disease, but the specificity is lower than the sensitivity (60%), hence the need for correlation with plain radiographs and CT.
The poor specificity is because any process involving bone will result in increased bone turnover and an abnormality on the bone scan. Thus, inflammatory, traumatic, and metabolic abnormalities will result in increased areas of localization on the bone scan.

2. Bone X-ray

Compared with other imaging techniques, radiography is relatively insensitive in detecting bone metastases, especially subtle lesions.

Benefits

  • Can detect lesions that are 2 cm or larger. Metastases to bone become apparent on radiographs only after the loss of more than 50% of the bone mineral content at the site of disease.
  • Useful in confirmation of lesions that are detected by bone scan.

3. CT scan of bone lesion

CT scans of the bone is useful in detection of metastasis or confirmation of bone lesions detected by bone scan.

Benefits

  • More sensitive than radiography in the detection of metastatic lesions and is useful for confirmation of the results obtained by scintigraphy (bone scans), especially in sacral lesions - specificity 90%.

4. MRI of the bone

Benefits

  • Whole body MRI has been reported to be superior to bone scans in detection of bone metastasis. Sensitivity is 80% and specificity is >90%.

5. PET scan for bone lesions

Benefits

  • FDG PET has the highest sensitivity in detecting bone metastasis: 90%. Its specificity approaches 100%

Pulmonary metastasis (25%)

1. Chest x-ray

A chest radiograph in two planes is indicated on a regular basis to screen for metastatic disease in the follow-up of patients with primary tumors that preferentially spread to the lungs.

Benefits

  • Sensitivity and specificity for chest radiography were 50 and 90%, respectively for nodules >5mm.
  • It more accurately detects a 1-cm nodules 1cm or greater.

2. Chest CT

When metastatic nodules are identified, helical computed tomography (CT) of the chest  should be performed to assess their number and characteristics.

Benefits

  • A high-resolution CT scan can identify nodules 3 mm in diameter.
  • CT has an overall sensitivity 62% in detecting pulmonary nodules (all sizes). However it underestimated the extent of the disease in 25%, and overestimated the extent of the disease in 14%.
  • Sensitivity is increased to 95% for intrapulmonary nodules ≥ 6 mm and 100% for intrapulmonary nodules > 10 mm.
The limitations of CT scan in this study were mainly associated with pleural-based nodules and intrapulmonary nodules < 6 mm.

Liver metastasis (20%)

1. Ultrasonography of the liver

Ultrasonography is inexpensive and readily available, but its value compared to single-slice helical CT (SSCT), MSCT, and MRI is limited as a consequence of reduced sensitivity and specificity. In general, the US appearance of liver metastases is nonspecific.

Benefits

  • Sensitivity is operator dependent. It is valuable, inexpensive, quick, and portable, and it can depict lesions as small as 1 cm with a sensitivity approaching 80%.
  • The specificity of US in detecting liver metastases is poor, and its overall false-negative rate is 50%. However, the presence of multiple hepatic nodules of different sizes within the liver is nearly always due to metastases.

2. Abdominal CT

CT is the most sensitive technique for the detection of liver metastases.

Benefits

  • Contrast-enhanced scans offer a high degree of sensitivity, as high as 80-90%. The specificity is 99%.

Brain metastasis (15%)

Screening for brain metastasis is not routinely done in breast cancer and is only done for those with symptoms suggestive of brain involvement.

1. CT scan of the brain

CT scan of the brain is currently the method of choice in screening for brain metastasis. Patients with multiple lesions are even more likely to have metastatic disease. Prior to definitive therapy, patients with a single metastasis by contrast-enhanced CT should undergo a contrasted MRI examination, if available.

Benefits

  • 92% sensitivity, 99% specificity

2. MRI of the brain

Gadolinium-enhanced MRI is superior to contrast-enhanced CT in the diagnosis of brain metastases. It is particularly useful in patients shown to have a single metastasis by contrast-enhanced CT prior to definitive therapy.

3. FDG-PET for brain lesions

FDG-PET is not considered superior to CT or MRI in the initial evaluation of suspected brain metastases.

Benefits

  • Sensitivity of 90% but low specificity. Neoplasm, inflammation, vascularity, or trauma may cause the abnormal uptake.

Staging of breast cancer

  • The TNM staging system for breast cancer

Prognosis (Risk factors for recurrence)

The challenge for the clinician is to determine which patients have the highest risk of recurrence and, thus, are most likely to benefit from adjuvant therapy. In this chapter, we will detail the prognostic factors that affect whether adjuvant therapy is indicated and then describe the various adjuvant treatments that are available.
Memory Aid for breast cancer prognostic factors:
(HrGAT - Hormone receptor, Grade, Age, Tumor)
 HRGradeAgeTumor
Low risk+veI>=35<=1cm
Interm. risk+veI,II>=351-2cm
High risk-veII,III<35>2cm
HER-2/neu oncogene: Overexpression of the HER-2/neu oncogene reflects an increase in the proliferative activity of a tumor. Overexpression has been demonstrated in 15% to 30% of patients with breast cancer and has been found by most investigators to be associated with shorter survival.
Ploidy and S-phase fraction: The degree of cellular proliferation in breast cancer specimens has shown a strong correlation with outcome. DNA ploidy is the DNA content and number. S-phase fraction is the fraction of cells actively cycling or synthesizing DNA. Aneuploid (those with abnormal DNA content and number) tumors with a high percentage of cells in S-phase are more likely to recur than are tumors with a low S-phase fraction.
Prognostic factors currently under investigation
  • Angiogenesis markers
  • Histologic subtype
  • Lymphatic invasion
  • Epidermal growth factor receptor
  • Ki-67
  • pS2
  • Stress response proteins
  • Type IV collagenases
  • nm23
  • p53
  • Plasminogen activators

Breast cancer
Treatment


Stage 0

1. Lobular carcinoma in situ (LCIS)

Lobular carcinoma in situ. Presently, treatment options include close follow-up, participation in a chemoprevention trial, tamoxifen (Nolvadex), or bilateral total mastectomy with or without reconstruction. At present, the decision for a given treatment will depend upon the patient�s individual risk profile after careful counseling.

2. Ductal carcinoma in situ (DCIS)

Ductal carcinoma in situ (DCIS). Breast-conservation surgery, followed by radiation therapy to the intact breast, is now considered the standard treatment for patients with DCIS.

Axillary lymph nodes

Routine axillary lymph node evacuation is not indicated in the treatment of DCIS since the incidence of positive lymph nodes after axillary lymph node dissection for DCIS is 1%-2%.
 Factors associated with an increased risk of axillary metastasis with a diagnosis of DCIS are
  1. Extensive DCIS requiring mastectomy
  2. Suspicion of microinvasion
  3. DCIS associated with a palpable mass
  4. Evidence of lymphovascular permeation or invasion seen on review of the slides.
These factors likely are associated with unknown (nondiagnosed) invasive disease and may benefit from sentinel lymph node dissection.

Adjuvant radiotherapy

A surgical margin of 1 mm has been associated with a 43% chance of having residual disease at the time of re-excision. When a surgical margin of 10 mm (which may not be practical due to cosmetic reasons) can be obtained, there is an extremely low rate of recurrence (4%), and radiotherapy to the breast may not be necessary.

Adjuvant tamoxifen therapy

Adjuvant tamoxifen therapy was shown to benefit women with DCIS in a recent NSABP trial (NSABP-24) in which the tamoxifen group had fewer breast cancer events than those in the placebo group.

Stage I & II

1. Conservative surgery

Breast-conserving surgery followed by radiation therapy to the intact breast is now considered a standard treatment for the majority of patients with stage I or II invasive breast cancer.

Technique

The extent of breast conservation is debatable. Techniques for breast conservation include: lumpectomy, segmental mastectomy, quadrantectomy & others all of which have a similar in outcome. Quadrantectomy is used by some as it has good safety margin (the radical form of conservative surgery).
A consensus statement on breast-conserving therapy issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins and that a level I-II axillary lymph node dissection be performed. The patient should subsequently be treated with adjuvant breast irradiation. This should be followed by radiation as part of the 1ry therapy.

Benefits

  • Multiple studies have demonstrated that patients with stage I breast cancer who are treated with either breast-conservation therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free and overall survival rates.
Contraindications to conservative surgery:
  1. Tumor is more than 5cm in size.
  2. Diffuse malignant or indeterminate appearing microcalcifications on mammogram.
  3. Contraindication to proper cosmesis.
  4. Prior breast irradiation or contraindication to radiation.
  5. Persistantly positive surgical margins.
  6. 1st or 2nd trimester pregnancy.
  7. Multicentricity.
  8. Intraduct & retroareolar tumors are relative contraindications.
  9. History of collagen vascular disease (interfering with healing).

Axillary lymph node surgery following breast conservation

The role of axillary lymph node surgery is controversial when breast conservation is the aim of therapy. Currently, axillary evaluation is recommended in this setting. In these cases sentinel node dissection is recommended when feasible.
The ability to identify the sentinel node can reach as high as 97% when both blue dye and Tc-99m sulfur colloid are used together.

Adjuvant radiation therapy following breast conservation

Breast conservation should be followed by radiation as part of the 1ry therapy.
For patients who undergo axillary dissection and are found to have negative nodes, regional nodal irradiation is no longer routinely employed. For patients with positive nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis.

2. Mastectomy

Patients who are not candidates for breast conservation or are not interested in breast conservation are offered mastectomy.

Adjuvant radiotherapy after mastectomy

Available data suggest that in patients with the following criteria the risk of locoregional failure remains significantly high enough to consider postmastectomy radiation therapy.
  • Positive postmastectomy margins
  • Primary tumors > 5 cm
  • Involvement of 4 or more lymph nodes at the time of mastectomy
Even with the use of high-dose chemotherapy, locoregional failure is a significant problem in these patients without the use of postmastectomy irradiation.

3. Adjuvant chemotherapy

Systemic therapy is indicated only for invasive (infiltrating) breast cancers larger than 1cm in size (in smaller tumors there is a very low risk of recurrence <10%).
The sequence of systemic therapy and definitive radiation therapy in women treated with breast-conserving surgery is a subject of continued clinical research. The use of concomitant chemotherapy and irradiation is not recommended due to the radiomimetic effects of chemotherapy and the potential for increased locoregional toxicity.
Delaying chemotherapy up to 8-10 weeks after surgery does not appear to have a negative impact on the development of metastasis or survival.

Common regimens

  • CMF (Bonadonna regimen) and its variants (CMF day 21 and CMF day 28).
  • CMF-P (In which prednisone 40mg/m2 from day 1 to day 14).
  • AC
  • FAC
  • TAC
  • CAF
  • AC --> TAC
  • FEC (CEF)
The role of the taxanes, ie, paclitaxel and docetaxel (Taxotere), in adjuvant therapy is being investigated in clinical trials.
Benefit:
  1. For all women under 50 years of age at randomization, combination chemotherapy improved 10-year survival from 71% to 78% for those with node-negative disease (an absolute benefit of 7%), and from 42% to 53% for those with node-positive disease (an absolute benefit of 11%).
  2. For women 50 to 69 years of age at randomization, combination chemotherapy improved 10-year survival from 67% to 69% for those with node-negative disease (an absolute gain of 2%), and from 46% to 49% for those with node-positive disease (an absolute gain of 3%).

4. Adjuvant hormonal therapy

Hormonal therapy with tamoxifen (20 mg PO qd for 5 years) has been shown to be of value in women ≥ 50 years of age with estrogen- and/or progesterone-receptor�positive tumors as shown in the (ATAC trial).

Benefit:

The most recent meta-analysis, which included information on 37,000 women in 55 trials of adjuvant tamoxifen, was published in 1998. In this analysis, the benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors.
  • In these women, the 10-year proportional reductions in recurrence and mortality associated with 5 years of use were 47% and 26%, respectively.
  • An additional observed benefit was an approximately 50% decrease in the incidence of contralateral breast cancer in patients receiving tamoxifen, regardless of the ER status of the primary tumor.
The benefit of tamoxifen is independent of menstrual status. Long-term follow-up from the NSABP conclusively demonstrates that there is no benefit to continuing tamoxifen therapy beyond 5 years.

Stage III (Locally advanced disease)

The optimal treatment for patients with locally advanced breast cancer has yet
to be defined, due to the heterogeneity of this group (stage IIIA and IIIB, M1 supraclavicular nodes).

Neoadjuvant chemotherapy

Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity testing, can downstage locally advanced disease and render it operable, and may allow breast-conservation surgery to be performed.
Types of neoadjuvant chemotherapy regimens
Preoperative chemotherapy regimens reported to result in high response rates (partial and complete responses) include:
  • CAF
  • FAC
  • CMF
  • CMFVP
Combination chemotherapy with an anthracycline-based regimen FAC or AC is used most often. Recently published data suggest that the AT regimen of Adriamycin and docetaxel
(Taxotere) given concomitantly may produce equivalently high response rates.
Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response rate for women with locally advanced disease.

Benefit:

  • Neoadjuvant chemotherapy results in complete response rates ranging in about 25% and partial response rates (≥ 50% reduction in bidimensionally measurable disease) in 50% of cases, with total response rates in about 90%.
Patients with large lesions are more likely to have partial responses. Pathologic complete responses do occur and are more likely to be seen in patients with smaller tumors.

Radiation therapy

Radiation therapy remains an integral component of the management of patients with locally advanced breast cancer.
Operable cases: For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 5,000-6,000 cGy) is usually employed.
Inoperable cases: For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery.

Multimodality treatment plan

A multimodality approach for locally advanced breast cancer (stage IIIA and IIIB, M1 supraclavicular nodes) consists of
  • 4 cycles of neoadjuvant chemotherapy (FAC)
  • Followed by surgery for responders / by radiotherapy then surgery for those who do not respond.
  • After surgery adjuvant treatment is given in the form of chemotherapy, radiotherapy (unless used in downstaging) and hormonal therapy in those with receptor positive tumors.
Benefit: This approach has been shown to result in the following benefits:
  • Stage IIIA disease - 84% 5-year survival rate of
  • Stage IIIB disease - 44% 5- year survival rate
  • Inflammatory breast cancer - 35%-50% 5-year survival rates

Stage IV (Metastatic disease)

Patients with metastatic cancer can be divided into two groups: those with stage IV disease at presentation and those who develop metastases after primary treatment. They can be divided into low and high risk groups based on the biologic aggressiveness of the disease.

Low-risk patients

The low-risk group includes
  • Patients who develop metastatic disease after a long disease-free interval (i.e. a long disease-free interval from primary breast cancer diagnosis to presentation with metastasis),
  • those whose tumors are positive for hormone receptors (estrogen and progesterone),
  • those with bone-only disease, and
  • those without extensive visceral organ involvement.

Hormone therapy in stage IV

First-line hormonal therapy
These drugs aim at reducing the levels of estrogen hormones in hormone receptor positive cancers. First line hormonal therapy consists of an aromatase inhibitor or tamoxifen, with careful serial assessment of clinical and disease responses. Hormone therapy may be associated with a �flare� response, a temporary worsening of signs and symptoms of disease within the first few weeks of treatment. This response generally means clinical benefit will follow. 

Benefits

  • Overall response rates is 40% for ER positive tumors
  • Complete remission occurs in about 13% in ER positive tumors
  • Prolonged disease stability (including minor responses) was achieved in an additional 20 to 30% of patients during hormonal therapy. Stable disease for longer than 6 months is associated with survival durations similar to those of patients who achieve a partial or complete response with endocrine therapy.
Second-line hormonal agents
The most commonly used second-line hormonal agents had been progestational drugs, such as megestrol acetate. Recent randomized trials have indicated that the aromatase inhibitors are equally effective for palliation of metastatic disease, have less toxicity, and may provide a survival advantage compared with megestrol acetate. Therefore, they are the drugs of choice for second-line therapy following tamoxifen administration.
  • Anastrozole (Arimidex)
  • Letrozole (Femara)
  • Fulvestrant (Faslodex)
  • Exemestane (Aromasin)
Tamoxifen may also be considered as second-line therapy for patients initially treated with an aromatase inhibitor.
Hormonal therapy continues until evidence of disease progression or drug related toxicity precludes further therapy with the same agent. If a partial or complete response to the first hormonal treatment is documented at the time of disease progression, a second hormonal agent may provide further palliation of symptoms and avoid the initiation of systemic chemotherapy. However, subsequent hormonal responses tend to be of shorter duration, and, ultimately, the disease will become refractory to hormonal treatment.

Cytotoxic agents

Hormone-refractory disease can be treated with systemic cytotoxic therapy.
Combination chemotherapy
  • FAC
  • Paclitaxel
  • TAC (docetaxel, doxorubicin [Adriamycin], cyclophosphamide), or docetaxel may be used in this situation.
Benefits: see below.

Intermediate- or high-risk patients include

  • Patients with rapidly progressive disease
  • Patients with visceral involvement
  • Disease shown to be refractory to hormonal manipulation by a prior therapeutic trial.

Combination chemotherapy in stage IV

Anthracycline-containing combinations are preferred for these patients.
  • FAC
  • Newer combinations of doxorubicin and a taxane are gaining favor for use in patients who have not received > 450 mg/m2 of an anthracycline and whose relapse has occurred more than 12 months after the completion of adjuvant therapy.
Benefits:
  • Between 50 and 75% of patients with metastatic breast cancer have responses to first-line chemotherapy.
  • Only 15 to 20% of patients will achieve a complete remission, and most of those patients will develop progressive disease within the subsequent 5 years.
  • Anthracycline-based combinations appear to be more effective than CMF and CMFVP in several randomized trials, producing not only higher overall and complete remission rates but, in some studies, significant prolongation of survival as well (about 10% of all complete remissions achieved with anthracycline containing regimens last more than 10 years).

Single agents in stage IV

  • Vinblastine (Velban)
  • Mitomycin (Mutamycin)
  • Thiotepa
  • Vinorelbine (Navelbine): Vinorelbine has an objective response rates ranging from 40 to 50% in first-line and 20 to 35% in second-line therapy; however, it has not gained FDA approval, although it is widely used for the treatment of advanced breast cancer.
  • Gemcitabine (Gemzar): This agent was approved by the FDA for the treatment of pancreatic cancer, even though its efficacy against breast cancer is substantially higher. Gemcitabine produces responses in about 40% of patients with untreated metastatic breast cancer and in 20 to 30% of those with previous exposure to chemotherapy, including anthracycline-refractory tumors.
  • Paclitaxel: One of the most active agents is paclitaxel. Both taxanes have significant antitumor activity in this group of patients with anthracycline-resistant breast cancer, with reported overall response rates of up to 57% and median survival ranging up to 10 months.
  • Docetaxel, approved by the FDA for anthracycline-resistant locally advanced or metastatic breast cancer, has demonstrated overall response rates of 41% in doxorubicin-resistant disease. It has been shown to be superior to mitomycin/ vinblastine in patients whose disease progressed after an anthracycline-based chemotherapy regimen. Docetaxel as a single agent produces objective responses in up to 60% of patients with metastatic breast cancer previously unexposed to chemotherapy.
  • Capecitabine (Xeloda): has been shown to have substantial antitumor effect in patients whose disease has recurred or progressed after prior anthracycline chemotherapy or after taxane therapy. Prolonged survival, limited toxicity, and response in visceral as well as soft tissue disease add to the benefit of capecitabine.
Benefits:
  • 40 to 50% of previously untreated patients with metastatic breast cancer achieve an objective regression after single-agent anthracycline therapy.
  • Mitoxantrone and the alkylating agents produce partial or complete responses in 30 to 40% of patients, whereas the other drugs are estimated to have a 20 to 30% response rate.

Trastuzumab (Herceptin)

Trastuzumab is a humanized monoclonal antibody to the HER-2/neu protein, has been approved for use as a single agent in second- and third-line therapy for metastatic breast cancer and in combination with paclitaxel as first-line therapy in this setting.
Benefit:
  • The combination of trastuzumab with chemotherapy yields a 45% overall response rate, as compared with a 29% rate with chemotherapy alone. Recent data has shown a superior median overall survival with chemotherapy plus trastuzumab compared with chemotherapy alone (25.4 vs 20.9 months).
  • In a multicenter phase II trial of docetaxel, carboplatin / cisplatin, and trastuzumab (TCH) in HER2-positive advanced breast cancer overall responses were observed in 80% of patients receiving cisplatin 60% in those receiving carboplatin. Median times to progression were 10 months for those receiving cisplatin and 13 months in those receiving the carboplatin regimen. Toxicities were mainly hematologic in the carboplatin regimen in the form of grade III and IV thrombocytopenia, neutropenia (with or without fever). In the cisplatin regimen toxicities were mainly non-hematologic and in the form of alopecia, asthenia, GIT toxicities, renal, ototoxicity and neurotoxicity.
Pegram MD, Pienkowski T, Northfelt DW, Eiermann W, Patel R, Fumoleau P, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004;96:759�69.
Chemotherapy regimens for breast cancer

Bone metastasis

Surgery for bone metastasis

If x-ray shows a metastatic lesion is in a long bone with cortical destruction, particularly the femur or humerus, pathologic fracture must be prevented if possible. Generally this will require local irradiation and internal fixation with or without systemic therapy.
If the patient presents with or develops a pathologic fracture, internal fixation followed by radiotherapy is a most effective approach, assuming the patient can undergo the operative procedure.
Spinal metastases represent a more difficult problem. Cord compression, nerve root compression, and leptomeningeal metastases can develop. Depending on the results of myelography, CT myelography, or MRI and the patient's status and short-term prognosis, decompressive laminectomy followed by radiotherapy or radiotherapy alone may be selected.
Patients with spinal cord compression who have progressive symptoms during irradiation, disease recurrence after irradiation or who require diagnosis are candidates for surgery. Patients who present with spinal instability often require internal fixation.

Radiation therapy for bone metastasis

External-beam radiotherapy has become a mainstay in the palliative treatment of metastatic bone disease.
1. Postoperative radiotherapy: Postoperative radiotherapy is used after fixation of impending and pathologic fractures and after decompression and stabilization of the spine. When surgery is planned, radiation should be delivered postoperatively to the entire surgical area.
Benefits:
  • Only 3% of patients treated with surgery and radiotherapy developed loosening of prostheses or hardware requiring revision surgery, compared to 15% of patients treated with surgery alone. In addition, return to a higher level of function was seen in the combined modality group. 
2. Spinal metastatic disease: Indications for surgery include spinal instability, pathologic fracture with structural canal compromise, circumferential epidural tumor, occult primary tumor, and radioresistant tumors. In spinal metastatic disease, the earlier the diagnosis is made and treatment is initiated, the better the outcome. Radiotherapy should be the first-line therapy when no surgical indication is present.
Among those with spinal metastatic disease, 94% of patients who have the ability to walk maintain their ambulatory status after radiotherapy, whereas ambulation is restored in 60% with motor weakness and 11% with paraplegia at presentation.
3. Palliative radiotherapy:
  • Pathologic fractures heal in 35% of patients treated with radiotherapy and nonoperative management.
  • Palliative radiotherapy has been shown to provide some relief in 80% to 90% of patients and complete relief in 50% to 85% of patients with localized skeletal disease.
  • Before palliative radiotherapy, the bone must be assessed for risk of fracture and the need for surgery. In one study, 13% of long bone and 6% of spinal sites fractured after radiotherapy.

Adjunctive bisphosphonate therapy

Multiple published reports have now confirmed the benefit of bisphosphonates, such as IV pamidronate disodium (Aredia) or zoledronic acid (Zometa), as an adjunct to chemotherapy and hormonal therapy for metastatic breast cancer with osteolytic disease of bone. A significant reduction in skeleton-related events, including bone pain, pathologic fracture, and the need for radiation therapy to bone, occurs in patients treated with chemotherapy and pamidronate disodium for metastatic disease.
Systemic therapy
For breast carcinoma, treatment options are determined by estrogen and progesterone receptor status. In the literature, significant tumor shrinkage with endocrine therapy is 30% to 65%.36 In one study among patients with only bone metastases who were treated with a multiagent regimen (5-fluorouracil, doxorubicin, and cyclophosphamide), complete response rate was 7% and partial response rate was 52%, and an additional 32% experienced stabilization of disease.36 Another large multicenter study evaluated the use of various endocrine agents (megestrol acetate, tamoxifen, aminoglutethimide, dexamethasone, hydrocortisone, and fluoxymesterone) in a placebo arm against pamidronate. A partial response was seen in 21% and a stabilization of disease was seen in an additional 32%.37

If bone metastases are not complicated by pathologic fracture or do not involve the spinal cord or nerve roots, treatment is dictated by symptoms, the risk of pathologic fracture, and the potential for effective systemic therapy. Breast cancer can be effectively palliated using therapies that include castration or treatment with hormones or hormone antagonists. Chemotherapy will often be effective. If the bone metastases are diffuse, palliative radiotherapy may be impractical. In such cases, use of effective oral analgesics will provide effective palliation. If there are a limited number of painful metastatic lesions, radiotherapy delivered to those sites can dramatically alleviate pain and allow the patient to function with less or no analgesics.

Lung metastasis

Lung metastases are preferentially treated with chemotherapy for tumors with a high degree of chemosensitivity. Breast cancer metastasis may respond to hormonal suppression, cytotoxic agents, and molecular targeted therapies.
Also, the lung metastasis is usually coincidental to the discovery of widespread metastatic disease. Significant prognostic factors were a complete resection and a disease-free interval of at least 36 months.
Solitary lesions can be resected with good results, but this represents fewer than 1% of all patients with metastatic breast cancer.
  • Reported survival rates of 38% after 5 years, 22% after 10 years, and 20% after 15 years.

Liver metastasis

Breast cancer metastasis may respond to hormonal suppression, cytotoxic agents, and molecular targeted therapies.
Actuarial 5-year survival after resection of clinically isolated hepatic metastases in breast cancer patients is reported between 9% and 18%. Based on the typical systemic pattern of recurrence in patients with advanced breast cancer, this approach must be considered palliative in nature with little expectation of long-term disease control.

Brain metastasis

The median survival time for breast cancer patients with untreated brain metastases is 4 weeks, and can be increased to 4-6 months with whole-brain radiotherapy and stereotactic radiosurgery, or up to 16 months if solitary metastases can be removed surgically.
Corticosteroids and antiseizure medication should be given when indicated.

Radiation therapy

Irradiation remains an integral component of the management of metastatic breast carcinoma.
  • In metastatic bony disease (in addition to bisphosphonates).
  • Unresectable central nervous system metastases
  • Bronchial obstruction
  • Painful/fungating breast or chest wall lesions
  • Following surgery for decompression of intracranial or spinal cord metastases and following fixation of pathologic fractures

Surgery in metastatic disease

The role of surgery at this point is generally palliative.
  • Spinal cord compression
    Patients with spinal cord compression who have progressive symptoms during irradiation, disease recurrence after irradiation, or spinal instability or who require diagnosis are candidates for surgery.
  • Solitary brain metastasis 
    Patients with a long disease-free interval and solitary brain metastasis may be candidates for resection. Evidence suggests an improved disease-free survival, overall survival, and quality of life in this subset of patients when treated with surgery combined with postoperative cranial irradiation, as compared with radiation therapy alone.
  • Bone metastasis
    Pathologic (or impending) fractures may require orthopedic surgery.
  • Chest wall resection 
    Fungating/ painful breast lesions may require palliative surgical resection. It is extremely rare for a patient with distant metastatic disease to be a candidate for chest wall resection; however, patients with symptomatic recurrence of disease in the chest wall who have limited distant disease and a life expectancy of > 12 months may be appropriate candidates.
  • Isolated lung metastases
    The curative benefit of surgery in the treatment of metastatic disease to the lungs or liver is not proven, but, in highly selected cases, surgery may be beneficial.
  • Pleural or pericardial effusions
    Symptomatic pleural or pericardial effusions not controlled by other means.

Recurrent breast cancer

Locoregional recurrence of breast cancer can be diagnosed by surgical biopsy or FNA cytology. Whichever modality is appropriate, material should be sent for hormone-receptor studies, since there is only an 80% concordance in hormone-receptor status between the primary tumor and recurrent disease.

Recurrence after breast conservation

Most patients whose disease recurs after conservative treatment for DCIS can be treated with salvage mastectomy. The optimal treatment of a local or regional recurrence after mastectomy has yet to be defined. Locoregional recurrences are associated with initial nodal status and primary tumor size. Appropriate treatment may result in long-term control of locoregional disease.

Recurrent disease in the chest wall after mastectomy

In general, patients who develop minimal recurrent disease in the chest wall after a long disease-free interval may be treated by excision alone, although this approach is controversial and may not be ideal. Locoregional control obtained by radiation therapy alone is related to the volume of residual disease and may not be durable. When possible, disease recurring in the chest wall or
axillary nodes should be resected and radiation therapy should be delivered to aid in local control.

Adjuvant systemic therapy for locoregional recurrence

These data suggest that women whose tumors recur in the ipsilateral breast / regional lymph nodes within the first few years following the original diagnosis may be considered for adjuvant systemic therapy. Given the lack of prospective, randomized data, specific treatment recommendations for these women remain highly individualized.

Adjuvant hormonal therapy in recurrence

Benefits: A recently reported randomized trial demonstrated a disease-free survival benefit with the use of adjuvant tamoxifen following radiation therapy at the time of postmastectomy recurrence of disease in the chest wall in patients with estrogen-receptor�positive tumors.
The 5-year disease-free survival rate was increased from 36% to 59%, and median disease free survival was prolonged by > 4.5 years.

Adjuvant cytotoxic chemotherapy in recurrence

Patients with estrogen-receptor�negative tumors and aggressive locoregional recurrences may also be considered for systemic cytotoxic chemotherapy, given their relatively poor prognosis and the high rate of metastasis.

Follow up

During the months subsequent to therapy patient follow up is usually required every 6 months or every year depending on the risk of breast recurrence. A thorough examination is done aiming primarily at the detection of breast cancer in the opposite breast (due to a slightly increased incidence of contralateral breast cancer).
* Examination should include: bilateral breast & axillary exam in addition to supraclavicular lymph node enlargement and liver examination for enlargement and tenderness. A mammogram is requested annually. In cases that have undergone conservative surgery mammographic examination is recommended every 6 months initially then annually.
A chest x-ray, bone scan (sensitive but not specific) and abdominal sonography is requested as dictated by a patients complaints or the results of the examination.

Warning signs that should alert the physician during an examination:
  1. Bony pains accompanied by tenderness
  2. Cough or dyspnoea
  3. Right hypochondrial pain
  4. Neurological manifestations
  5. Abnormal CBC (bone marrow infiltration).
  6. Edema of arm + pain / parasthesia (possibly an early sign of recurrence).
  7. Patients on Tamoxifen may complain of uterine bleeding (endometrial carcinoma) or DVT.
  8. Patients on Anthracyclines may complain of manifestations of heart failure.

Prognosis and survival

Stage5yr10yr
0>9090
I8065
II6045
IIIA5040
IIIB3520
IV & inflammatory105
Memory Aid for breast cancer survival:
The 50% cutoff point is at stage IIIA (50% survive 5yrs, 40% survive 10 years).
From that point add or reduce 10 - 15% with each subsequent or previous stage.

References

Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 351(9114): 1451-1467, 1998.

 

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