metastatic breast cancer

Metastatic breast cancer is defined as the occurrence of metastasis to the bone, lung, brain, liver, supraclavicular node, and cervical node or contra lateral axillary lymph node in a patient of breast cancer.

Fewer than 10% of patients will present with metastatic disease, but nearly 50% of newly diagnosed patients may eventually develop it. In a classic study of untreated patients, the median survival was 2.7 years from the onset of symptoms. Most patients who relapse do so within two to three years after the diagnosis of the primary tumor. In a minority of patients, the disease will recur 5 or more years after the initial diagnosis; 3-5%of patients remain in remission longer than 10years. Survival after relapse is directly related to the extent of the disease, not the site of the relapse with the exception of disease in the central nervous system, which portends very short survival.

Diagnostic work up:

Steps in the evaluation of metastatic breast cancer

NCC networks recommendations

· Complete history

· Careful clinical examination

· CBC

· LFT

· CXR

· Bone scan

· Other scans based on symptoms

· Tumor markers like CEA, CA15-3

· Pathological confirmation of metastatic disease

· If easily feasible

· If alternate diagnosis is of high suspicion

· If provides receptor status

· If it provides her-2/neu status

History: Once metastatic disease is suspected, careful evaluation of the primary disease, history, current symptoms and the existing co morbid disease is essential. The history of the primary disease should include

· Review of the initial presentation

· State of the disease

· Hormone receptor status

· Pathology report

· Treatment modalities employed.

Knowledge of the initial tumor type may yield clues about the sites of the disease. For instance IDC most commonly involves the lung, pleura, brain, whereas infiltrating lobular carcinoma most commonly involves the bone marrow, peritoneum and retroperitoneal structures such as ureter. Other ancillary information’s such as DNA ploidy, S-Phase fraction and presence of oncogen products (C-erbB-2) or P53 has been studied in primary breast cancer, but the influence of these factors on metastatic disease progression is unclear.

The length of disease free interval and the menopausal status should be ascertained. Any current symptoms should be clearly evaluated to assess potential metastatic sites and tumor burden. Any coexisting medical condition should also be noted because they may affect the choice of chemotherapeutic drugs.

PHYSICAL EXAMINATION

A comprehensive physical examination is essential for establishing the initial baseline status. The usual site of metastasis include soft tissue, bones, lungs, liver should be assessed. Evaluation of the soft tissue should include a careful survey of all lymph-nodes basins of the upper torso, with documentation of the size and location of enlarged nodes and assessment of the chest wall, operative site, and opposite breast tissue. Photographs or diagrams of these areas often add invaluable information for subsequent comparison. A complete neurological examination can determine the need for specific diagnostic imaging. Ascites caused by peritoneal metastases is less common but not rare.

LABORATORY TEST

It should include a complete blood count with differential, LFT, KFT, serum calcium. In addition CEA and CA 15-3 are potentially helpful in detecting and monitoring metastatic disease. CEA levels are elevated in 40 to 50% of cases with metastasis. The CA 15-3 test is a combination of 2 monoclonal antibodies bearing two reactive determinants directed against DF3 and MAM-6 antigens expressed on the mammary epithelial cells. CA15-3 is much more sensitive than CEA and is elevated in 70 to 80% of patients with metastasis.

DIAGNOSTIC IMAGING:

The chest radiograph is usually sufficient to assess the lungs unless there is compressed bronchus or solitary lesion or the disease is primarily mediastinal. An ultrasonography is used to detect hepatic metastases, however a CT scan can be done in doubtful cases.

Only 50% of patients with a positive bone scan will have increase alkaline phosphatase level, conversely only 20% of patients is elevated alkaline phosphatase level are disease free. The bone scan shows areas of abnormal uptake, radiograph of the affected site is necessary to confirm metastatic disease and to exclude benign pathology.

PATHOLOGY:

The histological slides of the primary tumor should be reviewed and compared with the biopsy results of lesions suspected of being metastases. Patients with solitary lesion, easily assessable lesions that may be confused with benign processes and suspicious lesions in patients with the disease free interval longer than five years should undergo biopsy to confirm or rule out metastatic breast cancer. Estrogen and progesterone receptor status should also be evaluated.

TREATMENT:

The goals of therapy

Improvement or maintenance of the quality of life
Prolongation of survival, if feasible

Therapeutic modalities available

Although most women with metastatic breast cancer will succumb to their disease, there are many effective therapeutic modalities to choose from.

These include

· Chemotherapy

· Hormonal therapy

· Radiation therapy

· Surgery

· Immunotherapy

The selection of treatment is guided by the results of previous evaluations, commonsense and the realization that metastatic breast cancer differs greatly in its clinical course from one patient to another. Metastatic disease often shows one of the two patterns, the first pattern is a relatively a symptomatic, indolent disease. Patients whose disease follows this pattern typically have primary disease that is estrogen receptor positive, a disease free interval of longer than two years and metastases to bone, soft tissue, non-life threatening visceral sites. In such a patient hormonal therapy should be tried first .The second pattern is highly symptomatic, receptor negative, aggressive, widely disseminated, life threatening visceral disease. Patients with this type of disease should receive cytotoxic chemotherapy with or without sequential radiation.

Hormonal Therapy:

Principles: When systemic therapy is indicated, endocrine therapy is a appropriate first step in patients with the following clinical characteristics: indolent disease course; positive estrogen – receptor (ER) or progesterone receptor (PR) status; disease-free interval longer than 2 to 5 years; postmenopausal status; or disease limited to the soft tissues, such as the nodes, chest wall, or skin. Other indications are cachexia, failure to thrive, and anorexia. Currently, hormonal castration obviates surgery as a first choice; there is no indication for adremalectomy or hypophysectomy. There is no conclusive data to support combined hormonal treatments. In trials of combinations, some minimal increases in response rate were seen, but there was no significant improvement in survival, and additional toxicity was observed.

Hormone Receptors and Response: The probability of response to hormone therapy is directly related to the status of hormone receptors. If the tumor is negative for both ER and PR, the probability of response is less than 10%. If ER is negative and PR is positive or vice versa, the response rate is 30% to 60%. Finally, if both ER and PR are positive, the response rate ranges from 75% to 80%(14). The quantitative ER level also correlates positively with the response rate, as seen in table (15). Recently quantitative PR levels have been shown to correlate significantly and independently with increased response to tamoxifen, longer time to treatment failure, and longer overall survival in patients with ER – positive tumors.

Correlation of Estrogen Receptor Levels with response rates

Approximately 30% of women whose ER status is unknown will respond to the first hormonal manipulation. Of patients with a prior history of hormonal response, 33% to 50% will respond to another hormonal regimen. Patients with low-volume disease and better performance status generally have higher response rates. The duration of first response is usually 9 to 12 months, similar to that with chemotherapy. The side-effect profile aids in the determination of which hormonal therapy to use, because the efficacy of all agents is nearly equal. Additionally, for patients whose tumors are usually sensitive to hormonal manipulation, retreatment with a previously effective agent may again be effective if a long interval has elapsed since it was discontinued.

Recommended Hormonal Treatment Sequences for Metastatic Breast Cancer

LHRH = Lutinizing hormone-releasing hormone

Ooporectomy may be considered in patients who are premnopausal or within 1 year of their last menstrual period.

CHEMOTHERAPY

Several clinical clues may predict the likelihood of response to treatment. Usually, better performance status, smaller tumor burden, and less prior exposure to chemotherapy all translate into a higher probability of response. In a previously untreated patient with a good performance status and small tumor burden, the response to chemotherapy is only 50%-70%. If the patient has a poor performance status and extensive burden, the probability of response to chemotherapy is only 20 –30 %(20,21). Age, menopausal status, hormone receptor status, and dominant disease site are not related to the probability of response to chemotherapy but are important to the response to hormonal therapy. With the exception of the central nervous system and the bones, the site of disease is less important than the volume of disease when estimating the probability of response.

Although current treatment modalities are palliative in most patients, some patients achieve durable complete or partial remission with standard-dose regimens after initial induction therapy.

Restoring or maintaining response after initial treatment remains a therapeutic problem and an area of controversy. Some studies have suggested that although overall survival is unchanged, quality of life, time to disease progression, and tumor response are better in patients treated with maintenance chemotherapy after induction than in patients given intermittent chemotherapy for tumor progression. In one study, reinduction with the same chemotherapeutic regimen for metastatic breast cancer showed an overall response rate of 18% and a time to treatment failure of 3 months, but 50% of the patients had life-threatening or severe toxic reactions. Response rates were high in patients initially in complete remission (44%) or partial remission (15%) but poor in patients with stable disease or no change. Unfortunately, response rates decline rapidly with subsequent salvage attempts after induction therapy.

Several recent retrospective studies have shown overall response rates of 11% to 16% to either cytotoxic or hormonal salvage therapy after induction chemotherapy, but predicting who will benefit is still difficult These data are in agreement with the lack of enthusiasm among community medical oncologists for administering subsequent salvage regimens. Clearly, the decision to pursue maintenance therapy after induction, subsequent salvage regimens, or observation and treatment for progression depends on tumor response, extent of palliation, and the patient’s wishes.

At Lok Nayak Hospital the, initial chemotherapy for metastatic breast cancer is usually a doxorubicin – based regimen, such as 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC), with doxorubicin administered by a 48 to 72 hour infusion. The continuous infusion reduces nausea, vomiting, and cardiac damage. Although doxorubicin is the most active single agent in the treatment of breast cancer, the difference in reported response rates between doxorubicin and methotrexate based regimens is only 10% to 15%, and differences in response duration and survival also have been small.

1^st line ct CMF OR CAF

2^nd line ct TAXOLS

3^rd line ct VINCA ALKALOIDS

The mean time to response to chemotherapy with these regimens varies with the site of disease. The mean to response is 6 to 9 weeks in skin and nodes, 9 to 12 weeks in lungs, 15 to 18 weeks in liver, and 18 weeks in bone The median duration of response after the first remission is 9 to 12 months; this decreases to 3 to 6 months for subsequent remissions. The data from Coates et al and Tannock et al suggest that continuing therapy after response improves quality of life. Treatment is generally continued for an additional 3 to 6 months after the maximum response. Unfortunately, in many patients, the disease progresses by the time treatment is scheduled to be stopped. At this point, it is reasonable to consider a trial of a phase II regimen or other single agents that the patient has not received Analysis of older clinical trials comparing survival advantage among patients treated with polychemotherapy vs. single-drug chemotherapy in the phase II setting showed a very modest survival advantage (3.7 months) for patients receiving polychemotherapy.

The heterogeneous behavior of metastatic breast cancer is such that some patients may still experience meaningful palliation with other standard drugs. Also, if the patient is more symptomatic from the increased tumor burden or the cumulative effect of prior treatments, toxicity is often increased. The median duration of survival is usually 24 to 30 months. Patients who have a complete remission tend to live longer than patients who have partial remissions or stable disease. However, patients whose disease is refractory to the initial chemotherapeutic regimen tend to do poorly, with a median survival of only 4 to 6 months regardless of the regimen used.

Paclitaxel: Paclitaxel (Taxol) is the newest agent to show significant activity in untreated, heavily pretreated, and doxorubicin-refractory patients in phase I or II trials. Paclitaxel is approved by the US Food and Drug Administration at a dose of 175 mg /m² by 3-hour infusion for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, provided that the previous chemotherapeutic regimen included an anthracycline.

The current optimal dose for paclitaxel in untreated, heavily pretreated, or doxorubicin-refractory metastatic breast cancer is under study. Paclitaxel schedules tested are 135, 175 or 250 mg/m² given by 24-hour continuous infusion or 135 or 175 mg/m² given over 3 hours every 21 days.

Paclitaxel has a unique pattern of toxicity. The side effects of paclitaxel given by 3 or 24-hour infusion can be divided into dose-dependent effects (for example, an early but brief granulocyte nadir, sensory and motor peripheral neuropathy, mucositis, and arthralgias / myalgias) and dose-independent effects (for example, total and sudden alopecia, HSRs and rhythm disturbances. Neuropathy may be cumulative but is reversible upon discontinuation of the drug. Recently, optic – nerve disturbances causing photopsia, scotomata, and decreased visual acuity have been described in patients receiving more than 175 mg/m² by 3-hour infusion schedules; although most cases have been readily reversible with cessation of the infusion, some patients have sustained visual loss Radiation recall dermatitis following paclitaxel infusion have also been described, as has local irritation with extravasations.

Paclitaxel might cause G2/M cell-cycle block, thereby leaving fewer cells in the S phase, the most doxorubicin – sensitive phase of the cell. With concurrent 72-hour infusion of doxorubicin and paclitaxel, the gastrointestinal toxicity is primarily in the lower gastrointestinal tract and may include abdominal pain, diarrhea, and typhlitis. Because of the sequence-dependent toxicities that have been seen, combinations of paclitaxel with other drugs outside a clinical trial are not recommended.

Vinorelbine: Vinorelbine (Navelbine), a semisynthetic vinca alkaloid, has been approved in France for non-small cell lung cancer and breast cancer. In the United States, it has been approved for non-small cell lung cancer but is still in phase II testing for breast cancer. From phase I testing, the recommended dose is 30 mg/m²intravenously per week. However, in most trials in the United States, investigators have not been able to administer the full dose. Often, the day 14th dose must be delayed because of neutropenia. A dose of 20 mg/m²appears to be more consistently tolerated. As a single agent in patients previously untreated for metastatic disease, vinorelbine produces overall response rates of 24% to 52%, with average complete response and partial response rates of 7% and 34%, respectively. The median time to treatment failure is 6 months, the median duration of response is 9 months, and the median survival is 18 months or not reached.

Furthermore, vinorelbine is active in the salvage setting for patients who have received prior anthracylcines; the drug produces overall response rates of 16% to 36%.

Toxic reactions associated with vinorelbine include phlebitis at a peripheral vein insertion site, myelosuppression, peripheral neuropathy, and myalgias. Transient increases in aspartate aminotransferase and alanine aminotransferase levels were reported in approximately 50% of patients but did not require discontinuation of therapy. In up to 5% of patients, a unique respiratory toxic effect may occur, it includes both an acute reaction, which resembles bronchospams and is readily reversible with bronchodilators and a subacute reaction of cough and dyspnea, which occurs within 1 hour and is treated with steroids.

Role of combined chemo-hormonal therapy

Regardless of the regimen only one systemic modality should be given at a time. The addition of hormones to chemotherapy is generally not recommended. Although the exact mechanism of action of most hormonal agents is not well understood, it is known that tamoxifen arrests cells in the G1 phase of the cell cycle. This is antagonistic to the action of most of the cytotoxic agent, the majority of which are most effective against cells actively progressing through the cell cycle. There is no adverse affect on response rates and survival with the use of combined hormonal and cytotoxic therapy in-patient with metastatic disease. In some postmenopausal women the combination may increase the response rate by 10 to 20 percent. Biopsies studies of metastatic lesions exposed to estrogen recruitment before chemotherapy did show an increase in the fraction of cells in the S phase . But estrogenic recruitment did not translate into improved response rate, time to disease progression are medial survival duration. The risk of thromboembolic phenomena is increased when hormones and chemotherapy are combined specially with regimen using cyclophosphamide, Mtx and 5FU.

Role of high dose chemotherapy with autologous marrow transfusion

The premise of high dose chemotherapy in metastatic breast cancer is based on in vitro studies showing a steep dose response curve for alkylating agents in breast and mammary tumor cell lines.

The same effect, in theory should be achieved in humans by giving the highest tolerable doses of chemotherapy to over come the drug resistance. Harvesting autologous heamatopoietic stem cells and reinfusing them after therapy could limit the toxic effects to the marrow.

Although the use of high dose chemotherapy with BMT seemed promising in retrospective studies, but the preliminary results of the only us phase 3 trial were recently released in 1999 American society of clinical oncology (ASCO) and had shown that there was no difference in complete response rates, time to progression, 3year progression free survival, or over all survival. On the contrary the toxicities in the high dose arm were higher than in conventional dose chemotherapy.

Currently there are several ongoing randomized phase 3 trials of HDC /ABMT including the national cancer institute sponsored nci-g96-1014 and the French eu –96032.

Given the widespread availability of HDC/ABMT and the overall acceptance by physicians and the patients the results have been sub optimal. Until more randomized data are available, it is difficult to determine the true benefits of this expensive and labor-intensive procedure.

Investigational Agents: Drug development has proceeded rapidly in the past few years in an attempt to find single agents with high activity and low toxicity that produce durable responses. Table lists several of these agents. Referrals of patients to centers studying agents should be encouraged when clinically appropriate.

Investigational Agents for Metastatic Breast Cancer

Radiation therapy

Majority of patients with osseous metastasis have a significant life of approx 48months,therefore every effort should be made in these patients to provide symptomatic relief.

The main aim of radiotherapy is to provide relief of pain. The exact mechanisms by which it does so is largely unknown, various hypothesis include

By shrinkage of tumor it relieves periosteal tension

Inhibition of humoral factors

Various forms of radiotherapy used in metastatic disease include

External beam radiotherapy for localized bony metastasis, scar or chest wall recurrence

Hemibody radiotherapy for diffuse multiple metastasis

Stereotactic radiotherapy for brain metastasis

Hepatic irradiation for hepatic metastasis

Surgery in metastatic breast cancer

Local excision in scar, chest wall, single bony metastasis

Total mastectomy for loco-regional disease

Oophorectomy

Laminectomy, cord decompression, fixation of pathological fractures

Craniotomy for solitary brain metastasis

Liver resection in hepatic metastasis?

Metastases at Specific Sites

Isolated Hepatic Metastases: 20% of patients with metastatic breast cancer have liver metastases, either isolated or with other sites or metastatic disease. Standard treatment of liver metastases is chemotherapy, although hormonal therapies may provide a transient benefit in asymptomatic patients with low-volume, ER – positive disease. Resection of liver metastases cannot be recommended, except in selected cases. Hepatic artery infusion of chemotherapeutic agents may expose to tumor to a higher drug concentration. The overall response rate to intra-arterial infusion therapy is 50%. No phase III trials have been performed to compare this approach with standard intravenous therapy. Reported phase II trials for breast cancer have used intra-arterial infusion of fluoroauracil, fuoroauracil plus mitomycin, flourouracil or (FUDR), vinblastine, cisplatin plus vinblastine, or FAC. The potential side effects are chemical choloecystitis, gastric ulceration, pancreatic, selerosing cholangitis (more common with chronic use of fluororacil or floxuridine), and occlusion of the femoral artery. A high response rate can be seen in patients with liver-predominant disease, but the impact of intra-arterial infusion therapy on overall survival remains unknown.

Bone Metastases: Breast cancer metastases are bone are lytic (48%), blastic (13%) or mixed (38%) or a diffuse osteoporosis without bone destruction (1%), they are the initial metastases in 29% to 46% of patients with breast cancer and may develop in up to 70% of patients during the course of the disease. Although patients with bone-predominant or bone-only metastases often have prolonged survival, this usually offset by substantial clinical morbidity. Clinically, bone metastases manifest as pain, pathologic fracture, limited mobility, hypercalcemia, nerve-root or spinal cord compression, and compromised hematopoiesis. Because patients with bone metastases often have metastases to other sites as well, the first approach is to employ the most effective systemic therapy. Localized complications are managed by orthopedic surgery or neurosurgery with or without external-beam radiation; the optimal does and fractionation schedule are controversial. The response to chemotherapy or external-beam radiation often parallels the systemic response and is notoriously difficult to measure by plain films or nuclear bone scans. Treatment of bone metastases can be undertaken either as an adjunct to anticancer therapy or as palliation of bone pain when the patient’s tumor is refractory to further therapy.

Understanding the pathogenesis of malignant bone disease has allowed for the development of therapies specifically targeted to the skeleton. Bone seeking radioisotopes have been developed in attempt to deliver medium to high energy beta radiation directly to tumor involved sites in the skeleton while sparing normal tissues. One of the most promising agents to date has been strontium 89. This radioisotope is chemically similar to calcium, is preferentially deposited in skeletal tissue, and may be absorbed 10 fold more by bone metastases than by bone marrow. It is most efficacious in blastic bony metastases. Its biologic half life is longer than 50 days at sites of bone metastases, compares with 14 days in normal bone; its physical half life allows for a long shelf life in the pharmacy. Most studies have used relief of bone pain as the principal endpoint; its effect on overall survival, fracture rate, and other markers of tumor progression is unknown. A total of 50% to 89% of patients with breast cancer experience moderate or greater pain relief. Side effects are limited to a transient flare to bone pain 1 to 2 days after injection in 15% of patients (usually predictive of a chemical response) and mild, reversible thrombocytopenia and leukopenia 5 to6 weeks after treatment.

Bisphosphates are synthetic analogs of the endogenous substance pyrophosphate and are capable of regulating bone turnover by inhibiting osteoclast activity by mechanisms that are not well understood. They are used clinically to treat Paget’s disease of bone, oesteoporos, and hypercalcemia, and they have evaluated for the treatment of bone metastaes in breast and prostate cancer and multiple myeloma. Three bisphosphonates are currently available: etidronate (Didronel), pamidronate(Aredia) and clodronate.

It has been suggested that biphosphonates can

Reduce bony pain and less use of narcotics

Reduce the incidence of hypercalcemia

Reduce the risk of skeletal events in women with osteolytic lesions.

Clodrinate in conjunction with adjuvant chemotherapy can reduce the occurrence of bony metastasis inpatient with primary breast cancer. (Preliminary evidence)

Slows the deterioration of performance status and hence quality of life

Stage IV – No evidence of Disease: In 1 – 10 % of patients who have meatastatic disease, the metastasis is an isolated event in a location from which it can be removed by either surgery or radiotherapy, the disease is than classified as stage four with no evidence of disease (NED). The most common situation involves patients with isolated chest wall metastasis, 50% have distant metastasis at the time of presentation and 25% will develop further metastasis in next several months, the remaining 25%have single isolated metastasis. The majorities of these lesions are solitary and near the mastectomy scar. If these nodules are not controlled they have significant effect on the quality of life The dismal survival rates after a chest wall recurrence are quite different from those after a recurrence in a breast after a BCT, 50 – 60 % of these patients can be salvaged by surgery alone. There is disagreement in the literature about whether local or systemic therapy is more appropriate .It is reasonable to provide the optimum local regime with surgery and radiotherapy whenever possible. Although the use of systemic therapy is controversial, the literature supports the use of CMF or CAF for 6 – 8 cycles, tamoxifen or both in sequence or combined.

Brain metastasis; Metastasis to the brain are a late finding .The overall incidence of brain metastasis in autopsy studies is 30%;only 10% of patients with brain metastasis were symptomatic during life. Headache may occur in 50% of the affected patients. CT scan or MRI with contrast is the diagnostic test of choice. The median survival after diagnosis is 4 months, with a wide range. A patient with an isolated brain metastasis may improve with surgery followed by radiotherapy. However whole brain radiation therapy is the treatment of choice in patients with multiple brain lesions or widespread or uncontrolled metastatic disease. Because seizures occur in 20 – 30 %of patients, only these patients require anticonvulsant therapy.

Leptomeningeal disease; Metastases to the leptomeninges occur in approximately in 1-5%of the patients with metastatic breast cancer. They usually present as progressive neurological dysfunction involving multiple central nervous system sites. Untreated they usually are fatal in 4 – 6weeks. Clinically symptoms and signs are grouped by the site of origin; cerebrum, cranial nerve, or spinal cord. Treatment consists of whole body irradiation and intathecal therapy with methotrexate or thiotepa. Systemic chemotherapy alone is ineffective. Median survival from time of diagnosis is 6 months in responders but only 6weeks in nonresponders.

Epidural metastases; In several large series, breast cancer was the most common malignancy to cause epidural compression of the spinal cord and cauda equina. Approximately 60 –70%of these patients will have multiple lesions in the vertebral column, the thoracic spine being the most commonly affected site. Patients with bony metastases complaint of back pain, weakness, sphincter dysfunction. Early diagnosis and treatment are imperative in preventing any further neurological damage .MRI scan is the diagnostic tool of choice. Treatment consists of high dose steroids and radiation. Surgery should be considered when diagnosis is in question or when there is progressive neurological deterioration despite radiation therapy

Future direction

Herceptin-the her2/neu gene has been an attractive target for antibody therapy because of the association of over expression of this gene with poor prognosis and response to therapy. Approximately 25-30% of all breast cancer over expresses her23/neu, a 185 kd tansmembrane glycoprotein receptor. These tumors have a high recurrence rates, a high rate of visceral metastasis at first recurrence, an aggressive biological behavior and a low likelihood of ER receptor positivity.

Herceptin, a recombinant humanized monoclonal antibody that binds to a protein encoded by her2/neu has antitumor efficacy, and is administered alone or in combination with doxorubicin or taxol based regimes. Updated data on herceptin –taxol combination has indicated that this new combination increases median disease free survival when compared to chemotherapy alone as first line therapy for metastatic breast cancer. There is compelling reason to use herceptin in the initial management of patients with her2/neu positive disease, receptor negative disease, However there are many unanswered questions in the use of herceptin in clinical practice.

· How long should herceptin be administered?

· What is the role of herceptin in neoadjuvant and adjuvant setting?

· Whether herceptin should be used alone or in combination with chemotherapy

· If to used with chemotherapy, then whether it should be combined with first line or second line chemotherapy?

Angiogenesis inhibitors (Agm1470, Pf4, Ds4152); angiogenesis is defined as the formation of new blood vessels from an extant capillary bed. it is a complex multistep process, whereby endothelial cells in a preexisting blood vessels are stimulated to multiply and invade the surrounding matrix to form new tubular structure, which ultimately form loops of blood vessels by laying new basement membrane and recruiting pericyte. This complex process is controlled by conventional endogenous positive and negative regulating factors.

In 1972 Judah folk man proposed that the growth of the tumor is dependent on angiogenesis, and that tumor in the absence of angiogenesis cannot grow beyond 1 to 2 mm. it was subsequently shown that angiogenesis also contributed to the distant metastasis and that antiangiogenesis therapy could cause involution of blood vessels and regression of growing tumor in animals.

Angiogenesis is therefore recognized as novel target for anticancer therapy in human cancers

Tumor cells are genetically unstable, heterogeneous and have a high mutation rate that increases their likelihood of developing resistance to chemotherapy, in contrast, the targets of antiangiogenic agents are nontransformed endothelial cells that are genetically stable, homogenous and had a low mutation rate. Therefore antiangiogenic therapy directed against tumors endothelial cells would in principle, induce little or no drug resistance.

Neovascularization permits rapid tumor growth by providing exchange of nutrients and oxygen to the tumor .the vascularized also receives various paracrine stimuli from endothelial cells like igf1, igf2.pdgf, bfgf, il1, il6il8.gmcsf.

Therefore, paracrine signals within a tumor are considered to operate in two directions; tumor cells and endothelial cells stimulating the proliferation of each other.

Problems and promises with antiangiogenesis agents

These agents in general have demonstrated only cytostatic effects in animal models

Tumor angiogenesis may not be maximally inhibited by the current available agents

Since angiogenesis is a complex multistep process, multiple agents may need to be given in combination to maximally inhibit the process

Antiangiogenesis therapy is rapidly evolving field, and new molecular insights into this complex process may help design rational antiangiogenic therapy .it now seems possible that this powerful therapy may play important part in the anticancer therapy in the future

Inhibitors of matrix metalloproteinase

The extra cellular matrix is an essential part of every organ. Metalloprotienase are the key components of the system that maintains the integrity of the structure during normal physiological condition such as angiogenesis tissue modeling and developmental morphogenesis.

Imbalance between the production or activation matrix degrading protease and their inhibitors contribute to a variety of pathological conditions including malignancy.

MMP belong to a group of zinc metalloproteinase. These enzymes are produced by macrophages, t-lymphocytes, chondrocyte S, and epithelial cells, neutrophils.

MMP can be broadly divided into three classes

Collagenase

Gelatinase

Stromelysins

MMP2, mmp9 are thought to play a critical role in tumor invasion and are frequently co expressed in human cancers. Several MMP inhibitors are in the early stages of clinical development

Batimastat

Marimastat

Bay129566

MMP inhibitors are a promising new class of drugs With many potential application, but it is too early to speculate about their efficacy of these drugs in various malignancy. The ongoing and the future randomized trials should provide us with the information on the utility of MMP inhibitors in malignancy.

Gene therapy

Quality of life and supportive care issue

A growing emphasis has been placed on the quality of life issues in women with breast cancer. Although only a small number of randomized trials in women with breast cancer have demonstrated difference in quality of life, this research has likely led to a greater awareness of quality of life issue in clinical practice

Variety of ways of improving quality of life include

Use of newer chemo and hormonal therapy with less side effects

Emphasis on single agent chemotherapy rather on multi agent chemotherapy

Administration of all therapies in an outpatient setting

Growing interest in oral therapy

Use of biphosphonates in bony metastasis

Growing awareness of fatigue and its relation with anemia

Judicious use of newer antiemetic agents in the control of nausea and vomiting.

Summary

The unfortunate reality of breast cancer is that all treatment modalities are palliative in nature. This is a disease that currently has no cure and for which therapy is directed towards accentuating survival and relieving symptoms. Current technologies allow the prediction and detection of metastasis earlier and with greater accuracy. These achievements need to be consolidated by the discovery of innovative therapies that can alter the inevitable outcome of this disease and by individualization of the treatment.