Metastatic breast cancer

Metastatic breast cancer

Goals of treatment in mbcProlong survivalRelieve symptomsImprove quality of lifeSurgical option in mbcLocal treatmentlumpectomy or mastectomy with complete resectionreducing the tumour load influences metastatic growth - correlation was found between the level of circulating tumour cells (CTCs) and the prognosis of metastatic breast cancerTumour-induced immunosuppression is a mechanism allowing tumours to escape immune destructionSome observation found that resection of breast lesion in MBC accelerate relapse in 2 mechanism(1) due to removal of inhibitors of angiogenesis there will be an angiogenic surge (2) surgical wounding will lead to the release of growth and immunosuppressive factors

oligometastatic disease - which is characterized by solitary or few detectable metastatic lesions that are usually limited to a single organCommon sites include the bones, lungs, liver and brain

investigationbiopsy : Tumour characteristics e usually obtained from the initial pathological specimen if possible and include grade, type, nodal status and receptor statusBlood : full blood count, liver function test, bone profile, tumour markers CA15-3 and carcinoembryonic antigen (CEA)Radiology: - chest radiography e limited benefit - isotope bone scan and plain films of hot spots and symptomatic areas / MRI bone - ultrasound scan of liver - CT scan thorax/abdomen/pelvis and occasionally head (if indicated clinically) - positron emission tomography fused with computer tomography (PET-CT) is a new modality used to diagnose metastases in patients whose imaging is suspicious but not diagnosticAspiration of pleural effusions and ascites for cytology

Surgery for lung secondary Breast Cancer

Identified prognostic factors for lung resection include - disease-free interval (disease-free interval >36 months) - number of metastases (solitary metastases being the most favorable) - size of metastases - ER status - completeness of resection

Surgery for liver secondary Breast CancerRole of liver metastasectomy in MBC is less recognized compared to colorectal cancerRadiofrequency ablation thermal energy to induce coagulation necrosis in tumour cells, effective in local control in solitary lesion < 3cm

Surgery for brain secondary Breast Cancerhalf of patients with HER2-positive advanced breast cancer will develop brain metastaseshormone receptor-negative/HER2-positive tumours experiencing increased risk of the CNS as site of first relapse compared with patients with hormone receptor-positive/HER2-positive tumourstriple-negative (ER,PR and HER2 negative) breast cancer are also at high risk, with 2546% of patients developing brain metastasesnon-luminal tumours (e.g. triple-negative cancers) appear to experience a shorter time to CNS relapse compared with patients with luminal tumoursFactors determining treatment(a) the number, size, and location of brain lesions (b) the presence or absence of neurological symptoms(c) the patients performance status and medical comorbidities(d) the status of systemic metastases (e) the availability of systemic treatment options(f) patient preference.combination of surgical resection, radiosurgery, and/or WBRTno FDA-approved systemic therapies for the treatment of breast cancer brain metastasesMalaysian Management of Breast Cancer CPG 2010

no RCT addressing surgery for the primary tumour in metastatic breast cancerretrospective study showed that surgical removal of the primary tumour was associated with a significantly longer survival time in patients with distant metastatic disease at diagnosis with 5-year survival rates of 24.5% with mastectomy and 13.1% without mastectomy (p < 0.0001)Another retrospective study (n=111) concluded that improvement in local control may play a role in improving outcomes in women with stage IV breast cancer, and resection of in-breast tumours can help to achieve this

* Recommendation : surgery of primary tumour may be considered in stage IV breast cancer

San Antonio breast cancer symposiumMastectomy might not be the best choice for all women with metastatic breast cancerRCT of 350 women with metastatic breast cancer between 2005 2013 Mumbai India, - 173 women received LRT - 177 women no LRTthose who underwent mastectomy and removal of axillary lymph nodes (plus radiation therapy) did not have better overall survival rates than women treated with medication alone7% excess death rate in those who receive LRTLimitation : none of the HER2 positive patient received targeted hormonal or anti-HER2 therapy Assoc. Prof of Surgery from Memorial Sloan-Kettering Cancer in New York City, studied outcome of 127 women with stage IV breast cancer at first diagnosis with surgery or no surgeryNone of the women in this group had died of metastatic disease at 2-year follow-up, and more than 60% had not progressedSystemic treatment Hormone receptor-negative breast cancerPatients with symptomatic hormone receptor-positive breast cancer, in whom endocrine therapy is unlikely to result in a prompt clinical response. These include patients who present with: Rapid disease progression following more than one endocrine therapy (ie, endocrine-resistant disease) A large tumor burden involving visceral organsFactors influencing chemotherapy choice

Tumour burdenGeneral health statusPrior treatment and toxicities Patient preferenceTumour burdenSingle agent limited tumour burden of minimal symptomcombination - symptomatic disease due to the location of specific metastatic lesions (eg, right upper quadrant pain due to expanding liver metastases, or dyspnea related to diffuse lung metastases), a large tumor burden, and those with rapidly progressive diseaseBrain metastasis no systemic treatment requiredGeneral health statusSingle agent - patient with cardiac disease not for anthracycline - unable to swallow cant take capecitabine (xeloda) - patient with diabetes cant premedication with steroid (paclitaxel, capecitabine, and gemcitabine). - poor performance no benefitCombination - anthracycline-containing regimen chemotherapy nave stage IV - taxane based cardiac diseasePrior treatment and toxicitiesPrevious Anthracycline - may not be good candidates for repeat anthracycline therapy due to increasing risk of cardiac toxicity at higher cumulative doseshistory of myelosuppression with prior therapy that resulted in dose modification or treatment delay may not be good candidates for combination chemotherapyhistory of serious (grade 3/4) neuropathy may not be good candidates for microtubulin-directed agents (eg, taxanes, ixabepilone, eribulin, or vinorelbine) appropriate candidate for anthracyclinePatient preferencesprefer less frequent visits for intravenous treatments may opt for treatment administered every three weeks, rather than weekly - single-agent taxanes, anthracyclines, or ixabepilone, or combination therapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin plus cyclophosphamide (AC).prefer a low risk of alopecia may want to avoid taxanes and anthracyclines gemcitabine / capecitabineless intrusion on their lifestyle may opt for an orally administered agent, such as capecitabine

TaxanesAmong the most active agents for metastatic breast cancerDocetaxel can be administered every three weeks or weekly, significant risk of fluid retention, which is reduced by premedication with dexamethasone, improvement of disease free survival (DFS) if administered 3 weeklyPaclitaxel - can be administered weekly or every three weeks , studies show weekly administration overall response rate and overall survival Nab-paclitaxel better for pt with risk of hyperglycaemia and cant tolerate steroidsThe risks of neuropathy and myalgia are greater with paclitaxel than with docetaxelPaclitaxel can be administered in the setting of mild-moderate hepatic dysfunction, docetaxel should not be administeredDocetaxel given every three weeks is the more myelosuppressive taxane agent. Risks from docetaxel also include febrile neutropenia, edema, and gastrointestinal toxicities.

AnthracyclinesLimited role for metastatic breast cancerDoxorubicin every three weeks, or weekly for three weeks followed by one week offEpirubicin every three weeks, or weekly for three weeks followed by one week offrisk for cumulative cardiac toxicitydexrazoxane may minimize the risk of treatment-related cardiac damagecapecitabineprodrug of the anti-metabolite fluorouracilAvailable in oral formfirst-line treatment for metastatic breast cancer, particularly in patients with bone-predominant, estrogen receptor-positive metastatic disease who have progressed despite at least two trials of endocrine therapycross the blood brain barrierprimary toxicities are hand-foot syndrome and diarrheacan be used in settings of hepatic dysfunction

Gemcitabine, Vinorelbine, Eribulin, IxabepilonePlatinum agents Carboplatin and cisplatin cOmbination therapyEastern Cooperative Group (ECOG) 1193 trial in which over 700 women were randomly assigned to doxorubicin plus paclitaxel (AP), doxorubicin, or paclitaxel - A higher overall response rate (ORR) compared to doxorubicin or to paclitaxel (47 versus 36 and 34%) - no difference in overall survival (OS; 22 versus 19 and 22 months)Anthracycline containing regimensDoxorubicin plus cyclophosphamide (AC) ORR ranges from 47 to 54 percent Epirubicin with cyclophosphamide and fluorouracil (FEC) ORR ranges from 45 to 55 percentDoxorubicin, docetaxel, plus cyclophosphamide (TAC) ORR 77 percentDoxorubicin plus paclitaxel or docetaxel ORR is approximately 40 percent for either combinationTaxane based regimensGemcitabine plus paclitaxel or docetaxelCapecitabine plus docetaxelOther regimesCyclophosphamide, methotrexate, and fluorouracil (CMF)Combination regimens incorporating platinum salts Monitoring therapyHistory and physical examination before start of each treatmentRepeat imaging studySerial assay of serum tumour marker - (eg, cancer antigen [CA] 15-3, CA 27.29, and/or carcinoembryonic antigen [CEA]) Duration of treatment No predetermined durationcontinue chemotherapy to the best response, disease progression, or if toxicity requires discontinuation of treatmentA 2011 meta-analysis of first-line treatment randomized trials that included almost 2300 women compared maintenance treatment to treatment over a prespecified duration (range, three to eight cycles) . Longer chemotherapy duration was associated with improvement in progression-free survival (PFS; hazard ratio [HR] 0.64, 95% CI 0.55-0.76) and overall survival (OS; HR 0.91, 95% CI 0.84-0.99)A randomized trial published in 2013 consisted of 324 patients with metastatic breast cancer, all of whom were treated with paclitaxel and gemcitabine [68]. Patients who achieved disease control (complete or partial response, or stable disease) to treatment (n = 231) were randomly assigned to observation or maintenance chemotherapy with the same agents until disease progression.The administration of maintenance chemotherapy resulted in a higher Progression-free survival (PFS) rate at six months compared to observation (60 versus 36 percent, respectively; HR 0.73, 95% CI 0.55-0.97) and improved OS (median, 32 versus 24 months; HR 0.65, 95% CI 0.42-0.99). However, continuation of paclitaxel and gemcitabine resulted in a higher incidence of serious (grade 3/4) neutropenia (61 versus 0.9 percent) and grade 2/3 neuropathy (0.9 versus 0 percent)Despite these findings, several issues limit the universal application of these data in metastatic breast cancer:Over 70 percent of patients in this study had hormone-positive breast cancer; of these patients, only about 20 percent of these women had received prior endocrine therapy and, for those in the control arm, endocrine therapy was not initiated after chemotherapy was discontinued.The median age of participants was 48, suggesting that younger patients were preferentially enrolled.The benefit in PFS was seen predominantly in the subgroup of women who were age