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Literature Review - TheraSim Virtual Patient Simulator

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Literature Review

Literature Review
Breast Cancer

Breast cancer is one of the most common cancers in women, with approx. 230,000 cases of invasive disease expected to be diagnosed in the United States in 2013 (in addition to approx. 64,000 cases of in situ cancer). Breast cancer is the secondleading cause of cancer deaths among women, behind lung cancer, with 40,000 deaths projected for 2013. The 5year relative survival rate for invasive breast cancer is 90% (5991). Approximately 6% of breast cancers are metastatic at initial diagnosis and approx. 50% of patients with earlystage cancer eventually progress to metastatic breast cancer (MBC), where the 5year survival rate drops to 21% (6000).
BREAST CANCER SUBTYPING

Approximately 70% of human breast cancers express one or both hormone receptors (HRs)the estrogen receptor (ER) and the progesterone receptor (PR)and are defined as HR+ tumors. The ER is the primary transcription factor that drives tumor growth in HR+ breast tumors (6013). About 20% of breast cancers are HER2+; ie, they express the human epidermal growth factor receptor 2, an aggressive phenotype but one for which HER2targeted therapies have been developed and approved for use (5992). In 1 study that stratified 1134 invasive breast cancer patients according to HR and HER2 status, 68.9% were HR+ and HER2. This status was associated with the highest rates of 5year overall and diseasefree survival among subtypes (6018).
TREATMENT OVERVIEW

In patients with MBC, the primary goals of therapy are disease control, palliation of symptoms, and maintenance of quality of life (5992). Factors that influence the choice of treatment include the histology and HR/HER2 status of the tumor, the disease burden, the patient's menopausal status, the patient's prior therapeutic exposure, and the patient's and physician's preferences (6017). For the considerable proportion of MBC patients with HR+, HER2 disease, the generally preferred treatment is endocrine therapy. In early stage breast cancer, endocrine therapy is adjuvant therapy, employed after the primary therapy of surgery, chemotherapy, and/or radiation therapy to reduce the risk of relapse. In patients with advanced disease, endocrine therapy is often administered as initial therapy and is favored over chemotherapy because of its clinical activity, low toxicity, and ease of treatment (6003). Surgery is also an option in cases of advanced disease when metastasis is limited and well defined, and thus it may be coupled with adjuvant endocrine
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therapy (6000). In endocrine therapy, treatment involves sequencing agents until the onset of intolerance, resistance, or disease progression that necessitates the switch to chemotherapy (6003). Some 30% of women with MBC have primary resistance to endocrine therapy, defined as progressive disease within 6 months of initiation of treatment for advanced disease or recurrence within the first 2 years of adjuvant therapy, and many other patients develop secondary resistance. As a result, cytotoxic chemotherapy also plays an important role in the treatment paradigm for MBC (6019). The optimal sequence of endocrine therapy in metastatic breast cancer is not clearly defined.
TREATMENT GUIDELINES

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Breast Cancer, Version 3.2013 (6017), recommend that endocrine therapy be given to patients with HR+, recurrent or stage IV breast cancer. In postmenopausal women, the possible agents include selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen downregulators (SERDs). AIs stop estrogen production and are used only in postmenopausal women. For premenopausal women, endocrine therapy is used in conjunction with ovarian ablation (by surgical oophorectomy or irradiation) or suppression (using luteinizing hormonereleasing hormone agonists). The NCCN guidelines recommend that the therapy be continued until there is disease progression or unacceptable toxicity and that up to 3 consecutive endocrine therapy regimens be attempted; if there is no clinical benefit at that point, chemotherapy can be initiated (6017). Recent guidelines from the European Society for Medical Oncology (ESMO) propose similar recommendations for HR+, locally recurrent or metastatic disease, with the SERM tamoxifen plus ovarian ablation being the preferred option for premenopausal women. For postmenopausal women, the ESMO guidelines recommend as firstline treatment the thirdgeneration AIs (anastrozole, letrozole, or exemestane) if they have not been administered previously; otherwise, tamoxifen is an acceptable firstline option. Secondline hormone therapy for postmenopausal patients may include tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, the progestin megestrol acetate, and androgens. ESMO does not offer a definitive recommendation for endocrine treatment cascade because the best option after progression on a thirdgeneration AI is currently unknown (6000). Another analysis of treatment algorithms for HR+, advanced breast cancer also cites the paucity of evidence on which to establish recommendations for thirdline hormonal treatment and beyond, but suggests that fulvestrant and exemestane are reasonable options following progression on tamoxifen and a nonsteroidal AI as the first 2 lines. The preferred option would be the combination of exemestane and everolimus (6025).
ENDOCRINE THERAPY SERMs

SERMs possess mixed ER antagonist/agonist activity that is dependent on the target tissue and that can vary from drug to drug. A potential risk of SERMs is that because of their agonist activity in the uterus, they may increase the possibility of endometrial cancer.
Tamoxifen

Tamoxifen is an ER antagonist in breast tissue and an agonist in bone and liver cells and in uterine endometrial cells. The agent was long established as the preferred treatment for hormoneresponsive MBC
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based on its superior efficacy and favorable toxicity profile compared with highdose estrogens, androgens, progestins, and the firstgeneration AI aminoglutethimide. It has recently come to be largely displaced by thirdgeneration AIs as a firstline treatment (6024).
Toremifene

Toremifene is an alternative to tamoxifen approved by the FDA for the treatment of MBC in postmenopausal women with ER+ or statusunknown tumors (6006). A recent metaanalysis assessing 7 clinical trials in women with advanced breast cancer determined that the 2 drugs are equally effective as first line treatments and that the safety profile of toremifene is no worse than that of tamoxifen (6014).
AIs ThirdGeneration AIs

anastrozole (a nonsteroidal AI) letrozole (a nonsteroidal AI) exemestane (a steroidal AI) AIs are orally administered drugs designed to prevent estrogen synthesis by inhibiting the aromatase enzyme, which is involved in the conversion of adrenal androgens to estrogen. They are less susceptible than SERMs to the emergence of resistance and less prone to cause adverse events, such as thromboembolic events and vaginal bleeding (6015,6016). The thirdgeneration AIsthe nonsteroidal AIs anastrozole and letrozole and the steroidal AI exemestanehave been found to be superior to megestrol acetate in the secondline setting, ie, patients with advanced breast cancer in whom tamoxifen has failed (6015). A metaanalysis evaluated 37 trials in postmenopausal women comparing the effects of any AI vs other endocrine therapy, no endocrine therapy, or a different AI in the treatment of advanced (metastatic) breast cancer. The analysis showed a significant survival benefit for treatment with an AI over other endocrine therapies (hazard ratio [HR] = 0.90). A subgroup analysis of just the commonly prescribed agents anastrozole, letrozole, and exemestane showed a similar survival benefit (HR = 0.88). Limited headtohead comparative data suggested an advantage for letrozole over anastrozole (6009).
Anastrozole

In a North American trial (trial 0030), anastrozole was compared with tamoxifen as firstline therapy in 353 women with advanced breast cancer whose tumors were HR+ or HR statusunknown. Anastrozole and tamoxifen were similar in terms of overall response rate (ORR) (21% and 17%, respectively), and the former had a significant advantage in terms of time to tumor progression (TTP) (11.1 vs 5.6 months; HR, tamoxifen vs anastrozole, 1.44; P = 0.005) (6016). TARGET (Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability), a larger European study (N = 668) with a similar design, found no significant difference in median TTP (8.2 months for anastrozole and 8.3 months for tamoxifen) and ORR (32.9% vs 32.6%, respectively) (5999). Anastrozole was not associated with a survival advantage in either trial, but it did cause fewer adverse events than tamoxifen (6025). Two other controlled trials (trials 0004 and 0005) compared anastrozole at dosages of 1 and 10 mg/d to megestrol acetate in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen treatment for either advanced or early breast cancer. Most of
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the subjects were ER+. No significant differences were found between treatment arms with respect to 2year survival, median TTP, ORR, and other efficacy endpoints. In addition to being approved by the FDA as adjuvant therapy for postmenopausal women with HR+ early breast cancer, anastrozole is indicated for first and secondline treatment of postmenopausal women with HR+ or statusunknown, locally advanced or metastatic breast cancer (5996).
Letrozole

In the PO25 study, 907 postmenopausal patients with advanced breast cancer (ER+ and/or PR+ or unknown HR status) received tamoxifen or letrozole daily until disease progression. Letrozole was associated with a significantly longer TTP (9.4 vs 6.0 months; HR = 0.72; P < 0.0001) and a significantly higher ORR (32% vs 21%; odds ratio [OR] = 1.77; P = 0.0002) than tamoxifen. Exploratory analyses also demonstrated that letrozole significantly improved overall survival (OS) compared with tamoxifen (6015). In another study in patients with advanced breast cancer who had progressed despite antiestrogen therapy, letrozole at 2.5 mg/d produced a 23.6% ORR, compared with 16.3% for megestrol acetate (OR = 1.58; P = 0.08), and reduced the relative risk of progression (0.77) compared with megestrol (P = 0.03). In addition to being FDAapproved as adjuvant therapy for HR+ early breast cancer, it is indicated for first and second line treatment of postmenopausal women with HR+ or statusunknown, locally advanced or metastatic breast cancer (6008). Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy (5997). In a phase 3 study, 769 postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen were randomized to receive exemestane or megestrol daily. The ORR was higher with exemestane than with megestrol (15.0% vs 12.4%), but not significantly so. Median survival time was significantly longer with exemestane (median not reached) than with megestrol (123.4 weeks; P = 0.039), as were the median duration of overall success (overall response or stable disease 24 weeks; 60.1 vs 49.1 weeks; P = 0.025), TTP (20.3 vs 16.6 weeks; P = 0.037), and time to treatment failure (16.3 vs 15.7 weeks; P = 0.042) (6012) In an openlabel, phase 3 headtohead trial of exemestane and tamoxifen in 371 postmenopausal patients with hormonesensitive, locally advanced or metastatic breast cancer, a higher ORR was seen with exemestane (46% vs 31%; OR = 1.85; P = 0.005), as well as a longer median progressionfree survival (PFS), but these advantages did not extend to a longerterm benefit in PFS, the primary endpoint (logrank P = 0.121). There was also no difference in OS between the 2 regimens (4228).
SERDs

Fulvestrant

Fulvestrant, a pure antagonist of the ER, is approved by the FDA for the treatment of HR+ MBC in postmenopausal patients whose disease progresses following antiestrogen therapy. Fulvestrant is given via intramuscular injection (6007). Although the drug was originally approved at a dosage of 250 mg, a phase 3 trial in 736 postmenopausal women with advanced, ER+ breast cancer, CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer), compared the 250mg dose, administered every 28 days, to a 500mg dose, administered on days 0, 14, and 28 and every 28 days thereafter. At a followup analysis, median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR = 0.81; nominal P = 0.016) (6005). The phase 3 EFECT trial (Evaluation of Faslodex vs. Exemestane
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Clinical Trial) compared fulvestrant to exemestane in 693 postmenopausal women with HR+, advanced breast cancer that was progressing or recurring after nonsteroidal AI therapy. Subjects were randomized to receive fulvestrant at 500 mg on day 0 and 250 mg on days 14, 28, and every 28 days thereafter, or exemestane at 25 mg once daily. Median TTP (3.7 months in both groups), ORR (7.4% and 6.7%, respectively), and clinical benefit rate (32.2% and 31.5%) were similar between the 2 arms. Median duration of clinical benefit (complete or partial response or stable disease for 24 weeks) was 9.3 and 8.3 months, respectively. No significant differences were found in the incidence of adverse events or quality of life (6001). Fulvestrant has also demonstrated potential as a firstline therapy. FIRST (Fulvestrant fIRstline Study comparing endocrine Treatments) was a phase 2, randomized, openlabel study that compared fulvestrant 500 mg with anastrozole 1 mg as firstline endocrine therapy for postmenopausal women with HR+ advanced breast cancer. Fulvestrant was administered at 500 mg on days 1 and 14 and then 500 mg/month thereafter; anastrozole was administered at 1 mg/d. Median TTP was 23.4 months for fulvestrant vs 13.1 months for anastrozole, a 34% reduction in risk of progression (HR = 0.66; P = 0.01) (6020). A phase 3 trial, called FALCON, is now under way to compare these same 2 agents as firstline endocrine therapy in 450 postmenopausal women with HR+, locally advanced or metastatic breast cancer.
TARGETED BIOLOGIC AGENTS mTOR Inhibitors

One mechanism of resistance to endocrine therapy is activation of the mTOR (mammalian target of rapamycin) signaling pathway. This has raised the prospect of using mTOR blockers in conjunction with endocrine therapy to modulate resistance (6024).
Everolimus

The oral mTOR inhibitor everolimus was approved by the FDA in July 2012 for use in combination with exemestane for the treatment of postmenopausal women with metastatic, HR+, HER2 breast cancer who have experienced progression on letrozole or anastrozole (5995). Approval was based on the positive outcome of the phase 3 BOLERO2 study (Breast cancer trials of OraL EveROlimus2), which enrolled 724 patients with HR+ breast cancer who had experienced recurrence or progression while on a nonsteroidal AI. Participants were randomized 2:1 to everolimus/exemestane or exemestane/placebo. Median PFS on the basis of central assessment was 10.6 and 4.1 months, respectively (HR = 0.36; P < 0.001), and the response rate was 9.5% and 0.4%, respectively (P < 0.001). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus group vs 1% in the control group), anemia (6% vs < 1%), dyspnea (4% vs 1%), hyperglycemia (4% vs < 1%), fatigue (4% vs 1%), and pneumonitis (3% vs 0%) (5994). According to the NCCN guidelines, the evidence from BOLERO2 warrants consideration of the addition of everolimus to exemestane in women who fulfill the entry criteria for the trial. Everolimus has also demonstrated efficacy when combined with other endocrine therapies. In the phase 2 TAMRAD (tamoxifen [TAM] plus everolimus [RAD]) trial, 111 patients with HR+, HER2 MBC who had previously received adjuvant therapy with an AI were assigned to receive tamoxifen with or without everolimus. The primary endpoint, clinical benefit rate (complete or partial response or stable disease) at 6 months, was achieved by 61% of patients in the combination therapy arm and 42% in the tamoxifen arm (P = 0.045). TTP also favored the combination group (4.5 vs 8.6 months; HR = 0.54; P = 0.0021), as did OS
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(HR = 0.45; P = 0.007 (5993). In a trial in 270 postmenopausal women with operable, ER+ breast cancer, the response rate, as assessed by clinical palpation, following treatment with everolimus and letrozole was higher than that with letrozole alone (68.1% vs 59.1%; P = 0.062) (5998). Concerns about the use of everolimus with exemestane in clinical practice include increased toxicity, evidence of a lesser effect in patients with primary resistance rather than acquired resistance, the fact that there are no predictive markers for identifying patients most likely to benefit from the addition of the mTOR inhibitor, and the possibility that other endocrine agents rather than exemestane might prove more efficacious in this setting (6024, 6021).
Temsirolimus

Another mTOR inhibitor, temsirolimus, was evaluated in a phase 3 trial in 992 women with locally advanced or metastatic breast cancer. The subjects took letrozole in combination with oral temsirolimus (30 mg daily for 5 days every 2 weeks) or placebo. At the interim analysis, there were no differences in ORR, clinical benefit rate, and PFS between the 2 groups, and the study was closed (6002). There are several possible reasons for the discrepancy between the efficacy of temsirolimus and everolimus. The patients in the temsirolimus trial had not received prior endocrine therapy for MBC, and mTOR inhibitors may be more effective in patients who have acquired resistance to ERtargeted treatment. In addition, the dose evaluated in the temsirolimus study may have been inadequate (6021).
CHEMOTHERAPY Cytotoxic Agents

According to the NCCN guidelines, cytotoxic chemotherapy is recommended in patients with HR+ MBC that is refractory to endocrine therapy. The preferred single agents are the anthracyclines doxorubicin and pegylated liposomal doxorubicin, the antitubulin taxane paclitaxel, the antimetabolites capecitabine and gemcitabine, and the microtubule inhibitors vinorelbine and eribulin. Other single agents include cyclophosphamide, carboplatin, docetaxel, albuminbound paclitaxel, cisplatin, epirubicin, and ixabepilone. Eribulin and ixabepilone are nextgeneration agents that received FDA approval relatively recently. Standard practice is to continue firstline chemotherapy until disease progression if possible. The guidelines support the use of sequential singleagent chemotherapy rather than combination chemotherapy because of its generally lower toxicity and equivalent survival benefit. None of the current guidelines, however, offer clear direction on choosing among the many available agents.(6017).
Eribulin

Eribulin was approved by the FDA in 2010 for the treatment of patients with MBC who have previously received at least 2 chemotherapeutic regimens (including an anthracycline and a taxane) for the treatment of metastatic disease (6010). In the phase 3 EMBRACE (Eribulin Monotherapy vs. treatment of physician's choice in patients with metastatic BReast cAnCEr) study, heavily pretreated patients were randomized 2:1 to receive eribulin at 1.4 mg/m2 on days 1 and 8 of a 21day cycle or the treatment of the physician's choice (TPC). OS was significantly improved in the eribulin vs the TPC group (median, 13.1 vs. 10.6 months; HR = 0.81; P = 0.041).
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The most common adverse events in both groups were asthenia or fatigue (54% and 40%, respectively) and neutropenia (52% and 30%). Peripheral neuropathy was the most common adverse event leading to discontinuation of eribulin treatment, occurring in 5% of patients (6004).
Ixabepilone

Ixabepilone received FDA approval in 2007 and is indicated for the treatment of metastatic or locally advanced breast cancer, both in combination with capecitabine after failure of an anthracycline and a taxane and as monotherapy after failure of an anthracycline, a taxane, and capecitabine (6011). In an openlabel, phase 3 trial, 752 patients with anthracyclinepretreated or resistant and taxaneresistant, locally advanced or metastatic breast cancer were randomized to receive ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2000 mg/m2 orally on days 1 through 14) or capecitabine alone (2500 mg/m2 on the same schedule) given every 21 days. The combination regimen extended median PFS relative to capecitabine alone (5.8 vs 4.2 months; HR = 0.75; P = 0.0003) and increased ORR (35% vs 14%; P < 0.0001). Adverse events observed more frequently in the combination arm than the capecitabine arm included grade 3/4 treatmentrelated sensory neuropathy (21% vs 0%), fatigue (9% vs 3%), and neutropenia (68% vs 11%), as well as rate of death as a result of toxicity (3% vs 1%) (6023) Ixabepilone was also the subject of a second phase 3 trial in 1221 women with MBC who were previously treated with anthracycline and taxane agents but were not required to meet the chemotherapy resistance criteria of the other phase 3 trial. The patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone according to the same regimen as in the other phase 3 study. There was not a significant difference in OS between the 2 groups, which was the primary endpoint. In the 79% of patients with measurable disease, the combination was superior to capecitabine alone for the secondary endpoints of PFS (median, 6.2 vs 4.2 months; HR = 0.79; P = 0.0005) and ORR (43% vs 29%; P < 0.0001). Grade 3 to 4 neuropathy occurred in 24% of patients treated with the combination, but was reversible (6022). 2003-2014 TheraSim, Inc. All Rights Reserved. Clinical Simulator. MedSims

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