Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Surveillance of Echinococcus tapeworm in coyotes and domestic dogs in Winnipeg, Manitoba: Abstract.

BACKGROUND: The Echinococcus species, including E. multilocularis and E. canadensis, are tapeworms that primarily infect canids such as dogs, foxes and coyotes, but which can also infect humans. In humans, E. multilocularis can cause alveolar echinococcosis; a serious condition that mimics metastatic malignancy and has a poor prognosis. It is known that coyotes in rural Manitoba are infected with Echinococcus species, but it is not known if coyotes in peri-urban areas are also infected. OBJECTIVES: To document and map Echinococcus species in wild canids and domestic dogs in Winnipeg, Manitoba (Canada). METHODS: There were 169 fecal samples collected between April 18 and June 1, 2018. These included 44 samples of domestic dog feces, 122 of coyote scat, one of fox scat and two of coyote colonic tissue specimens. Samples were frozen (-80°C) for at least 72 hours to inactivate tapeworm ova. Polymerase chain reaction analyses of E. multilocularis and E. canadensis were performed on all frozen samples. RESULTS: Echinococcus multilocularis-positive samples were detected in nine (10.6%) of 85 locations, with one positive sample in a suburban Winnipeg dog park and two positive samples in a popular provincial park. No dog samples were positive for E. multilocularis; one sample was positive for E. canadensis. In contrast, nine coyote samples (7.3%) were positive for E. multilocularis and eight samples (6.5%) were positive for E. canadensis. The one fox sample was positive for each. Overall, six samples (3.6%) were positive for both infections. CONCLUSION: This is the first confirmation of the presence of E. multilocularis in coyote feces in the metropolitan area of Winnipeg, Manitoba. In light of the risk this could pose to domestic dogs and human health, periodic surveillance that maps the distribution of this tapeworm could inform the need for additional public health actions.

Clinical characteristics of pediatric pertussis cases, Quebec 2015-2017.

BACKGROUND: The introduction of the acellular pertussis vaccine may have changed the epidemiological and clinical features of pertussis in Canadian children. OBJECTIVE: To describe the demographics, clinical presentation and outcomes of children and adolescents with pertussis presenting to a tertiary care hospital. METHODS: Retrospective cohort of consecutive patients evaluated at the Centre Hospitalier Universitaire Sainte-Justine (CHUSJ) and tested with a bacterial multiplex real-time polymerase chain reaction (PCR) for Bordetella pertussis or B. parapertussis between June 2015 and March 2017. Demographics, clinical presentations and outcomes were described for positive test results. The Modified Preziosi Scale was used to assess disease severity; severe disease was defined as a score ≥7. RESULTS: The age distribution of the 144 positive patients with a clinical encounter at CHUSJ was as follows: less than three months (n=25/144, 17.4%), four months to nine years (n=63/144, 43.8%) and 10 to 18 years (n=56/144, 38.9%). The most common symptoms at presentation were paroxysmal cough (70.1%), post-tussive emesis (47.2%) and coryza (33.3%). Over 84.0% of cases in infants less than three months of age had severe pertussis (92.0% required hospitalization and 28.0% intensive care admission). In children four months to nine years of age, 22.2% had severe pertussis and 11.1% required hospitalization. Only two (3.6%) children greater than 10 years had severe disease. CONCLUSION: Pertussis still affects children of all ages in Quebec. In older children, it tends to be a milder disease. When it affects infants, who do not yet have full protection from pertussis vaccination, it often causes severe disease, especially in those less than three months of age. This evidence further supports the implementation of a pertussis vaccination program in pregnant women.

Should equivocal Bordetella pertussis PCR results in children be reported to public health?

INTRODUCTION: Real-time polymerase chain reaction (PCR) is the preferred method for the diagnosis of pertussis. In Quebec, positive and equivocal results are reportable to public health; in contrast, in Ontario equivocal results are not reportable. OBJECTIVE: To determine the clinical significance of equivocal, compared with positive results, in children with suspected pertussis. METHODS: Retrospective cohort of consecutive patients seen at the Centre Hospitalier Universitaire Sainte-Justine in Montréal, Quebec, with suspected pertussis and tested with a bacterial multiplex PCR (including Bordetella pertussis) between 2015 and 2017. Medical records were reviewed using a standardized form. Univariate analyses (Student's t-test and chi-square test) and multivariable logistic regression were used to compare cases of positive and equivocal results. RESULTS: Of the 1,526 multiplex PCR performed, 109 were positive and 24 equivocal. Both groups were similar in terms of demographics and disease severity assessments, but patients in the equivocal group had less paroxysmal cough (33.3% vs 79.8%, adjusted odds ratio [aOR] 0.11, 95% confidence interval [CI] 0.04-0.29) and whoop (0% vs 18.3%, p<0.001), lower lymphocyte counts (6.6 vs 11.9 x109/L, p=0.008), were more likely to be diagnosed with a viral co-infection (16.7% vs 3.7%, aOR 5.62, 95% CI 1.17-27.54) and were less likely to receive a macrolide (25% vs 89%, aOR 0.04, 95% CI 0.01-0.11). When admitted, patients with equivocal results had a shorter average length of stay (3.3 vs 12.2 days, p=0.001). CONCLUSION: Although there were similarities in disease severity, children with suspected pertussis who had equivocal PCR results had significantly different clinical presentations compared with those with positive results. In the context of limited public health resources, these results may inform the decision whether or not equivocal results need to be reported to public health by laboratories.

Knowing about you: eliciting dimensions of personhood within tuberculosis care.

BACKGROUND: Knowing someone with tuberculosis (TB) as a person, rather than defining them by their illness, is part of recognising their dignity and unique individuality, and a requirement for effective care. OBJECTIVE: An adaptation of the Patient Dignity Question (PDQ) was formalised for persons receiving treatment for active TB or latent tuberculous infection (LTBI), and its impact was evaluated for both the person and health care providers (HCPs). DESIGN: Individuals with active TB or LTBI receiving treatment in Winnipeg, MB, Canada, were asked the PDQ as part of routine care. Patients and HCPs were subsequently invited to evaluate the application of the PDQ. RESULTS: Of the 58 participants who responded to the PDQ, 97% felt both that it was important to ask about them as an individual, and that the PDQ should be asked of all patients, while 55% thought it made a difference to their care. Thirty-eight per cent of HCPs said they learned something new about their patient, and 31% said it influenced their sense of connectedness with and sense of empathy for patients, as well as their personal satisfaction in providing care. CONCLUSION: Formalising a dignity question as part of person-centred care provides a mechanism to create a respectful environment that is caring of the most marginalised who carry the burden of TB.

Impact of a social media campaign targeting men who have sex with men during an outbreak of syphilis in Winnipeg, Canada.

BACKGROUND: The city of Winnipeg has experienced a surge of infectious syphilis cases since the fall of 2012, concentrated among men who have sex with men (MSM) and who use social media technologies-including phone applications-to meet sexual contacts. OBJECTIVE: To evaluate the acceptability, cost and effectiveness of a campaign promoting syphilis testing on popular websites and applications used by MSM in the Winnipeg Health Region (WHR). METHODS: The Winnipeg Regional Health Authority developed a campaign in March 2014 highlighting the syphilis outbreak and the importance of seeking testing. Over one month, advertisements appeared on four web-platforms: Grindr, Facebook, Squirt and the Gay Ad Network. When clicked, ads would direct the user to an information website. Acceptability was assessed using the number of 'clicks' elicited by advertisements on each platform. The cost of each platform's run of advertisements was compared to the number clicks elicited to produce a cost-per-click ratio for each platform. Effectiveness was assessed by comparing the number of syphilis tests ordered for male residents of the Winnipeg Health Region in the seven-week period before and after the campaign, as well as to the same time periods in 2012 and 2013. RESULTS: Out of 800,000 appearances purchased, the advertisements elicited 2,166 clicks, suggesting good acceptability. Grindr and Squirt advertisements had a better cost-per-click ratio than Facebook or the Gay Ad Network. There was no significant difference in testing before (2,049 tests) versus after (2,025 tests) the campaign and these findings were similar to testing trends in 2012 and 2013. CONCLUSION: Although this web-based campaign showed good acceptability and low cost, it did not appear to increase syphilis testing. This may be due to a poor campaign design; it also suggests that an education campaign alone may be insufficient to change behaviour.

Illness in Canadian travellers and migrants from Brazil: CanTravNet surveillance data, 2013-2016.

BACKGROUND: In light of the 2016 summer Olympic games it is anticipated that Canadian practitioners will require information about common illnesses that may affect travellers returning from Brazil. OBJECTIVE: To identify the demographic and travel correlates of illness among recent Canadian travellers and migrants from Brazil attending a network of travel health clinics across Canada. METHODS: Data was analyzed on returned Canadian travellers and migrants presenting to a CanTravNet site for care of an illness between June 2013 and June 2016. RESULTS: During the study period, 7,707 ill travellers and migrants presented to a CanTravNet site and 89 (0.01%) acquired their illness in Brazil. Tourists were most well represented (n=45, 50.6%), followed by those travelling to "visit friends and relatives" (n=14, 15.7%). The median age was 37 years (range <1-78 years), 49 travellers were men (55.1%) and 40 were women (44.9%). Of the 40 women, 26 (65%) were of childbearing age. Nine percent (n=8) of travellers were diagnosed with arboviruses including dengue (n=6), chikungunya (n=1) and Zika virus (n=1), while another 14.6% (n=13) presented for care of non-specific viral syndrome (n=7), non-specific febrile illness (n=1), peripheral neuropathy (n=1) and non-specific rash (n=4), which are four syndromes that may be indicative of Zika virus infection. Ill returned travellers to Brazil were more likely to present for care of arboviral or Zika-like illness than other ill returned travellers to South America (23.6 per 100 travellers versus 10.5 per 100 travellers, respectively [p=0.0024]). INTERPRETATION: An epidemiologic approach to illness among returned Canadian travellers to Brazil can inform Canadian practitioners encountering both prospective and returned travellers to the Olympic games. Analysis showed that vector-borne illnesses such as dengue are common and even in this small group of travellers, both chikungunya and Zika virus were represented. It is extremely important to educate travellers about mosquito-avoidance measures in advance of travel to Brazil.

Summary of recommendations on malaria issues in special hosts.

BACKGROUND: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. OBJECTIVE: To provide guidelines on malaria issues related to special hosts. METHODS: CATMAT reviewed all major sources of information on malaria prevention, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. RECOMMENDATIONS: All people visiting malaria endemic regions should use effective personal protective measures (PPM; topical repellants, bed nets, behavioural choices) and the prescribed chemoprophylaxis. Chemoprophylaxis for pregnant and breastfeeding women and for children requires careful consideration in the context of the pregnancy trimester, the age or size of the infant/child as well as their glucose-6-phosphate dehydrogenase (G6PD) status. Recommendations for long-term travellers, expatriates and people visiting friends and relatives (VFRs) do not differ markedly from those for short-term travellers. Some underlying medical conditions may make individuals more vulnerable to malaria. In addition, some conditions or their treatment may preclude the use of one or more antimalarial medications.

Summary of recommendations for the prevention of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT).

BACKGROUND: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. OBJECTIVE: To provide guidelines on risk assessment and prevention of malaria. METHODS: CATMAT reviewed all major sources of information on malaria prevention, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. RECOMMENDATIONS: Used together and correctly, personal protective measures (PPM) and chemoprophylaxis very effectively protect against malaria infection. PPM include protecting accommodation areas from mosquitoes, wearing appropriate clothing, using bed nets pre-treated with insecticide and applying topical insect repellant (containing 20%-30% DEET or 20% icaridin) to exposed skin. Selecting the most appropriate chemoprophylaxis involves assessment of the traveller's itinerary to establish his/her malaria risk profile as well as potential drug resistance issues. Antimalarials available on prescription in Canada include chloroquine (or hydroxychloroquine), atovaquone-proguanil, doxycycline, mefloquine and primaquine.

Summary of recommendations for the diagnosis and treatment of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT).

BACKGROUND: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. These recommendations aim to achieve appropriate diagnosis and management of malaria, a disease that is still uncommon in Canada. OBJECTIVE: To provide recommendations on the appropriate diagnosis and treatment of malaria. METHODS: CATMAT reviewed all major sources of information on malaria diagnosis and treatment, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. RECOMMENDATIONS: Malarial management depends on rapid identification of the disease, as well as identification of the malaria species and level of parasitemia. Microscopic identification of blood samples is both rapid and accurate but can be done only by trained laboratory technicians. Rapid diagnostic tests are widely available, are simple to use and do not require specialized laboratory equipment or training; however, they do not provide the level of parasitemia and do require verification. Polymerase chain reaction (PCR), although still limited in availability, is emerging as the gold standard for high sensitivity and specificity in identifying the species.

Two-year trends of peripherally inserted central catheter-line complications at a tertiary-care hospital: role of nursing expertise.

We found reductions in peripherally inserted central catheter (PICC) complication rates over 2 years of observation (20.4 vs 13.8/1,000 line-days; relative risk, 0.5-0.9). This difference represents a cost saving due to reduced line reinsertions and reduced use of thrombolytic agents. The presence of a dedicated PICC insertion nursing team and education of ward nurses in PICC maintenance is a plausible explanation for the observed differences.

Regional dissemination and control of epidemic methicillin-resistant Staphylococcus aureus. Manitoba Chapter of CHICA-Canada.

A methicillin-resistant Staphylococcus aureus (MRSA) strain introduced into the largest tertiary-care teaching hospital in Manitoba in 1993 led to a sustained outbreak with secondary outbreaks at one community hospital, two large long-term-care facilities, and nosocomial transmission at a second teaching hospital. Control measures were consistent at each institution and were coordinated on a province-wide basis. MRSA is not currently endemic in any facility in the province.

Accuracy and costs of rapid human immunodeficiency virus testing technologies in rural hospitals in Zambia.

OBJECTIVE: To evaluate the accuracy and costs of newer rapid human immunodeficiency virus (HIV) antibody tests in primary health care settings in rural Zambia. METHODS: Three rural hospitals participated in this study. During a baseline assessment period, HIV testing practices were recorded on 250 consecutive clients at each hospital. Baseline evaluation was compared with 250 subsequent consecutive clients tested using a testing algorithm consisting of an initial screening HIV Dipstick test (McDonald Scientific [PVT] Limited, Harare, Zimbabwe) followed by confirmatory testing of all reactive specimens using the HIV Capillus test (Cambridge Diagnostics, Galway, Ireland), in conformity with World Health Organization HIV testing recommendations. Quality control was performed at a national university teaching hospital laboratory. RESULTS: A total of 1,500 clients was entered, with an HIV seropositivity rate of 53.2%. Most HIV testing was performed on patients with signs and symptoms suggestive of HIV infection. Same-day results were provided for only 16%. The HIV Dipstick testing algorithm sensitivity was 96.9%, and specificity was 98.0%. Counselor dissatisfaction was greater with the Dipstick algorithm as a result of 5.3% discordant results. Use of the HIV Dipstick testing algorithm cost between US $3.00 and US $3.80 per client tested. CONCLUSIONS: The accuracy of HIV testing in unsophisticated rural laboratories in Zambia is acceptable. Although HIV Dipstick testing algorithm costs were relatively high for a developing country, this HIV testing procedure is currently the most economical method available in Zambia. Accurate, less costly HIV testing algorithms are still needed.

PIP: The Program for Appropriate Technology in Health (PATH) HIV Dipstick antibody test was developed to make a low-cost tool available to primary health services, especially in rural areas where laboratory facilities are often inadequate. The accuracy and costs of this test were evaluated at three rural hospitals in Zambia in 1996. During a baseline assessment period, HIV testing practices were recorded for 250 consecutive patients at each hospital. The baseline evaluation was compared with 250 subsequent consecutive patients tested using an algorithm consisting of an initial screening HIV Dipstick test followed by confirmatory testing of all reactive specimens using the HIV Capillus test. The HIV seropositivity rate among the 1500 patients tested was 53.2%. The HIV Dipstick testing algorithm sensitivity was 96.9% and the specificity was 98.0%. Counselor dissatisfaction was greater with the Dipstick algorithm because of a 5.3% discordant result rate. The cost of the HIV Dipstick testing algorithm was US$3.00-3.80 per client tested. Despite this relatively high cost, the HIV Dipstick procedure is currently the most economical technology available in Zambia. Further study is needed to find more accurate, less costly HIV testing algorithms.

Outbreak of parainfluenza virus type 3 in an intermediate care neonatal nursery.

BACKGROUND: Of the four serotypes of human parainfluenza virus, parainfluenza type 3 causes the majority of infections in young children and infants. Parainfluenza type 3 can occur in newborns, although most are born with neutralizing antibodies. There have been only infrequent reports of parainfluenza type 3 causing nosocomial respiratory infection in the newborn nursery setting. We report an outbreak occurring in the intermediate care nursery (IMCN) at St. Boniface Hospital, Winnipeg, Canada. METHOD: On August 6, 1996, nursing staff of IMCN notified Infection Control that six infants had developed respiratory tract symptoms including nasal discharge and cough. Three more cases were recognized by August 8, 1996. Infection control precautions including cohorting of infant cases and ill staff, gowning and reinforcement of hand washing practices and visitor regulations were instituted. When two further cases occurred on August 9, 1996, the unit was closed to all admissions and remained closed until August 30, 1996. The last infant case occurred on August 10, 1996. RESULTS: The attack rate among infants was 63% (12 of 19). No mortality was associated with this outbreak and morbidity was minimal (no ventilator support was required), although one-half of the infants developed radiologic pulmonary infiltrates and one-half required supplemental oxygen therapy. Parainfluenza type 3 was isolated from nasopharyngeal secretions in 6 of 12 infant cases. There was a significant difference (P = 0.02) in age between the ill and non-ill infants; ill infants were a mean age of 42 days compared with a mean age of 11 days for non-ill infants at the midpoint of the outbreak. Sixteen of 65 (25%) IMCN nursing/medical staff reported an upper respiratory tract illness between July 10 and August 18, 1996. None of the staff was cultured. CONCLUSIONS: High patient census, limited numbers of full time staff, inadequate cohorting attempts because of staffing constraints and crowding in the IMCN were thought to be contributors to this outbreak. Institution of basic barrier precautions and temporary closure of the unit were effective in preventing further spread of the outbreak.

ARIMIDEX: a potent and selective aromatase inhibitor for the treatment of advanced breast cancer.

Aromatase inhibitors have been available for a number of years and their ability to reduce circulating estradiol levels has been shown to produce clinical benefit in women with advanced breast cancer. Until recently, the only commercially available aromatase inhibitor was aminoglutethimide. Although aminoglutethimide has been shown to be efficacious in the treatment of advanced breast cancer, it does cause significant toxicity and requires the use of concomitant hydrocortisone therapy. Anastrozole is one of a new class of potent aromatase inhibitors able to suppress estradiol to the limit of detection of sensitive assays without suppressing adrenal steroidal synthesis. Two large clinical trials (n = 764) conducted in the U.S.A. and in Europe evaluated two doses of anastrozole, 1 and 10 mg a day, compared to megesterol acetate, 40 mg four times a day, in postmenopausal women who had progressed while on tamoxifen. Response rates and time to progression with anastrozole were similar to those of megesterol acetate. Objective responses (CR + PR) were 10.3%, 8.9% and 7.9% in the 1 and 10 mg of anastrozole and megesterol acetate treatment groups, respectively. Another 25.2%, 22.6% and 26.1% had stable disease for over 24 weeks on 1, 10 mg anastrozole and megesterol acetate, respectively. Anastrozole and megesterol acetate were well tolerated; however, more patients had significant weight gain on megesterol acetate than with anastrozole treatment. The weight gain seen with megesterol acetate continued to increase over time. Anastrozole has a better therapeutic index (fewer side-effects) and has recently been approved by the FDA and a number of other regulatory agencies around the world for the treatment of advanced breast cancer.

A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group.

BACKGROUND: Anastrozole is a new oral aromatase inhibitor with highly potent and selective activity for the aromatase enzyme. In a Phase III trial, the efficacy and tolerability of anastrozole, given in doses of 1 and 10 mg orally once daily, and megestrol acetate, given in doses of 40 mg orally 4 times daily, were compared in 386 postmenopausal women with advanced breast carcinoma who progressed after tamoxifen therapy. METHODS: The trial was randomized, double blind for anastrozole, open label for megestrol acetate, parallel group, and multicenter. Patients were randomly assigned to receive anastrozole, 1 mg (n = 128); anastrozole, 10 mg (n = 130); or megestrol acetate (n = 128). The primary efficacy measures were time to progression and tumor response; secondary measures were time to treatment failure, duration of response, quality of life, and time to death. RESULTS: With a median duration of follow-up of 6 months, there was no statistical evidence of a difference between either 1 or 10 mg doses of anastrozole and megestrol acetate for any efficacy endpoint. According to rigid response criteria, 10%, 6%, and 6% of patients in the anastrozole 1 mg, anastrozole 10 mg, and megestrol acetate groups, respectively, had an objective response (complete response or partial response) and 27%, 24%, and 30% of patients in the respective groups had stable disease for a duration of 24 weeks or longer. Quality-of-life assessments revealed that anastrozole in a 1-mg dose was associated with better physical scores and anastrozole in a 10-mg dose with better psychologic scores than megestrol acetate. Both anastrozole and megestrol acetate were generally well tolerated. Among anticipated adverse events, gastrointestinal disturbance was more common among patients in the anastrozole groups, whereas weight gain occurred more frequently among patients in the megestrol acetate groups. Weight increases of 5% or more and 10% or more were more common among megestrol acetate-treated patients; moreover, patients in this group continued to gain weight over time. CONCLUSIONS: Anastrozole, given in doses of 1 and 10 mg once daily, represents a well tolerated and effective therapeutic option for the treatment of postmenopausal women with advanced breast carcinoma who progress after tamoxifen treatment.