Optimal adjuvant chemotherapy for early-stage breast cancer balances efficacy and toxicity. We sought to determine whether single-agent paclitaxel (T) was inferior to doxorubicin and cyclophosphamide (AC), when each was administered for four or six cycles of therapy, and whether it offered less toxicity.
Patients and Methods
Patients with operable breast cancer with 0 to 3 positive nodes were enrolled onto the study to address the noninferiority of single-agent T to AC, defined as the one-sided 95% upper-bound CI (UCB) of hazard ratio (HR) of T versus AC less than 1.30 for the primary end point of relapse-free survival (RFS). As a 2 × 2 factorial design, duration of therapy was also addressed and was previously reported.
With 3,871 patients enrolled onto the trial, a median follow-up period of 6.1 years, and 437 RFS events, we achieved an HR of 1.26 (one sided 95% UCB, 1.48; favoring AC does not allow a conclusion of noninferiority of T with AC; UCB > 1.3). With 266 patient deaths, the HR for overall survival (OS) was 1.27 favoring AC (UCB, 1.56). The estimated absolute advantage of AC at 5 years is 3% for RFS (91 v 88%) and 1% for OS (95 v 94%). All nine treatment-related deaths were patients receiving AC and are included in the analyses of both RFS and OS. Hematologic toxicity was more common in patients treated with AC, and neuropathy was more common in patients treated with T.
This trial did not show noninferiority of T to AC, a conclusion that is unlikely to change with additional events and follow-up. T was less toxic than AC.
Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays an important role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent research in rodents found that exposure to stress led to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress responses, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, one day later participants in the stress group (n = 27) demonstrated significantly less extinction retrieval (i.e., greater fear recovery) than those in the control group (n = 25). Our results suggest that acute stress impairs extinction memory retrieval and offers insight into why treatment strategies used in the clinic may be challenging to recruit in daily life where stress is pervasive.
extinction retrieval; fear conditioning; stress; cortisol
Triple-negative breast cancer (TNBC) has been demonstrated to carry poor prognosis, but whether or not there exists any age-related variation in TNBC outcomes has yet to be elucidated. The current population-based study investigated the early survival pattern of elderly women with TNBC and identified outcome-correlated factors.
Patients and Methods
We searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled female primary non-metastatic TNBC cases. The patients were subdivided into elderly (≥70 years) and young groups (<70 years). The survival status of elderly patients was compared to that of the younger women. The primary and secondary endpoints were cancer-specific survival (CSS) and overall survival (OS) respectively.
9908 female TNBC patients diagnosed from 2010 to 2011 were included in the current study (20.4% elderly). Elderly patients with relatively advanced diseases exhibited distinctly worse cancer-specific (log-rank, p<0.001) and overall survival (log-rank, p<0.001) than their young counterparts. Advanced age at diagnosis (≥70 years) was significantly predictive of poor outcome in terms of CSS (hazard ratio (HR), 2.125; 95% confidence interval (CI), 1.664 to 2.713; p<0.001) and OS (HR, 3.042; 95%CI, 2.474 to 3.740; p<0.001). Underuse of curative treatment especially radiotherapy was more prevalent in elderly women with stage II or III diseases than in younger patients.
Elderly patients with TNBC displayed elevated early mortality within the first two years of diagnosis compared to the younger individuals. The observed lower rate of loco-regional treatment might be associated with worse cancer-specific outcome for these patients.
Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.
This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC).
Patients and Methods
Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS).
Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2.
In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.
Individuals use both passive and active defensive responses to environmental threats. Much is known about the neural circuits of passive defensive responses (e.g., freezing), but less is known about the substrates of active defensive responses (e.g., avoidance). We developed an active avoidance task in which rats learn to avoid a tone-signaled footshock by stepping onto a nearby platform. An advantage of this task is that freezing, which can interfere with avoidance, is reduced, thereby facilitating comparison of the effects of manipulations on avoidance versus freezing. After 10 d of avoidance training, rats were infused with muscimol to pharmacologically inactivate the prelimbic cortex (PL), infralimbic cortex (IL), ventral striatum (VS), or basolateral amygdala (BLA). Inactivating PL, VS, or BLA all impaired avoidance expression, but these areas differed with respect to freezing. Inactivating BLA decreased freezing consistent with loss of the tone–shock association, whereas inactivation of VS increased freezing consistent with loss of avoidance memory. Inactivation of PL had no effect on freezing. Inactivation of IL did not impair avoidance expression but did impair avoidance extinction. Our findings suggest that active avoidance is mediated by prefrontal–striatal circuits, which may be overactive in individuals suffering from trauma-related disorders.
amygdala; fear; infralimbic; prefrontal; prelimbic; striatum
Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer.
In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.
After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women.
In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.)
We conducted a multicenter phase II trial to assess the efficacy and toxicity of docetaxel (D) and carboplatin (C) combination as neoadjuvant therapy for stage II or III breast cancer (BC).
Patients received D 75 mg/m2 and C AUC 6 on day 1 followed by pegfilgrastim on day 2, every 14 days for 4 cycles, followed by definitive breast surgery. The primary endpoint was the proportion of patients achieving pathologic complete remission (pCR), defined as disappearance of all invasive and in situ tumor in the breast and axilla after chemotherapy.
Fifty-seven women, median age 53 y were enrolled. 38 (67%) had ER+, 31 (54%) PR+, and 6 (11%) HER2+ disease; 9 had triple negative BC (TNBC). Forty-three (75%, 95%CI: 62%–86%) out of 57 eligible patients had clinical response (15 cCR, 28 cPR). Nine (16%, 90% CI :10%–28%) patients had pCR. Four of 9 (44%) pts with TNBC achieved pCR. Thrombocytopenia (5%) was the only grade 4 adverse event (AE). The most common grade 3 AE were thrombocytopenia 19%, fatigue 12%, and anemia 9%.
4 cycles of 2-weekly D and C are feasible with acceptable toxicity and pCR rate of 16%. This regimen can be considered for neoadjuvant therapy of BC, particularly for patients not candidates for anthracycline therapy. High pCR rate of 44% noted in a subset of patients with TNBC is encouraging and needs to be validated in large prospective trial.
neoadjuvant; breast cancer; dose-dense; docetaxel; carboplatin
This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2+ trastuzumab breast cancer trial.
This analysis included 1736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray (TMA) sections containing three biopsies per patient or whole tissue sections (WS) using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC+) if the nuclear 3+ staining percentage was >30%.
574 (33%) tumors were MYC+. MYC+ was associated with hormone receptor positivity (χ2 p=0.006), tumors ≥ 2 cm (χ2 p=0.02), and a higher rate of nodal positivity (χ2 p<0.001). Hazard ratios (HRs) for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (p=0.006) and 0.65 (p=0.006) for patients with MYC+ and MYC- tumors, respectively (interaction p=0.40). For Arm B versus A, HRs for patients with MYC+ and MYC- tumors were 0.79 (p=0.21) and 0.74 (p=0.04), respectively (interaction p=0.71). For Arm C versus B, HRs for patients with MYC+ and MYC- tumors were 0.56 (p=0.02) and 0.89 (p=0.49), respectively (interaction p=0.17).
Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab.
trastuzumab; HER2-positive; breast cancer; MYC protein expression; disease-free survival
The estrogen receptor and human epidermal growth factor receptor (HER) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, targeting these pathways provides the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment. By increasing the understanding of the molecular mechanisms of combined HER2-targeted therapies, we aim to be better able to select patients who would respond to these treatments and understand some of the mechanisms of resistance to HER2-targeted treatments. Recent studies have demonstrated an increased effectiveness of dual targeted HER2 therapies against HER2-amplified breast cancer as compared with single blockade. These studies have resulted in the recent US Food and Drug Administration approval of the combination of taxane chemotherapy with pertuzumab and trastuzumab in the first-line metastatic setting as well as an accelerated approval in the neoadjuvant setting. Another mechanism for overcoming resistance to HER2 targeted therapies is the antibody–drug conjugate trastuzumab–emtansine, which targets the HER2 receptor conjugated to the potent antimicrotubule agent mertansine, allowing for intracellular release of the cytotoxic drug. Studies evaluating the efficacy of dual blockade with antibody–drug conjugate are currently ongoing. This article reviews recent data on different combinations of anti-HER2 treatments as well as ongoing and future research in this area.
To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.
ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.
The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations.
The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.
Data suggest that weight, and specifically BMI, plays a role in breast cancer development and outcome. We hypothesized there would be a correlation between BMI and clinical outcome in patients with early stage HER2-positive breast cancer enrolled in the N9831 adjuvant trial.
Patients were grouped according to baseline BMI: normal, BMI < 25; overweight, 25 ≤ BMI < 30; and obese, BMI ≥30. Disease-free survival (DFS) was estimated by the Kaplan-Meier method. Comparisons between treatment arms A, B, and C (chemotherapy +/− trastuzumab) were performed using a stratified Cox proportional hazards model.
Analysis was completed on 3017 eligible patients. Obese patients were more likely to be older and postmenopausal (p<0.0001 for both), have larger tumors (p=0.002) and positive lymph nodes (p=0.004). In the pooled analysis cohort, differences in DFS among the BMI groups were statistically significant (5-year DFS rates were 82.5%, 78.6%, and 78.5% for normal weight, overweight and obese women, respectively; logrank p-value = 0.02). The adjusted HR comparing the DFS of overweight to normal women was 1.30 (95% CI: 1.06 to 1.61) and obese to normal women was 1.31 (95% CI: 1.07 to 1.59). There were no statistically significant differences in DFS by weight group for women within any trial arm.
Patients with early stage HER2 positive breast cancer and normal BMI had a better 5-year DFS compared with overweight and obese women. Adjuvant trastuzumab improves clinical outcome regardless of BMI.
obesity; BMI; adjuvant therapy; trastuzumab
It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831.
Patients and Methods
The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years.
Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2
P < .001) and nodal positivity (χ2
P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47).
In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.
To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.
Patients and Methods
Patients with HER2-positive operable early breast cancer were randomized to 1 of 3 treatment arms: doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or paclitaxel plus trastuzumab then trastuzumab alone (Arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18–21 months post-registration.
A total of 1944 patients completed AC with a satisfactory LVEF and proceeded to post-AC therapy. Post-AC cardiac events (congestive heart failure [CHF] or cardiac death [CD]) were: Arm A, n=3 (2 CHF, 1 CD); Arm B, n=19 (18 CHF, 1 CD); Arm C, n=19 (all CHF); 3-year cumulative incidence was 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event after AC in Arms B and C were older age (P<.003), prior/current antihypertensive agents (P=.005), and lower registration LVEF (P=.033). Incidence of asymptomatic LVEF decreases requiring trastuzumab to be held was 8–10%; LVEF recovered and trastuzumab was restarted in approximately 50% of these patients.
The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus control arm but by <4%. Older age, lower registration LVEF, and antihypertensive medications increase the risk of cardiac dysfunction in patients receiving trastuzumab following AC.
HER2; trastuzumab; adjuvant; breast cancer; doxorubicin; cyclophosphamide; paclitaxel; cardiac safety
The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).
Patients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n = 70) or T-DM1 (n = 67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction.
HER2 mRNA levels were obtained for 116/137 patients (HT = 61; T-DM1 = 55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR) = 0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA ≥ median (HR = 0.39; 95% CI 0.18 to 0.85) versus < median (HR = 0.85; 95% CI 0.44 to 1.67). In the T-DM1 arm, median progression-free survival (PFS) was not reached in patients with HER2 mRNA ≥ median and was 10.6 months in patients with HER2 mRNA < median. In the HT arm, PFS was 8.8 versus 9.8 months in patients with HER2 mRNA ≥ median versus < median, respectively. The effect of HER2 mRNA expression on objective response rates was less pronounced.
This exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median.
Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch® system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement.
CellSearch® images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (κ) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test.
For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median κ of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and ≥3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median κ of 0.74 (range 0.25 to 0.90).
The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required.
In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non–cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
Patients and Methods
We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease–free survival, incidence of contralateral new primary breast cancer, and safety.
In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease–free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor–positive breast cancer.
Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA SNPs and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here.
Patients and Methods
E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. Fluorescence in situ hybridization to assess gene amplification status for VEGFA was performed on paraffin embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was performed.
ER+ or PR+ tumors were less likely to have VEGFA amplification compared with ER/PR-tumors (p=0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; p=0.013) in univariate analysis with a trend for worse OS in multivariate analysis (p=0.08). There was a significant interaction between VEGFA amplification, hormone-receptor status, and study arm. Patients with VEGFA amplification and triple negative breast cancers (TNBCs) or HER2 amplification had inferior OS (p=0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior PFS (p=0.010) and OS (p=0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant.
VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab.
Breast cancer; VEGF amplification; bevacizumab
Metastatic solid tumors are aggressive and mostly drug resistant leading to few treatment options and poor prognosis as seen with clear cell renal cell carcinoma (ccRCC) and triple negative breast cancer (TNBC). Therefore the identification of new therapeutic regimes for the treatment of metastatic disease is desirable. ccRCC and TNBC cell lines were treated with the HDAC inhibitor romidepsin and the methyltransferase inhibitor decitabine, two epigenetic modifying drugs approved by the FDA for the treatment of various hematologic malignancies. Cell proliferation analysis, flow cytometry, quantitative PCR and immuno-blotting techniques were utilized to evaluate the antitumor synergy of this drug combination and identify the re-expression of epigenetically silenced tumor suppressor genes. Combinatorial treatment of metastatic TNBC and stage 4 ccRCC cell lines with romidepsin/decitabine leads to synergistic inhibition of cell growth and induction of apoptosis above levels of individual drug treatments alone. Synergistic re-expression of the tumor suppressor gene secreted frizzled-related protein one (sFRP1) was observed in combinatorial drug treated groups. Silencing sFRP1 (shRNA) prior to combinatorial drug treatment demonstrated that sFRP1 mediates the growth inhibitory and apoptotic activity of combined romidepsin/decitabine. Furthermore, addition of recombinant sFRP1 to ccRCC or TNBC cells inhibits cell growth in a dose-dependent manner through the induction of apoptosis identifying that epigenetic silencing of sFRP1 contributes to renal and breast cancer cell survival. Combinatorial treatment with romidepsin and decitabine in drug resistant tumors is a promising treatment strategy. Moreover, recombinant sFRP1 may be a novel therapeutic strategy for cancers with suppressed sFRP1 expression.
Triple negative breast cancer; clear cell renal cell carcinoma; methyltransferase inhibitor; histone deacetylase inhibitor; secreted frizzled-related protein 1
Patients with the triple negative subtype of breast cancer have an overall poor outcome, with earlier relapses, distinct patterns of metastases, and lack of specific targets for treatment selection. Classification of these tumors has begun to be modified by inclusion of immunohistochemistry for various markers, and gene profiling, to further characterize this subtype of breast cancer, may aid in the identification of new targeted therapies. Anthracyclines and taxanes remain the standard of care in the adjuvant setting. However, novel anti-angiogenesis, anti-tubulin, and DNA repair agents are already under evaluation in (neo) adjuvant trials. Molecular characterization is being included in trials to identify optimal adjuvant strategies. The aim of this manuscript is to review data concerning the molecular characterization of triple negative breast cancers as well as the clinical outcomes of treating patients with existing adjuvant treatments, and to highlight newer adjuvant research strategies in development.
Breast cancer; triple negative; basal-like breast cancer; adjuvant therapy
This study measured the time taken for setting up the different facets of an international phase III study being conducted in 44 participating countries.
Discuss methods for improving the efficiency of global clinical trials.Explain the need for national regulatory authorities and collaborative cancer groups to initiate efforts to quicken the activation process in their countries.Describe the activation process of phase III studies and its complex and heterogeneous regulation across different geographic and economic regions.
This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries.
Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria.
South America had a significantly longer time to RA approval (median: 236 days, range: 21–257 days) than Europe (median: 52 days, range: 0–151 days), North America (median: 26 days, range: 22–30 days), and Asia-Pacific (median: 62 days, range: 37–75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21–257 days) than high-income (median: 47 days, range: 0–112 days) and lower-middle income economies (median: 57 days, range: 37–62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0–174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26–412 days).
This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research.
Activation; Phase III clinical trials; Ethics committee/institutional review board
Postmenopausal women with breast cancer (BC) are at increased risk for bone loss. Bisphosphonates improve bone mineral density (BMD) in normal postmenopausal women. The purpose of this study was to determine if immediate treatment with zoledronic acid preserves BMD in postmenopausal women with BC starting letrozole after tamoxifen. Postmenopausal women with BC completing tamoxifen were treated with daily letrozole 2.5 mg/vitamin D 400 I.U., calcium 500 mg twice daily and were randomized to upfront or delayed zoledronic acid 4 mg every 6 months. Patients in the delayed arm were only given zoledronic acid if they developed a post-baseline BMD T score <−2.0 or had a fracture. The primary endpoint was the mean percent change in lumbar spine (LS) BMD at 1 year. About 558 women enrolled; 395 provided 1 year BMD data. The upfront arm experienced a mean change of +3.66% in LS BMD versus -1.66% for the delayed group (P < 0.001). Changes at the femoral neck/total hip were also greater for the upfront versus delayed arms (P < 0.001; P < 0.001) with differences persisting at 2 years. Patients in the delayed arm were more likely to experience a clinically meaningful 5% loss of BMD at all sites versus the upfront zoledronate group. Patients in the upfront arm were slightly more likely to report limb edema, fatigue, fever, nausea and jaw osteonecrosis(1%). Upfront zoledronic acid prevents bone loss in postmenopausal women with BC starting letrozole after tamoxifen.
Breast cancer; Aromatase inhibitor; Bone loss; Zoledronic acid
Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF-B, and PIGF-1 and -2.
Patients and Methods
A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days.
Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2+ disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%–23.8%) and 6-month PFS was 9.5% (95% CI, 1.2%–30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted.
Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy.
Angiogenesis; Cooperative group; Monoclonal antibody; Breast cancer