Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the ...addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.
PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).
Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 95% CI 0·76–1·15; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 61·3% of 2840 patients on palbociclib and endocrine therapy vs 11 0·3% of 2903 on endocrine therapy alone), leucopenia (857 30·2% vs three 0·1%), and fatigue (60 2·1% vs ten 0·3%). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.
At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.
Pfizer.
Abstract Background Paraproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with diffuse ...or patchy pseudo lipid deposits. We present an atypical case of paraproteinemic keratopathy which lead to an initial misdiagnosis of infectious crystalline keratopathy. Case presentation a 69-year-old woman with an asymptomatic keratopathy detected during a cataract intervention. Slit-lamp examination revealed several hyper refringent subepithelial foci with fern-shaped branches, resembling crystalline keratopathy, in her left eye. Anterior segment optical coherence tomography revealed exclusively subepithelial hyperreflective lesions limited to the anterior stroma. The progressive bilateralization and progression of the condition prompted us to include other entities with crystalline corneal deposits in our differential diagnosis. Hematological analysis showed a high number of free Kappa light chains. Despite the typical clinical appearance of crystalline keratopathy, the atypical evolution and test results led us to consider that monoclonal gammopathy could be the cause of this entity. Conclusions Paraproteinemic keratopathy may present in its early stages as a unilateral subepithelial crystalline keratopathy. Thus, it must always be taken into account in the differential diagnosis of any crystalline keratopathy, particularly when there are no predisposing factors for an infectious crystalline keratopathy. Early recognition of this rare entity is important to address the associated potentially serious systemic disease.
This study analyzes the association of excessive energy intake and caloric restriction with breast cancer (BC) risk taking into account the individual energy needs of Spanish women. We conducted a ...multicenter matched case-control study where 973 pairs completed lifestyle and food frequency questionnaires. Expected caloric intake was predicted from a linear regression model in controls, including calories consumed as dependent variable, basal metabolic rate as an offset and physical activity as explanatory. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. The association with BC risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. While premenopausal women that consumed few calories (>20% below predicted) had lower BC risk (OR = 0.36; 95% CI = 0.21-0.63), postmenopausal women with an excessive intake (≥40% above predicted) showed an increased risk (OR = 2.81; 95% CI = 1.65-4.79). For every 20% increase in relative (observed/predicted) caloric intake the risk of hormone receptor positive (p-trend < 0.001) and HER2+ (p-trend = 0.015) tumours increased 13%, being this figure 7% for triple negative tumours. While high energy intake increases BC risk, caloric restriction could be protective. Moderate caloric restriction, in combination with regular physical activity, could be a good strategy for BC prevention.
Background
An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in ...preclinical models.
Methods
We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m
2
weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies.
Results
From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1–49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3–92), clinical benefit rate 82.8% (95% CI 64.2–94.2). Median time to progression 23.9 months (95% CI 14.9–not reached NR), median progression-free survival 23.9 months (95% CI 10.3–NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes.
Conclusions
Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%.
Trial registration
: NCT01306942, EudraCT 2010-023304-27.
Summary
Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral ...inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m
2
) in advanced TNBC patients. The primary objective was to ascertain the combination’s maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard “3 + 3” design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m
2
given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29–155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013–001750-96. Study GEICAM/2012–12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov:
NCT02027376
Background
Chemotherapy is one of the most widely used therapies for breast cancer, triggering important repercussions on people's quality of life. However, little research has been undertaken about ...podiatric adverse effects. This study aimed was to determine the prevalence of podiatric pathology developed in people with breast cancer who receive chemotherapy.
Methods
Observational, descriptive, and cross‐sectional study was conducted in the Oncology service of the A Coruña University Hospital (northwest Spain). People with breast cancer and undergoing chemotherapy treatment of legal age (≥ 18), who signed the informed consent (n = 117) were included. Sociodemographic, comorbidity, disease and foot health variables, as well as two self‐administered questionnaires (Foot Health Status Questionnaire and Foot Function Index) were studied. The current ethical‐legal aspects were followed.
Results
Foot health problems were highly prevalent, highlighting nail color changes (59.8%), onychocryptosis (39.7%), xerosis (62.4%), plantar fasciitis (12.8%), and neuropathic symptoms (75.2%). Some foot pain was presented in 77.8% of the sample, predominantly at nail level (15.4%) or sole of the foot and nail (14.5%). Most participants described their foot health as fair or poor (56.4%) and felt limited in walking (65.8%). The lowest score for the Foot Health Status Questionnaire was footwear (30.6(33.5)).
Conclusions
Foot health adverse effects represent worrisome problems in women with breast cancer undergoing chemotherapy, due to their high prevalence and negative implications on quality of life. These problems are critical as they may have implications for stopping or reducing chemotherapy. All these results call for the development of more research to contribute to the care and wellbeing of people with cancer who receive treatments such as chemotherapy. Thus, this line of research is a new path to be developed by the podiatry community.
Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour ...genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples.
A total of 57 paired primary and metastatic tumours from GEICAM/2009–03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion.
CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3–29) and 9 (range, 1–38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor–positive and human epidermal growth factor 2 (HER2)–positive tumours (P = 0.006).
Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution.
•Cancer cell fraction of mutations increases between primary tumours and metastases.•There is evidence for clonal remodelling during breast cancer progression.•Clinical subtype conversion correlates with clonal heterogeneity in primary tumours.
Abstract Objective To examine the influence of physical activity on breast cancer risk and evaluate whether adherence to international recommendations is associated with a decreased risk. Methods ...This is a multicenter matched case-control study where 698 pairs completed a physical activity questionnaire. Recreational physical activity during the last year was quantified in metabolic equivalent hours per week (MET-h/week) and categorized in activities of moderate (3.0–5.9 MET) and vigorous (> 6 MET) intensity. The adherence to World Cancer Research Fund and the American Institute for Cancer Research recommendation was also assessed. The association with breast cancer risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. Results Mean MET-h/week was 16.6 among cases and 20.4 among controls. Premenopausal breast cancer risk decreased by 5% ( P = 0.007) for every 6 MET-h/week increase in energy expenditure. By contrast, postmenopausal women needed to do more intense exercise to observe benefits. The protection was more pronounced for nulliparous women, as well as for hormone receptor positive and HER2 + tumors. Physically inactive women displayed a 71% increased risk when compared with those who met the international recommendation ( P = 0.001). Finally, women who were inactive during the previous year, regardless of the overall physical activity reported in previous periods, showed an increased risk when compared to always active women. Conclusions Women who report adherence to international physical activity recommendations entail a significant decrease in risk for all pathologic breast cancer subtypes. This is of particular interest in Spain, where a significant increase in overweight and obesity in recent decades is observed.
Background
Nanoparticle albumin‐bound paclitaxel (nab‐Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab‐Paclitaxel efficacy as neoadjuvant treatment ...for early estrogen receptor‐positive (ER+), human epidermal growth factor receptor 2‐negative (HER2‐) disease.
Materials and Methods
Women with ER+, HER2‐, stage II–III BC were treated preoperatively with four cycles of weekly nab‐Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden RCB III; Symmans criteria) would be ≤16%.
Results
Eighty‐one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval CI: 18.6%–38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%–34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%–13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine‐rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009–0.689; p = .0216).
Conclusion
Despite failing to confirm an RCB III rate ≤16% in nab‐Paclitaxel‐treated patients, the RCB 0+I rate indicates a significant drug antitumor activity with low rates of grade 3–4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011‐004476‐10; ClinicalTrials.gov: NCT01565499).
Implications for Practice
The pathological response rate (residual cancer burden RCB; Symmans criteria) of nanoparticle albumin‐bound paclitaxel administered as neoadjuvant treatment for early estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative disease was evaluated. Whereas poor response (RCB III) was 24.7%, similar to that for docetaxel, good response (RCB 0+I) reached 23.0%, far superior to the 13% for docetaxel, while keeping toxicity low. Exploratory biomarker analysis suggests secreted protein, acidic, cysteine‐rich overexpression in tumor cells as a potential predictor of complete response (RCB 0). Findings point to an encouraging single‐agent neoadjuvant treatment with low toxicity, which warrants future research and development.
摘要
背景.纳米微粒白蛋白结合型紫杉醇（nab‐紫杉醇）是乳腺癌（BC）标准紫杉烷类药物治疗的替代疗法。研究评价了nab‐紫杉醇作为新辅助疗法治疗早期雌激素受体‐阳性（ER+）、人表皮生长因子受体2‐阴性（HER2‐）的疗效。
材料与方法.罹患ER+、HER2‐、II–III期BC的女性在术前接受4个周期的nab‐紫杉醇（150 mg/m2, 每周一次）治疗, 每个周期用药3周, 停药1周。假设缓解率≤16%为病理学缓解不佳 残癌负荷（RCB）III级, Symmans标准。
结果：81名患者（中位年龄为47岁）接受治疗；64.2%的患者为绝经前女性, 69%为II期乳腺癌患者。RCB III级的比率为28.4%95%置信区间（CI）：18.6%–38.2%, RCB 0+I级（明显缓解）的比率为24.7%（95% CI：15.3%–34.1%）, RCB 0级（完全缓解）的比率为7.4%（95% CI：1.7%–13.1%）。经磁共振成像确定的客观缓解率为76.5%, 转为接受乳腺癌保乳手术的比率为40.0%。最常见的3‐4级毒性反应为中性粒细胞减少症（分别为12.3%及3.7%）, 未发生中性粒细胞减少性发热。2‐3级感觉神经病变分别见于25.9%及2.5%的患者。肿瘤富含半胱氨酸酸性分泌蛋白（SPARC）过表达与RCB 0级显著相关（比值比：0.079, 95% CI：0.009–0.689; p = 0.0216）。
结论.虽然未能证实nab‐紫杉醇治疗的患者的RCB III级比率≤16%, 但RCB 0+I级比率表明该药物明显具有抗肿瘤活性, 且3‐4级毒性的发生率较低。探索性生物标志物分析表明, SPARC对完全缓解具有潜在预测作用。需要进行验证性分析, 通过调整给药剂量和时间来减轻周围神经毒性。（试验注册：欧洲临床试验数据库研究编号：2011‐004476‐10; Clinical‐Trials.gov:NCT01565499）
The NABRAX study was designed to evaluate the antitumor activity and safety of single‐agent weekly nab‐paclitaxel as neoadjuvant treatment of estrogen receptor‐positive/HER2‐negative breast cancer patients. This article reports on the trial and efforts to define the role of this drug and biomarkers of activity in this particular subtype of breast cancer.
Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally ...evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone-responsive, advanced breast cancer.
Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second-line treatment also were explored.
In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥ 2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug-related serious adverse events were reported.
In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first-line setting.
PDF
