Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (
) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with ...centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with
amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (
< 0.0001, adjusted for hormone receptor status). Single-cell
FISH analysis of cellular heterogeneity identified the fraction of
nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies. SIGNIFICANCE: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of
nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection.
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To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma.
Patients diagnosed with early-stage invasive ductal carcinoma (IDC) ...or classic invasive lobular carcinoma (ILC) who were randomly assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor-positive with high (luminal B LB -like) or low (luminal A LA -like) proliferative activity by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling.
The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio HR, 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20).
The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma.
Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to ...neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer.
We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II–III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2–3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277.
Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 53% of 316 patients vs 49 31% of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 58% of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 56% of 628 patients), anaemia (180 29%), and thrombocytopenia (75 12%) through complete treatment, and febrile neutropenia (88 15% of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 13% of 628 patients) and anaemia (20 3%).
Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer.
AbbVie.
Purpose
Adverse events (AE) during oncology clinical trials are typically reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which provides ...information about the frequency and severity of AEs from the provider’s perspective. Instruments that track patient-reported outcomes (PRO) complement the CTCAE and provide additional patient-centered information about the toxicity profile of an anti-cancer drug.
Methods
We conducted a single-arm, open-label phase II study of eribulin as first- or second-line therapy for metastatic hormone receptor-positive/HER2-negative (HR+/HER2−) or triple-negative breast cancer (TNBC). Patients were recruited simultaneously into each cohort by tumor subtype. The primary endpoint was overall response rate (ORR). Secondary endpoints included evaluation of toxicity by CTCAE and PRO instruments and agreement between CTCAE and PRO. The study also investigated single-nucleotide polymorphisms (SNPs) associated with treatment-induced neurotoxicity.
Results
83 patients were enrolled: 45 into the HR+/HER2− cohort and 38 into the TNBC cohort. The ORR was 35.6% (90% CI 24–39%) in the HR+/HER2− cohort and 13.2% (90% CI 5–26%) in the TNBC cohort. Stable disease as the best response was recorded in 55.1% of patients with HR+/HER2− disease and 60.5% with TNBC. Toxicity analysis revealed a discordance between CTCAE and PRO assessment in many patients, with a focus on fatigue, alopecia, and neuropathy. Pharmacogenomic analysis identified SNPs associated with treatment-induced peripheral neuropathy.
Conclusions
Eribulin is active in HER2− breast cancer. This study reveals that provider-assessed AEs can vary greatly from patient experiences. Future studies should incorporate CTCAE and PRO instruments to improve reporting of treatment-related AEs.
ClinicalTrials.gov Registration:
NCT01827787
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.
The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone ...receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS.
Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS.
Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11).
Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.
Background
The diagnosis of mixed invasive ductal and lobular carcinoma (IDC‐L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. ...With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC‐L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC‐L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes.
Materials and Methods
In this retrospective cohort study, we identified 811 patients diagnosed with early‐stage breast cancer with IDC‐L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan–Meier method and compared using the Cox proportional hazards model.
Results
Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2‐negative disease. Histologic grade was prognostic for patients with IDC‐L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC‐L had significantly better outcomes when compared with those with ILC: disease‐free survival (DFS) and overall survival (OS; adjusted hazard ratio HR, 0.54; 95% confidence interval CI 0.31–0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29–0.87), which was similar for both histologic types (p = .212).
Conclusion
IDC‐L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC‐L but not in ILC.
Implications for Practice
This study compared mixed invasive ductal and lobular carcinoma (IDC‐L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC‐L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow‐up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC‐L, thus highlighting its clinical utility to guide treatment decisions of IDC‐L. Finally, the disease‐free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC‐L.
摘要
背景。临床实践中混合浸润性导管和小叶癌 (IDC‐L) 的诊断通常与其预后和系统治疗反应相关的不确定性有关。随着人们日益认识到浸润性小叶癌 (ILC) 是一种独特的疾病亚型，围绕 IDC‐L 而产生的问题变得更加相关。在本次研究中，我们利用详细的临床数据库来比较 IDC‐L 和 ILC 的临床病理和治疗特征、组织学分级的预后能力以及生存预后。
材料和方法。在本次回顾性队列研究中，我们找到了 811 名被诊断为患有 IDC‐L 或 ILC 的早期乳腺癌患者。我们执行了描述性统计，以比较基线临床病理特征和治疗。随后，我们使用Kaplan–Meier分析方法对生存率进行了分析，并使用Cox比例风险模型进行了比较。
结果。ILC 患者患有更常见的多灶性疾病，组织学分级介于低级至中级之间，且为 HER2 阴性。组织学分级对 IDC‐L 患者而言是预后因素，但在 ILC 患者中没有显著的区分能力。在绝经后女性中，IDC‐L 患者的预后明显好于 ILC 患者:无病生存期 (DFS) 和总生存期 OS；校正风险比 (HR)，0.54；95% 置信区间 (CI) 0.31–0.95。最后，采用芳香化酶抑制剂治疗的绝经后女性在 DFS 和 OS 方面比仅采用他莫昔芬治疗的绝经后女性更好(OS 校正 HR，0.50；95% CI，0.29–0.87)，后一种治疗方式对这两种组织学类型而言效果相似 (p = 0.212)。
结论。IDC‐L 肿瘤的预后要好于 ILC 肿瘤，尤其在绝经后女性中更是如此。在 IDC‐L(而非 ILC)中，组织学分级是一个重要的预后因素。
实践意义:本研究将混合浸润性导管和小叶癌 (IDC‐L) 与浸润性小叶癌(ILC)进行对比，以评估总体预后、组织学分级的预后作用以及系统治疗的反应。研究发现，IDC‐L 肿瘤患者的预后要好于 ILC 患者，尤其在绝经后女性中更是如此，这可能会影响随访策略。此外，尽管组织学分级未能对 ILC 的风险进行分层，但是，它在 IDC‐L 中显示出重要的预后能力，因而突显其指导 IDC‐L 治疗决策的临床实用性。最后，辅助芳香化酶抑制剂在 ILC 中相对于他莫昔芬的无病生存期优势与在 IDC‐L 中的优势是一致的。
In this retrospective analysis, a large, detailed, and curated single center database was used to compare clinicopathologic features and outcomes between invasive lobular carcinoma and mixed invasive ductal and lobular carcinomas, focusing on the prognostic implications of histological grade and taking into consideration the differences in systemic therapies.
Summary Alterations of signal transduction pathways leading to uncontrolled cellular proliferation, survival, invasion, and metastases are hallmarks of the carcinogenic process. The ...phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the Raf/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are critical for normal human physiology, and also commonly dysregulated in several human cancers, including breast cancer (BC). In vitro and in vivo data suggest that the PI3K/AKT/mTOR and Raf/MEK/ERK cascades are interconnected with multiple points of convergence, cross-talk, and feedback loops. Raf/MEK/ERK and PI3K/AKT/mTOR pathway mutations may co-exist. Inhibition of one pathway can still result in the maintenance of signaling via the other (reciprocal) pathway. The existence of such “escape” mechanisms implies that dual targeting of these pathways may lead to superior efficacy and better clinical outcome in selected patients. Several clinical trials targeting one or both pathways are already underway in BC patients. The toxicity profile of this novel approach of dual pathway inhibition needs to be closely monitored, given the important physiological role of PI3K/AKT/mTOR and Raf/MEK/ERK signaling. In this article, we present a review of the current relevant pre-clinical and clinical data and discuss the rationale for dual inhibition of these pathways in the treatment of BC patients.
Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC): ILC differs from invasive ductal carcinoma (IDC) in its clinicopathological characteristics and ...responsiveness to systemic therapy. From the clinical standpoint, data suggest that ILC derives a distinct benefit from systemic therapy compared to IDC. In addition, comprehensive molecular analyses have been reported for ILCs, confirming that these tumors have specific genomic profiles compared to IDC. Despite these differences, clinical trials and practical clinical guidelines tend to treat BC as a single entity. Here we discuss these clinical and molecular data and their therapeutic implications.
Summary Background Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant ...trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. Methods We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Results Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 2% of 1703 patients) and the observation group (32 2% of 1698; p=0·55 Gray's test). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 57% of 227) than in the group given trastuzumab for 1 year (88 47% of 186; p=0·06 Gray's test). Most CNS relapses were symptomatic (189 87% of 217). Conclusion Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. Funding None.
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