Abstract
Background
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive ...(HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups.
Methods
We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP).
Results
Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio HR = 0.68, 95% confidence interval CI = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%).
Conclusions
CDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.
ALPHABET is a randomized phase III trial assessing alpelisib + trastuzumab with or without fulvestrant in previously treated HER2-positive
-mutated advanced breast cancer. Patients will be included ...in two cohorts according to hormone receptor (HR) status. In the experimental arms, patients in the HR-negative cohort will receive trastuzumab + alpelisib, and patients in the HR-positive cohort will receive the same treatment plus fulvestrant. Patients in the control arms will receive trastuzumab + physician's choice chemotherapy (eribuline, capecitabine or vinorelbine). Key eligibility criteria include 1-4 previous lines of anti-HER2 therapy and prior trastuzumab emtansine. The primary end point is investigator-assessed progression-free survival. The study aims to recruit a total of 300 patients.
Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer ...(BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes.
We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil CMF or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years.
There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018).
In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 ...DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n = 294) or anthracycline (n = 210). We independently assessed estrogen receptor (ER)‐positive/HER2‐negative, HER2‐positive, and ER‐negative/HER2‐negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty‐two genes were consistently overexpressed in ER‐negative tumors, and five genes were overexpressed in ER‐positive tumors, but no differences in expression were associated with HER2 status. In ER‐positive/HER2‐negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment‐specific manner. In ER‐negative/HER2‐negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline‐treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2‐positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA‐damaging agents.
摘要
DNA 修复通路可使肿瘤细胞幸免于化疗所引起的 DNA 损害，因而具有重要的预后和/或预测价值。我们在未经治疗的乳腺癌 (BC) 患者 (n =684) 和接受过新辅助化疗方案包含紫杉烷/蒽环类 (n =294) 或蒽环类 (n =210) 的 BC 患者中评估了 145 种 DNA 修复基因的 Affymetrix 基因表达谱。我们分别评估了雌激素受体 (ER)‐阳性/HER2‐阴性、HER2‐阳性以及 ER‐阴性/HER2‐阴性乳腺癌亚组的 DNA 修复基因差异表达情况、双峰分布情况以及预后和预测价值。ER‐阴性肿瘤有 22 个基因一致性过表达，ER‐阳性肿瘤有 5 个基因过表达，但是 HER2 的状态并未导致基因表达的差异。在 ER‐阳性/HER2‐阴性肿瘤中，有九个基因（BUB1、FANCI、MNAT1、PARP2、PCNA、POLQ、RPA3、TOP2A 和 UBE2V2）的表达提示预后不良，有 1 个基因 (ATM) 的表达提示预后良好。此外，特定基因的预后价值与增殖并不存在相互关联。有几个基因与化疗应答存在关联，而且该应答因 BC 亚型和化疗类型而异。在 ER‐阴性/HER2‐阴性肿瘤中，MSH2、MSH6 和 FAN1 基因（以前称作 MTMR15）的表达在接受紫杉烷/蒽环类治疗的患者中提示与病理完全缓解和残余侵袭性癌相关。相反，PMS2 的表达在接受蒽环类单剂治疗的患者中提示残余侵袭性癌。在 HER2‐阳性肿瘤中，TOP2A 的表达提示患者可对蒽环类产生应答，但对紫杉烷/蒽环类联合化疗方案无应答。在呈双峰表达的基因中，RECQL4 与临床预后存在显著关联。体外研究表明，RECQL4 的缺陷可影响同源重组，使得 BC 细胞更容易受到 DNA 损伤剂的破坏。The Oncologist 2013;18:1063–1073
DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. In this study, the authors sought to assess the differential expression, bimodal distribution, and prognostic and predictive role of DNA repair genes in individual breast cancer molecular subtypes including estrogen receptor‐positive/ HER2‐negative, estrogen receptor‐negative/HER2‐negative, and HER2‐positive cancers. The predictive value of DNA repair gene expression was assessed in breast cancer patients treated with neoadjuvant taxane/anthracycline‐ or anthracycline‐containing regimens, and gene set analyses were performed by grouping DNA repair genes according to biological pathways.
The 14th St Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer. Further experience has supported the ...adequacy of tumor margins defined as ‘no ink on invasive tumor or DCIS’ and the safety of omitting axillary dissection in specific cohorts. Radiotherapy trials support irradiation of regional nodes in node-positive disease. Considering subdivisions within luminal disease, the Panel was more concerned with indications for the use of specific therapies, rather than surrogate identification of intrinsic subtypes as measured by multiparameter molecular tests. For the treatment of HER2-positive disease in patients with node-negative cancers up to 1 cm, the Panel endorsed a simplified regimen comprising paclitaxel and trastuzumab without anthracycline as adjuvant therapy. For premenopausal patients with endocrine responsive disease, the Panel endorsed the role of ovarian function suppression with either tamoxifen or exemestane for patients at higher risk. The Panel noted the value of an LHRH agonist given during chemotherapy for premenopausal women with ER-negative disease in protecting against premature ovarian failure and preserving fertility. The Panel noted increasing evidence for the prognostic value of commonly used multiparameter molecular markers, some of which also carried prognostic information for late relapse. The Panel noted that the results of such tests, where available, were frequently used to assist decisions about the inclusion of cytotoxic chemotherapy in the treatment of patients with luminal disease, but noted that threshold values had not been established for this purpose for any of these tests. Multiparameter molecular assays are expensive and therefore unavailable in much of the world. The majority of new breast cancer cases and breast cancer deaths now occur in less developed regions of the world. In these areas, less expensive pathology tests may provide valuable information. The Panel recommendations on treatment are not intended to apply to all patients, but rather to establish norms appropriate for the majority. Again, economic considerations may require that less expensive and only marginally less effective therapies may be necessary in less resourced areas. Panel recommendations do not imply unanimous agreement among Panel members. Indeed, very few of the 200 questions received 100% agreement from the Panel. In the text below, wording is intended to convey the strength of Panel support for each recommendation, while details of Panel voting on each question are available in supplementary Appendix S2, available at Annals of Oncology online.
Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene ...mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel.
The prognostic and predictive values of TP53 were analyzed in tumor samples by gene sequencing within exons 5 to 8. Patients were classified according to p53 protein status predicted from TP53 gene sequence, as wild-type (no TP53 variation or TP53 variations which are predicted not to modify p53 protein sequence) or mutant (p53 nonsynonymous mutations). Mutations were subcategorized according to missense or truncating mutations. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome.
TP53 gene status was determined for 18% (520 of 2887) of the women enrolled in BIG 02-98. TP53 gene variations were found in 17% (90 of 520). Nonsynonymous p53 mutations, found in 16.3% (85 of 520), were associated with older age, ductal morphology, higher grade and hormone-receptor negativity. Of the nonsynonymous mutations, 12.3% (64 of 520) were missense and 3.6% were truncating (19 of 520). Only truncating mutations showed significant independent prognostic value, with an increased recurrence risk compared to patients with non-modified p53 protein (hazard ratio = 3.21, 95% confidence interval = 1.740 to 5.935, P = 0.0002). p53 status had no significant predictive value for response to docetaxel.
p53 truncating mutations were uncommon but associated with poor prognosis. No significant predictive role for p53 status was detected.
ClinicalTrials.gov NCT00174655.
Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy.
Experimental Design: In available breast cancer tissue from EGF30001 ...(paclitaxel ± lapatinib in HER-2-negative/unknown metastatic breast cancer,
n = 579) and EGF100151 (capecitabine ± lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry
(IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with
clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial
reference laboratory.
Results: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation ( P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA
levels by RT-PCR ( r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival;
P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2
mRNA expression correlated with HER-2 FISH ( r = 0.83) and IHC status ( r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2
status. Although a significant correlation with lapatinib responsiveness was observed among “HER-2-negative” breast cancer
patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research
laboratory.
Conclusions: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast
cancer derive no incremental benefit from lapatinib.
Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme ...activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.
A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative ...metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26-41% and 12-27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60-0.65 vs. HR range for single agent ET: 0.59-1.37; OS HR range for combinations: 0.74-0.87 vs. HR range for single agent ET: 0.68-0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (
= 0.63) and endocrine sensitive disease (
= 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.
Abstract Current international guidelines recommend endocrine therapy as the initial treatment of choice in hormone receptor positive advanced breast cancer. Endocrine therapy has been a mainstay of ...hormone responsive breast cancer treatment for more than a century. To date it is based on different approaches,such as blocking the estrogen receptor through selective receptor estrogen modulators, depleting extragonadal peripheral estrogen synthesis by aromatase inhibitors or inducing estrogen receptor degradation using selective down-regulators. Despite estrogen and/or progesterone receptor positive status, up to a quarter of patients could be either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Different mechanisms, either intrinsic or acquired, could be implicated in endocrine resistance. In the present work available endocrine therapies and their appropriate sequences have been reviewed, and the most promising strategies to overcome endocrine resistance have been highlighted.
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