目录
1. THE EVOLUTION AND PROGNOSTIC IMPACT OF HER2‐LOW, HER2‐ULTRALOW, AND HER2‐NULL STATUS IN HER2‐NEGATIVE EARLY BREASTCANCER: A PRE-TO POST-NEOADJUVANT CHEMOTHERAPY STUDY
HER2阴性早期乳腺癌中HER2低表达、超低表达和零表达（HER2-NULL）状态及其预后影响：新辅助化疗前后研究
(Cancer，IF=12.70 ）
2. PIK3CA MUTATIONS AND FIRST-LINE OUTCOMES IN ENDOCRINE-RESISTANT HR+/HER2- METASTATIC BREAST CANCER: A MULTICENTRIC REAL-WORLD STUDY.
PIK3CA突变与内分泌耐药的HR+/HER2-转移性乳腺癌一线治疗结果：一项多中心真实世界研究
(European Journal of Cancer，IF=10.005 ）
3. THE IMPACT OF BREAST CANCER TREATMENT ON SLEEP DISTURBANCE: A SYSTEMATIC REVIEW
系统性综述：乳腺癌治疗对睡眠障碍的影响
(Breast Cancer Research and Treatment，IF=3.60 ）
4.EXTENDED ENDOCRINE THERAPY FOLLOWING 5 YEARS OF ADJUVANT LUTEINIZING HORMONE-RELEASING HORMONE AGONIST IN PREMENOPAUSAL PATIENTS WITH NODE-POSITIVE, HORMONE RECEPTOR–POSITIVE BREAST CANCER: A COHORT STUDY
绝经前淋巴结阳性激素受体阳性乳腺癌患者完成5年辅助促黄体生成素释放激素激动剂治疗后延长内分泌治疗：一项队列研究
(Journal of Clinical Oncology，IF=41.90 ）
5. CHARACTERIZATION OF ESR1 ALTERATIONS IN PATIENTS WITH BREAST AND GYNECOLOGIC CANCERS
乳腺癌及妇科肿瘤患者ESR1变异特征分析
(Breast Cancer Research，IF=8.41 ）
6. SEQUENTIAL USE OF PI3K/AKT/MTOR PATHWAY INHIBITORS ALPELISIB AND EVEROLIMUS IN PATIENTS WITH HORMONE RECEPTOR-POSITIVE METASTATIC BREAST CANCER
PI3K/AKT/MTOR通路抑制剂阿培利司与依维莫司在激素受体阳性转移性乳腺癌患者中的序贯应用
(Breast Cancer Research，IF=8.41 ）
1. The evolution and prognostic impact of HER2‐low, HER2‐ultralow, and HER2‐null status in HER2‐negative early breastcancer: A pre-to post-neoadjuvant chemotherapy study
HER2阴性早期乳腺癌中HER2低表达、超低表达和零表达（HER2-null）状态及其预后影响：新辅助化疗前后研究
(Cancer，IF=12.70 ）
Abstract：
Background:The prognostic relevance of HER2‐low, HER2‐ultralow, and null status in HER2‐negative early breast cancer (eBC), and its evolution during neoadjuvant chemotherapy (NAC), remains unclear.
研究背景：在HER2阴性早期乳腺癌中，HER2低表达（HER2-low）、超低表达（HER2-ultralow）和零表达（null）状态的预后相关性以及在新辅助化疗（NAC）过程中HER2状态的关系尚不明确。
Methods:The authors analyzed 810 HER2‐negative eBC patients (2011–2021) with centrally confirmed pre‐ and post‐NAC HER2 status. Pathologic complete response (pCR, ypT0/is ypN0) rates were analyzed using logistic regression, and invasive disease‐free survival (iDFS) and overall survival (OS) were evaluated via multivariable Cox proportional hazards models.
研究方法：本研究分析了2011年至2021年间810例HER2阴性早期乳腺癌患者的中心确认的术前和术后化疗（NAC）HER2状态。通过逻辑回归分析病理完全缓解（pCR，ypT0/is ypN0）率，采用多变量Cox比例风险模型评估侵袭性无病生存期（iDFS）和总生存期（OS）。
Results:HER2‐null tumors demonstrated significantly higher rates of hormone receptor negativity, grade III histology, and Ki‐67 ≥20% compared to HER2‐low
subgroup (p < .05 for all). The pCR rates were 8.4% (HER2‐low), 20.4% (HER2‐ultralow), and 25.0% (HER2‐null), respectively. HER2 expression inversely correlatedwith pCR rates across the entire cohort (odds ratio, 0.75; 95% confidence interval [CI], 0.58–0.98; p for trend = .033). After a median follow‐up of 70.8 months, survival analysis indicated that higher HER2 expression was associated with significantly improved iDFS (hazard ratio, 0.72; 95% CI, 0.62–0.83) and OS (hazard ratio, 0.67; 95% CI, 0.57–0.80) in the overall population (p for trend <.001 for both). Following NAC, nearly 41.0% of baseline HER2‐null tumors converted to HER2‐low or ultralow status. Notably, post‐NAC HER2 status remained predictive of improved survival in patients with residual disease (iDFS, hazard ratio, 0.72; 95% CI, 0.62–0.84; OS, hazard ratio, 0.65; 95% CI, 0.55–0.78; p for trend <.001 for both).
研究结果：HER2-null肿瘤的HR-、III级组织学和Ki-67 ≥20%的比例显著高于HER2-low亚组（p < .05）。pCR率分别为8.4%（HER2-low），20.4%（HER2-ultralow）和25.0%（HER2-null）。在整个队列中，HER2表达与pCR率呈负相关（比值比，0.75；95%置信区间[CI]，0.58–0.98；趋势p=0.033）。在中位随访70.8个月后，生存分析表明，HER2表达较高与iDFS（风险比，0.72；95% CI，0.62–0.83）和OS（HR=0.67；95% CI，0.57–0.80）显著改善相关（趋势p < 0.001）。NAC后，近41.0%的HER2-null肿瘤转化为HER2-low或ultralow状态。值得注意的是，术后HER2状态在有残留疾病的患者中仍能预测生存改善（iDFS，风险比，0.72；95% CI，0.62–0.84；OS，HR=0.65；95% CI，0.55–0.78；趋势p <0.001）。
Conclusions:HER2 expression levels (low/ultralow/null) stratify prognosis in HER2‐negative eBC. The dynamic evolution of HER2 status following NAC and its prognostic utility highlights the importance of reassessing HER2 status in residual disease in HER2‐negative eBC.
研究结论：HER2表达水平（低/超低/无）可分层预测HER2阴性早期乳腺癌的预后。NAC后HER2状态的动态变化及其预后作用突出了在HER2阴性早期乳腺癌残留疾病中重新评估HER2状态的重要性。
2. PIK3CA mutations and first-line outcomes in endocrine-resistant HR+/HER2- metastatic breast cancer: A multicentric real-world study.
PIK3CA突变与内分泌耐药的HR+/HER2-转移性乳腺癌一线治疗结果：一项多中心真实世界研究
(European Journal of Cancer，IF=10.005 ）
Abstract：
Background:Outcomes and characteristics of endocrine-resistant, PIK3CA-mutated HR+ /HER2- advanced breast cancer patients in real-world are poorly investigated.
Here, we explored the role of circulating PIK3CA mutations in endocrine-resistant patients in the ongoing prospective, multicentric CHAMBER study.
研究背景：内分泌耐药的PIK3CA突变HR+/HER2-晚期乳腺癌患者在真实世界中的结局和特征尚未得到充分研究。
在此，我们探讨了前瞻性多中心CHAMBER研究中，PIK3CA突变在内分泌耐药患者治疗中的指导意义。
Methods:PIK3CA was analyzed by NGS panel covering the full exonic region of PIK3CA gene.
Endocrine resistance was defined as: i) primary: relapse during the first 2 years of adjuvant ET, or ii) secondary:
relapse after 2 years of starting or within 1 year of completing ET.
Overall survival (OS) was calculated from the start of first-line to death from any cause. Progression free survival1 (PFS1) was calculated from the start of first-line to progression or death.
研究方法：通过NGS分析PIK3CA，覆盖PIK3CA基因的全外显子区域。
内分泌耐药的定义为：i) 原发性：在辅助内分泌治疗（ET）开始后的前两年内复发，或ii) 继发性：在ET开始后两年或完成ET后一年内复发。
总生存期从一线治疗开始至任何原因的死亡计算。无进展生存期1（PFS1）从一线治疗开始至进展或死亡计算。
Results:Among the overall CHAMBER population, 22 % patients met the criteria for endocrine-resistance (74/337).
The study population consisted in 95 % women and 5 % men; median age at diagnosis was 50 years (IQR 44–63);75 % of the women was postmenopausal;86% of the total population presented with a secondary endocrineresistance,64 % had visceral relapse, 74 % had less than 3 metastatic sites, 79 % had received first-line
CDK4/6 inhibitor.
PIK3CA status was available for 63/74 pts, with a 29 % prevalence of mutation.
PIK3CAmut was a negative prognostic factor for OS (median 65 [wt] vs 36 months [mut], log-rank p 0.024 HR 2.61 [95 % CI 1.10–6.22]) and PFS1 (median 22 [wt] vs 10 months [mut], log-rank p 0.012, HR 2.24 [95 % CI 1.18–4.26]).
研究结果：在总体CHAMBER人群中，22%的患者符合内分泌耐药标准（74/337）。研究人群中，女性占95%，男性占5%；诊断时的中位年龄为50岁（四分位数范围44–63）；75%的女性为绝经后；86%呈继发性内分泌耐药；64%有内脏复发，74%有少于3个转移灶，79%接受了一线CDK4/6抑制剂治疗。PIK3CA状态在63/74名患者中可评估，PIK3CA突变率为29%。结果分析表明，PIK3CA突变是OS的不良预后因素（中位OS：野生型65个月 vs 突变型36个月，P=0.024，HR=2.61 [95% CI 1.10–6.22]），中位PFS1：野生型22个月 vs 突变型10个月，P=0.012，HR=2.24 [95% CI 1.18–4.26]。
Conclusions:The co-occurrence of endocrine-resistance and PIK3CAmut identifies a population with unfavorable prognosis, reinforcing the rationale of escalated therapies.
研究结论：内分泌耐药和PIK3CA突变或可圈定一个预后不良的群体，该结论可进一步支持采用强化治疗的合理性。
3. The impact of breast cancer treatment on sleep disturbance: a systematic review
系统性综述：乳腺癌治疗对睡眠障碍的影响
(Breast Cancer Research and Treatment，IF=3.60 ）
Abstract：
Background:People receiving treatment for breast cancer often report sleep disturbance. This systematic review explored the prevalence and impact of breast cancer treatment on sleep disturbance.
研究背景：接受乳腺癌治疗的患者常常报告睡眠障碍。本系统综述探讨了乳腺癌治疗对睡眠障碍的发生率和影响。
Methods:The Medline, Embase, CINAHL Plus with full text, Psych INFO, Cochrane Library/Central Register of Controlled Trials, and Scopus databases were searched up to December 2024. Eligible studies recruited people undergoing breast cancer treatment and reported the impact of treatment on their sleep. Two authors reviewed full-text publications for eligibility, data extraction, and quality appraisal. Demographics and sleep outcomes were summarised via descriptive statistics.
研究方法：我们检索了截至2024年12月的Medline、Embase、CINAHL Plus（含全文）、PsychINFO、Cochrane图书馆/对照试验中心注册库和Scopus数据库。纳入的研究对象是正在接受乳腺癌治疗，并报告了治疗对其睡眠的影响患者。作者对全文文献进行审查，以确定其是否符合纳入标准，后提取数据并进行质量评价。运用描述性统计方法对人口特征和睡眠结进行总结。
Results:Among the 32,119 studies identified, 80 met the eligibility criteria. Studies have used a variety of sleep assessment measures and thresholds to define sleep disturbance. The Pittsburgh Sleep Quality Index (PSQI) and actigraphy were the most frequently used, 63% and 24%, respectively. The mean prevalence of poor sleep quality (as per the PSQI) for each treatment was as follows: surgery, 63%;chemotherapy, 62%; radiation therapy, 64%; and endocrine therapy, 57%; and clinically significant insomnia (as per the Insomnia Severity Index) for surgery, 20%; chemotherapy, 24%; radiation therapy, 23%; and endocrine therapy, 35%. A significant increase in sleep disturbance related to cancer treatment was reported in 62% of the studies assessing chemotherapy, 39% assessing radiation therapy, 20% assessing endocrine therapy, and 17% assessing breast surgery.
研究结果：在检索到的32,119项研究中，有80项符合纳入标准。这些研究采用了多种睡眠评估方法和阈值来定义睡眠障碍。匹兹堡睡眠质量指数（PSQI）和活动记录仪的使用频率最高，分别为63%和24%。根据PSQI评估，各治疗方案中睡眠质量差的平均患病率如下：手术63%；化疗62%；放疗64%；内分泌治疗57%；根据失眠严重程度指数评估，各治疗方案中临床显著性失眠的平均患病率分别为：手术20%；化疗24%；放疗23%；内分泌治疗35%。在评估化疗的研究中，62%的研究报告了癌症治疗相关的睡眠障碍显著增加；在评估放疗的研究中，这一比例为39%；在评估内分泌治疗的研究中为20%；在评估乳腺手术的研究中为17%。
Conclusions:Sleep disturbance is reported in approximately 60% of people receiving treatment for breast cancer, with chemotherapy being the most studied treatment. The prevalence and severity of sleep disturbance vary across studies due to the heterogeneity of assessment tools used, and thresholds to define poor sleep. This highlights the need for a consistent method of assessing sleep disturbance and the need for effective strategies to improve sleep.
研究结论：据报道，约60%接受乳腺癌治疗的患者存在睡眠障碍，其中化疗是研究最多的治疗方法。由于评估工具和睡眠质量差的定义标准各不相同，不同研究中睡眠障碍的患病率和严重程度也存在差异。这凸显了建立一致的睡眠障碍评估方法以及制定有效改善睡眠策略的必要性。
4. Extended Endocrine Therapy Following 5 Years of Adjuvant Luteinizing Hormone-Releasing Hormone Agonist in Premenopausal Patients With Node-Positive, Hormone Receptor–Positive Breast Cancer: A Cohort Study
绝经前淋巴结阳性激素受体阳性乳腺癌患者完成5年辅助促黄体生成素释放激素激动剂治疗后延长内分泌治疗：一项队列研究
(Journal of Clinical Oncology，IF=41.90 ）
Abstract：
Background:To evaluate the clinical benefit of extended endocrine therapy (eET) after 5 years of adjuvant treatment with luteinizing hormone-releasing hormone agonists (LHRHa) in premenopausal women with node-positive, hormone receptor–positive early breast cancer (eBC).
研究背景：评估绝经前淋巴结阳性激素受体阳性早期乳腺癌（eBC）患者在接受5年辅助促黄体生成素释放激素激动剂（LHRHa）治疗后，延长内分泌治疗（eET）的临床获益。
Methods:We conducted a cohort study analysis on two prospectively collected data sets (the Young Women’s Breast Cancer Study and IEO Breast Cancer Cohort). Eligible patients were diagnosed with eBC at age ≤40 years (between 2005 and 2016), had node-positive, hormone receptor–positive disease, and remained premenopausal after 5 years of adjuvant LHRHa with no evidence of recurrence. The primary end point was invasive breast cancer–free survival (IBCFS), calculated from the sixth year after the initiation of adjuvant endocrine therapy (ET; study baseline), and adjusted through the propensity score (PS) weighting analysis.
研究方法：对两个前瞻性收集的数据集（年轻女性乳腺癌研究和IEO乳腺癌队列）进行了队列研究分析。符合条件的患者为2005年至2016年间确诊早期乳腺癌（eBC）且年龄≤40岁，患有淋巴结阳性、激素受体阳性疾病，并在完成5年辅助促黄体生成素释放激素激动剂（LHRHa）治疗后仍处于绝经前状态且无复发证据。主要终点为侵袭性乳腺癌无瘤生存期（IBCFS），自辅助内分泌治疗（ET）开始后第六年起计算（研究基线），并通过倾向性评分（PS）加权分析进行调整。
Results:A total of 501 patients were included in the analysis: 287 received eET for a median duration of 3.7 years (IQR, 2.3-5.0), including 48% tamoxifen monotherapy and 52% LHRHa plus tamoxifen or aromatase inhibitor. After a median follow-up of 7.3 years from the study baseline, the PS weighted IBCFS rates at 5 years were 85% in the eET group and 78% in the non-eET group (hazard ratio [HR], 0.63 [95% CI, 0.44 to 0.89]; P 5 .0135). The PS weighted distant recurrence-free survival rates at 5 years were 91% and 83% in the eET and non-eET group, respectively (cause specific HR, 0.49 [95% CI, 0.31 to 0.79]). In both groups, bone fractures and major cardiovascular events were reported in 1% of patients.
研究结果：共纳入501例患者进行分析：其中287例接受eET，中位持续时间3.7年（四分位距[IQR]，2.3-5.0年），包括48%他莫昔芬单药治疗和52% LHRHa联合他莫昔芬或芳香化酶抑制剂。自研究基线起中位随访7.3年，eET组和非eET组的5年PS加权侵袭性乳腺癌无瘤生存（IBCFS）率分别为85%和78%（风险比[HR]，0.63 [95%置信区间，0.44-0.89]；P = .0135）。eET组和非eET组的5年PS加权远处无复发生存率分别为91%和83%（疾病特异性HR，0.49 [95%置信区间，0.31-0.79]）。两组中骨折和主要心血管事件的发生率均为1%。
Conclusions:In this cohort study analysis, extending ET in premenopausal patients with node-positive eBC after 5 years of LHRHa treatment was associated with a clinically meaningful reduction in both invasive and distant breast cancer recurrences.
研究结论：本队列研究分析显示，对于5年LHRHa治疗后仍为绝经前状态的淋巴结阳性早期乳腺癌患者，延长内分泌治疗与侵袭性及远处乳腺癌复发率的具有临床意义的降低相关。
5.Characterization of ESR1 alterations in patients with breast and gynecologic cancers
乳腺癌及妇科肿瘤患者ESR1变异特征分析
(Breast Cancer Research，IF=8.41 ）
Abstract：
Background:ESR1 alterations present a common mechanism of resistance to endocrine therapy (ET) in hormonally driven tumors. The clinical significance of these alterations continues to evolve with newly approved targeted therapies and a range of ongoing investigational trials.
研究背景：ESR1变异是激素驱动型肿瘤对内分泌治疗（ET）产生耐药的常见机制。随着新批准的靶向治疗和多项正在进行的研究试验，ESR1变异的临床意义仍在不断发展。
Methods:A retrospective study of 2,574 breast cancer (BC) and 1,110 gynecologic cancer samples that underwent whole exome and whole transcriptome profiling was conducted to assess the distribution of ESR1 and associated co-alterations in local (primary breast or regional lymph node) versus metastatic BC samples and in the major BC subtypes. Prior treatment history was unknown.
研究方法：本研究回顾性分析了2,574例乳腺癌（BC）和1,110例妇科肿瘤样本，均进行了全外显子组和全转录组测序，以评估ESR1及相关共变异在局部（原发乳腺或区域淋巴结）与转移性乳腺癌样本及主要乳腺癌亚型中的分布。既往治疗史未知。
Results:ESR1 alterations were present in 6.2% (n=159/2,574) of BC samples and 3.4% (n=38/1,110) of gynecologic cancer samples. In HR+/HER2- BC, ESR1alterations overall and ESR1 missense mutations were more frequent in samples from metastatic compared to local/regional sites (overall: n=86/321 (26.8%) and n=53/1,427 (3.7%), respectively (P<0.001); missense: n=72/321 (22.4%) and n=20/1,427 (1.4%), respectively (P<0.001)). Whole transcriptome sequencing detected ESR1 fusion genes in 2.1% (n=55/2,574) of BC samples and in 1.9%(n=21/1,110) of gynecologic cancer samples, and CCDC170 was the most common fusion partner in both cancer types. In HR+/HER2- BC, ESR1 fusions were more common in metastatic samples compared to local/regional (n=17/321 (5.3%) and n=29/1,427 (2.0%), respectively; P<0.001). Evaluation of 21 therapeutically actionable biomarkers identified co-alterations enriched in ESR1-altered HR+/HER2- BC, including FGF3/4/19 and CCND1 amplifications. No significant co-alterations were found in gynecologic cancer samples.
研究结果：ESR1变异在6.2%（n=159/2,574）的乳腺癌样本和3.4%（n=38/1,110）的妇科肿瘤样本中检出。在HR+/HER2-乳腺癌中，ESR1总体变异及ESR1错义突变在转移性样本中较局部/区域样本更为常见（总体：n=86/321（26.8%）与n=53/1,427（3.7%），P<0.001；错义突变：n=72/321（22.4%）与n=20/1,427（1.4%），P<0.001）。全转录组测序在2.1%（n=55/2,574）的乳腺癌样本和1.9%（n=21/1,110）的妇科肿瘤样本中检测到ESR1融合基因，CCDC170是两类肿瘤中最常见的融合伴侣。在HR+/HER2-乳腺癌中，ESR1融合在转移性样本中较局部/区域样本更为常见（n=17/321（5.3%）与n=29/1,427（2.0%），P<0.001）。对21个具有治疗意义的生物标志物评估发现，ESR1变异的HR+/HER2-乳腺癌中富集了FGF3/4/19和CCND1扩增等共变异。妇科肿瘤样本中未发现显著共变异。
Conclusions:ESR1 alterations were most frequent in HR+/HER2- BC samples and missense mutations were more frequent in metastatic samples, consistent with their role in ET resistance and disease progression. ESR1 alterations co-occurred with therapeutically relevant alterations in other genes that may help inform clinical decision-making. Gynecologic tumors harbored ESR1 alterations that have prognostic and potentially therapeutic relevance.
研究结论：ESR1变异在HR+/HER2-乳腺癌样本中最为常见，且错义突变在转移性样本中更为频繁，符合其在ET耐药和疾病进展中的作用。ESR1变异常与其他具有治疗意义的基因变异共存，有助于临床决策。妇科肿瘤中ESR1变异具有预后及潜在治疗相关性。
6. Sequential use of PI3K/AKT/mTOR pathway inhibitors alpelisib and everolimus in patients with hormone receptor-positive metastatic breast cancer
PI3K/AKT/mTOR通路抑制剂阿培利司与依维莫司在激素受体阳性转移性乳腺癌患者中的序贯应用
(Breast Cancer Research，IF=8.41 ）
Abstract：
Background:Everolimus, an mTOR inhibitor, is FDA-approved with endocrine therapy (ET) for hormone receptor-positive (HR+)/HER2- MBC regardless of PI3K/AKT/mTOR pathway mutation status. Alpelisib, a PI3K inhibitor, is FDA-approved with fulvestrant for PIK3CA-mutant HR+/HER2- MBC. The efficacy and safety of sequential treatment with these pathway inhibitors is not well described.
研究背景：依维莫司作为mTOR抑制剂，已获FDA批准联合内分泌治疗（ET）用于激素受体阳性（HR+）/HER2-转移性乳腺癌（MBC），不论PI3K/AKT/mTOR通路突变状态。阿培利司作为PI3K抑制剂，已获FDA批准联合氟维司群用于PIK3CA突变型HR+/HER2- MBC。关于这两类通路抑制剂序贯治疗的疗效与安全性，目前尚缺乏系统描述。
Methods:
This single-center observational study identified patients with PIK3CA-mutant HR+/HER2- MBC treated with everolimus and alpelisib sequentially from 2012-2023. We abstracted patient, tumor, and treatment information from medical records. Patients treated first with everolimus then alpelisib were categorized as Group 1 and those treated first with alpelisib then everolimus as Group 2. Median time to treatment failure on 1st pathway inhibitor (TTF1) and TTF on 2nd pathway inhibitor (TTF2) were computed using the Kaplan-Meier method.
研究方法：
本单中心观察性研究纳入2012-2023年间接受依维莫司和阿培利司序贯治疗的PIK3CA突变型HR+/HER2- MBC患者。通过病历收集患者、肿瘤及治疗相关信息。先用依维莫司后用阿培利司者归为1组（Group 1），先用阿培利司后用依维莫司者归为2组（Group 2）。采用Kaplan-Meier法计算首个通路抑制剂治疗失败时间（TTF1）及第二个通路抑制剂TTF（TTF2）
Results:115 patients were included, with 63 (55%) in Group 1 and 52 (45%) in Group 2. Median age was 61 and 53% of patients had visceral disease. Patients received a median 3 prior lines of metastatic treatment (interquartile range [IQR] 2-4.5) and 71% received prior CDK4/6 inhibitor; more patients in Group 2 received prior CDK4/6 inhibitor than Group 1 (87% vs. 59%, p=0.001). In Group 1, 50 (79%) patients discontinued everolimus for progression and 13 (21%) for toxicity. In Group 2, 33 (63%) patients discontinued alpelisib for progression and 19 (37%) for toxicity. Median TTF1 was 9.2 months (95%CI 5.5-12) in Group 1 and 9.7 months (95%CI 7.1-14) in Group 2 (p=0.5, Figure 1, left). In patients who received prior CDK4/6 inhibitor, median TTF1 was 4.3 months (95%CI 3.2-11) in Group 1 and 8.7 months (95%CI 6.4-12) in Group 2 (p=0.02). In univariable Cox proportional hazards analyses, factors associated with worse TTF1 included prior CDK4/6 inhibitor use and more prior lines of treatment; these remained significant in multivariable analyses. After adjusting for prior CDK4/6 inhibitor use and prior total/intervening lines of therapy, TTF1 was not significantly different between groups (p=0.2), nor was TTF2 (p=0.1). Presence of GATA3 mutation was significantly associated with poorer alpelisib-specific TTF (p=0.016).
研究结果：共纳入115例患者，1组63例（55%），2组52例（45%）。中位年龄61岁，53%有内脏转移。患者既往接受中位3线转移性治疗（四分位距2-4.5），71%曾用CDK4/6抑制剂；2组中CDK4/6抑制剂使用比例高于1组（87% vs. 59%，p=0.001）。1组中，79%因疾病进展停用依维莫司，21%因毒性停药；2组中，63%因进展停用阿培利司，37%因毒性停药。1组TTF1中位9.2个月（95%CI 5.5-12），2组TTF1中位9.7个月（95%CI 7.1-14）（p=0.5）。既往用过CDK4/6抑制剂者，1组TTF1中位4.3个月（95%CI 3.2-11），2组TTF1中位8.7个月（95%CI 6.4-12）（p=0.02）。单变量Cox分析显示，既往CDK4/6抑制剂使用及既往治疗线数增加与TTF1较差相关，多变量分析中仍显著。调整上述因素后，TTF1及TTF2两组间无显著差异（TTF1 p=0.2，TTF2 p=0.1）。GATA3突变与阿培利司TTF显著较差相关（p=0.016）。
Conclusions: Prior CDK4/6 inhibitor use was associated with worse TTF1 and TTF2. There were no significant differences in TTF1 nor in TTF2 between Groups 1 & 2 after adjusting for clinical predictors. Given the recent approvals of capivasertib and inavolisib,prospective studies testing optimal sequencing of pathway agents with integration of biomarker analysis are needed.
研究结论：既往CDK4/6抑制剂使用与TTF1和TTF2较差相关。调整临床预测因素后，两组间TTF1和TTF2无显著差异。鉴于capivasertib和inavolisib等新药获批，未来需前瞻性研究整合生物标志物分析，探索通路抑制剂的最佳序贯策略。
