Dose-Reduced Trastuzumab Emtansine: Active and Safe in Acute Hepatic Dysfunction

Breast cancer is the most common cancer in women worldwide. The majority of deaths attributed to breast cancer are a result of metastatic disease, and 30% of early breast cancers (EBC) will develop distant disease. The 5-year survival of patients with metastatic disease is estimated at 23%. Breast cancer subtypes continue to be stratified histologically on oestrogen, progesterone and human epidermal growth factor-2 (HER2) receptor expression. HER2-positive breast cancers represent 25% of all breast cancer diagnoses. The therapies available for metastatic breast cancer (MBC) are expanding, in particular within the field of HER2-positive disease, with the approval of trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (TDM-1). Recently, TDM-1 has been shown to improve progression-free survival in HER2 MBC when compared to capecitabine and lapatinib in clinical studies. Its main toxicities are deranged liver function tests and thrombocytopenia. There have also been cases of acute liver failure. Therefore, its use in acute hepatic dysfunction, to our knowledge, has been neither studied nor reported. We report a patient with progressive HER2-positive MBC who had previously responded to multiple HER2-targeted therapies that presented with acute hepatic dysfunction. She was treated with dose-reduced TDM-1 safely, with clear evidence of rapid biochemical, clinical and radiological response. This allowed dose escalation of TDM-1, and the patient maintains an ongoing response.Key Words: Human epidermal growth factor-2, Metastatic breast cancer, Hepatic dysfunction, Trastuzumab emtansine     

Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m², days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC.     

跨线曲妥珠单抗联合不同化疗方案治疗HER2阳性晚期乳腺癌的临床研究

目的 观察跨线曲妥珠单抗联合不同化疗方案治疗人表皮生因子受体2（human epidermal growth factor receptor 2, HER2）阳性晚期乳腺癌的疗效、不良反应和生存期。方法 收集2009年1月至2014年6月间应用跨线曲妥珠单抗（H）联合不同化疗方案治疗HER2阳性的晚期乳腺癌患者71例,均完成一线H治疗,30例患者疾病进展后继续二线H治疗,19例患者疾病再次进展后继续三线H治疗,主要观察疗效、不良反应、生存情况及预后分析。结果 一、二、三线治疗中,曲妥珠单抗联合紫杉类方案和联合非紫杉类方案相比在有效率（RR）和临床获益率（clinical benefit rate, CBR）方面差异均无统计学意义（P＞0.05）。一、二、三线治疗的中位无进展生存时间（PFS）和中位总生存时间（OS）分别为14、9、4月和26、39、53月,总的中位PFS为11月,总的中位OS为36月。一线治疗的PFS较二、三线治疗明显延长（P=0.000）,曲妥珠单抗持续应用至三线的中位OS较仅一线治疗的有延长（P=0.008）。全组患者的1、2、3年生存率分别为88%、66%、39%。71例患者中14例出现了17次心脏相关事件,1例患者因左心室射血分数（LVEF）下降至48%停止曲妥珠单抗治疗,无治疗相关性死亡发生。在OS的Log rank单因素分析中,术后淋巴结转移的个数、有无脑转移、治疗线数、一线治疗的PFS时间与OS有关（P=0.026, P=0.042, P=0.028, P=0.005）。在OS的多因素Cox比例风险模型分析中,治疗线数、有无脑转移、DFS和一线PFS时间为对OS有影响的独立因素（P=0.004,P=0.021, P=0.018, P=0.000）。结论 在HER-2阳性晚期乳腺癌治疗中,疾病进展后跨线曲妥珠单抗联合化疗的疗效优于未继续使用曲妥珠单抗的方案,曲妥珠单抗的跨线使用可以使患者持续获益,跨线曲妥珠单抗联合化疗的方案疗效确切,不良反应可以耐受,值得进一步研究。     

Dual HER2 Targeted Therapy With Pyrotinib and Trastuzumab in Refractory HER2 Positive Metastatic Colorectal Cancer: A Result From HER2-FUSCC-G Study

BackgroundDual-HER2 targeted therapy has led to a promising antitumor effect in HER2 positive cancers including gastrointestinal cancer. The present data focus on patients with HER2 positive colorectal cancer who received pyrotinib and trastuzumab after failure to standard second-line treatment.MethodsPatients diagnosed of HER2 positive refractory or metastatic colorectal cancer were enrolled to receive trastuzumab in combination with pyrotinib as third-line and beyond therapy. Trastuzumab was given as a loading dose at 8 mg/kg followed by 6mg/kg once every 3 weeks, and oral pyrotinib as 400 mg per day until progression. ORR was set as the primary endpoint. PFS and OS were set as a secondary endpoints. This trial is registered with Clinical Trial.gov, NCT04960943, and is ongoing.ResultsBetween February 2020 to December 2021, 16 patients including 14 with RAS wild-type status were enrolled in this cohort. ORR was 50.0% in the overall population, and 57.1% in RAS wild-type patients. At a median follow-up of 11.2 months, median PFS and OS were 7.53 and 16.8 months, respectively. The RAS/BRAF wild-type patients had prolonged survival (PFS: 7.53 vs. 1.63 months, P = .02; OS: NR vs.4.13 months, P = .001) compared with RAS/BRAF mutant patients. The most common treatment-emergent adverse event (TEAE) reported is diarrhea. Five (31.3%) patients reported grade 3 TEAEs, and no death was reported.ConclusionsTrastuzumab in combination with pyrotinib demonstrated encouraging antitumor activity that translated to prolonged survival benefit in HER2 positive refractory or mCRC patients who are RAS wild-type with acceptable tolerance.     

Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study

BackgroundThe development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC.Materials & MethodsData was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes.ResultsA total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02).ConclusionReal-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.     

Limited human epidermal growth factor receptor 2 discordance in metastatic breast cancer patients treated with trastuzumab,a population based study

BackgroundAccurate assessment of the human epidermal growth factor receptor 2 (HER2) in breast cancer is essential for proper treatment decisions. HER2 positivity confirmation rates in breast cancer trials by central testing pathology laboratories were reported to be approximately 85%. The aim of our study was to assess in a population based sample concordance of HER2 status in metastatic breast cancer (MBC) patients locally tested HER2 positive and treated with trastuzumab. Moreover cost-effectiveness of in situ hybridisation (ISH) in patients with an immunohistochemical score 3+ (IHC3+) was explored.MethodsMBC patients treated between 2005 and 2009 with trastuzumab-based therapy in North East Netherlands were identified by a survey of hospital pharmacies. Primary tumour samples were retested centrally for HER2 status using 1 immunohistochemical (IHC) method and two methods using ISH on tissue micro-arrays. Potential discordant patients were retested on whole tumour slides. HER2 positivity was defined as: (1) ISH amplification (according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice Guideline Update) and (2) when ISH failed an IHC score of 3+. Cost-effectiveness was estimated using potential ISH and treatment costs.ResultsHER2 status could be retested in 174 of 194 (90%) patients. The HER2 concordance rate was 87%. The 21 discordant patients were in the 67% due to primary HER2 testing with only IHC. Overall survival of HER2 discordant and concordant patients was not significantly different (18 versus 25 months, p = 0.131). Structural ISH in the case of IHC3+ has an estimated potential saving of €87,710 per 100 patients.ConclusionHER2 concordance in a population based study is comparable to those described in selected populations. Discordance is mostly due to testing with only IHC. ISH in the case of IHC3+ is cost-effective.     

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non–Small-Cell Lung Cancer: Study Protocol

The treatment outcome has been unsatisfactory for patients with non–small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer.     

Clinicopathologic Factors Associated With Response to Neoadjuvant Anti-HER2–Directed Chemotherapy in HER2-Positive Breast Cancer

BackgroundHER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2⁺ breast cancer.Patients and MethodsPatients with HER2⁺ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio.ResultsSmall tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses.ConclusionClinicopathologic features may help predict HER2⁺ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.     

Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

PurposeThe intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative.Patients and methodsIn part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens.ResultsIn part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6–12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2 = 6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3–9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy.ConclusionRepeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative.     

HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC,BIG 1-98 and TEAM with centrally determined HER2

BackgroundA meta-analysis of the effects of HER2 status, specifically within the first 2–3 years of adjuvant endocrine therapy, has the potential to inform patient selection for upfront aromatase inhibitor (AI) therapy or switching strategy tamoxifen followed by AI. The pre-existing standardisation of methodology for HER2 (immunohistochemistry/fluorescence in situ hybridization) facilitates analysis of existing data for this key marker.MethodsFollowing a prospectively designed statistical analysis plan, patient data from 3 phase III trials Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC), Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre Trial (TEAM)] comparing an AI to tamoxifen during the first 2–3 years of adjuvant endocrine treatment were collected and a treatment-by-marker analysis of distant recurrence-free interval-censored at 2–3 years treatment – for HER2 status × AI versus tamoxifen treatment was performed to address the clinical question relating to efficacy of ‘upfront’ versus ‘switch’ strategies for AIs.ResultsA prospectively planned, patient-level data meta-analysis across 3 trials demonstrated a significant treatment (AI versus tamoxifen) by marker (HER2) interaction in a multivariate analysis; (interaction hazard ratio [HR] = 1.61, 95% CI 1.01–2.57; p < 0.05). Heterogeneity between trials did not reach statistical significance. The HER2 negative (HER2−ve) group gained greater benefit from AI versus tamoxifen (HR = 0.70, 95% CI 0.56–0.87) than the HER2-positive (HER2+ve) group (HR = 1.13, 95% CI 0.75–1.71). However, the small number of HER2+ve cases (n = 1092 across the 3 trials) and distant recurrences (n = 111) may explain heterogeneity between trials.ConclusionsA patient-level data meta-analysis demonstrated a significant interaction between HER2 status and treatment with AI versus tamoxifen in the first 2–3 years of adjuvant endocrine therapy. Patients with HER2−ve cancers experienced improved outcomes (distant relapse) when treated with upfront AI rather than tamoxifen, whilst patients with HER2+ve cancers fared no better or slightly worse in the first 2–3 years. However, the small number of HER2+ve cancers/events may explain a large degree of heterogeneity in the HER2+ve groups across all 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded and warrant further exploration.     

Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer

Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S‐1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S‐1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF‐1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5‐year Relapse Free Survival (5y‐RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF‐1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF‐1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11–2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3‐positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.     

Prognostic value of tumour-infiltrating lymphocytes in small HER2-positive breast cancer

BackgroundThe standard treatment for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancer (BC) is still controversial. Our aim was to assess the prognostic role of tumour-infiltrating lymphocytes (TILs) in patients with stage pT1a–b HER2-positive BC.Patients and methodsHaematoxylin and eosin slides from node-negative, pT1a–b HER2-positive BC surgical specimens were retrieved from pathology archives to assess TILs and their association with outcome.ResultsTILs were evaluated in 205 patients with HER2-positive, pT1a–b tumours, who underwent breast surgery between 1997 and 2009 at the European Institute of Oncology. At a median follow-up of 11 years, we did not observe any association between the presence of TILs, either assessed as a continuous or dichotomous variable (<50 versus ≥ 50%), and outcome. Within the subgroup of patients with pT1a tumours who did not receive any adjuvant therapy (36/97 patients), the rate of disease-free survival events was lower in lymphocyte-predominant BC (LPBC) as compared with non-LPBC patients (p = 0.066).ConclusionsTILs cannot be used as a prognostic biomarker in pT1a–b HER2-positive BC. Additional biomarkers are needed for selecting patients with stage I HER2-positive BC who candidate to adjuvant therapy de-escalation.     

A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial

Purpose To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer. Patients and methods A total of 59 patients from 6 participating centers in Japan entered onto the study of trastuzumab and capecitabine. Eighty six percent of women had received prior chemotherapy as part of adjuvant (21.4%) or metastatic treatment (48.2%), or both (16.1%), including substantial portions of patients who had previously received either CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), or both types (25.0%) of chemotherapy. Results Responses were observed in 28 of 56 patients (overall response rate, 50%). The response rate was 65.0% in patients treated with trastuzumab and capecitabine as first-line therapy for metastatic disease, and 62.5% among HER2 +3 positive patients, while high response rates were also seen in women treated with second- or third-line therapy. Patients receiving trastuzumab and capecitabine as first-line therapy had a longer TTP than did patients receiving this treatment as second- or third-line therapy (median TTP, 280 vs. 130 days, P < 0.05). Further, patients receiving trastuzumab and capecitabine as first-line therapy had longer OS than did patients receiving this treatment as second- or third-line therapy (median OS, 780 days vs. 480 weeks, P < 0.05). The treatment-related adverse events were hand–foot syndrome (30.4%), nausea (25%), diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%), and vomiting (5.4%). However, the majority were Grade 1–2 adverse events and only six patients experienced Grade 3 adverse events. Further Grade 1 cardiac toxicity was observed in one patient, while there were no cases of alopecia and treatment-related death. Conclusion Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.     

Overview of the current status of human epidermal growth factor receptor inhibitors in lung cancer

Although chemotherapy remains the standard of care for lung cancer, new less toxic drugs are urgently needed. Targeted agents represent a new era in cancer therapy, and non-small-cell lung cancer (NSCLC) is at the forefront of many development programs. An exciting target is the human epidermal growth factor receptor (EGFR, ie, HER1), and agents targeting this receptor, including gefitinib, cetuximab, and erlotinib (OSI-774; Tarceva), are being investigated. These agents have antitumor activity and are less toxic than most therapies. Based on phase II data, gefitinib received US approval for third-line treatment of patients with locally advanced or metastatic NSCLC. Cetuximab is licensed in the United States for patients with metastatic colorectal carcinoma. However, erlotinib, recently approved in the United States for second- and third-line treatment of patients with locally advanced or metastatic NSCLC, is the only agent of this class to improve survival as monotherapy in patients with advanced, refractory NSCLC, as shown in a phase III placebo-controlled trial. Phase III trials of erlotinib and gefitinib combined with chemotherapy were disappointing, which could be the result of drug scheduling, chemotherapy combinations, or other factors. Patient characteristics may also affect outcome, and research is ongoing to identify predictive markers of response to enable patient selection and improve outcome. Recently identified mutations within the HER1/EGFR tyrosine kinase (TK) domain may provide insight into why some patients respond rapidly to HER1/EGFR tyrosine kinase inhibitors. Surrogate markers of efficacy are also being investigated, including rash, which could be used to monitor and optimize antitumor activity. Therefore, although more work is required, data indicate that HER1/EGFR inhibitors will play an important role in treating patients with NSCLC.     

Escalating and de-escalating treatment in HER2-positive early breast cancer

The current standard adjuvant systemic treatment of early HER2-positive breast cancer consists of chemotherapy plus 12 months of trastuzumab, with or without endocrine therapy. Several trials have investigated modifications of the standard treatment that are shorter and less resource-demanding (de-escalation) or regimens that aim at dual HER2 inhibition or include longer than 12 months of HER2-targeted treatment (escalation). Seven randomized trials investigate shorter than 12 months of trastuzumab treatment duration. The shorter durations were not statistically inferior to the 1-year duration in the 3 trials with survival results available, but 2 of the trials were small and 1 had a relatively short follow-up time of the patients at the time of reporting. The pathological complete response (pCR) rates were numerically higher in all 9 randomized trials that compared chemotherapy plus dual HER2 inhibition consisting of trastuzumab plus either lapatinib, neratinib, or pertuzumab with chemotherapy plus trastuzumab as neoadjuvant treatments, but the superiority of chemotherapy plus dual HER2-inhibition over chemotherapy plus trastuzumab remains to be demonstrated in the adjuvant setting. One year of adjuvant trastuzumab was as effective as 2 years of trastuzumab in the HERA trial, and was associated with fewer side-effects. Extending 1-year adjuvant trastuzumab treatment with 1 year of neratinib improved disease-free survival in the ExteNET trial, but the patient follow-up times are still short, and no overall survival benefit was reported. Several important trials are expected to report results in the near future and may modify the current standard.     

Prolonged time to progression with fulvestrant for metastatic breast cancer

Although the incidence of breast cancer has been declining in recent years, the disease is still one of the leading causes of cancer deaths in women. Recently, breast cancer has been treated with innovative approaches that use hormone-sensitive therapies. This is because in at least one-third of breast cancers, estrogens mediated via the estrogen receptor pathway act as endocrine growth factors. Fulvestrant has been studied as both first- and second-line therapy for locally advanced and metastatic breast cancer, but few studies have shown its effect as third-line therapy alone. To observe the disease time to progression (TTP) obtained with fulvestrant when used on metastatic breast cancer as first-, second-, and also third-line therapy. We also aimed to correlate the TTP obtained with fulvestrant with hormone receptor, HER2 expression, and metastatic site. This was a cohort study that retrospectively examined medical records of 73 postmenopausal women with advanced breast cancer who were treated with fulvestrant (250 mg/month i.m. injection) and followed at the Department of Medical Oncology at Hospital do Cancer A. C. Camargo in São Paulo, Brazil from August 2003 to December 2006. The median TTP with fulvestrant was about 11 months. When used as the first-line therapy, TTP was about 13 months; when used as second-line, TTP was about 6 months; and when used as third-line, it was about 12 months. No statistically significant difference was observed regarding the therapy line. In patients with positive ER tumors, TTP was 11 months. No significant difference in TTP was observed in negative ER tumors (TTP = 10 months). In patients with positive PgR tumors, TTP was 13 months and for negative PgR, TTP was 6 months (P = 0.008). According to the HER2 status, the TTP was 5 months for HER2+ and 10 months for HER2?. Our findings indicate that fulvestrant is an effective alternative for treatment of metastatic breast cancer.     

Safety and efficacy of trastuzumab every 3 weeks combined with cytotoxic chemotherapy in patients with HER2-positive recurrent breast cancer: findings from a case series

BACKGROUND: Trastuzumab has been repeatedly shown to result in significant clinical benefits and was subsequently accepted as the treatment of choice for HER2-positive advanced breast cancer - particularly as first-line treatment in combination with taxanes and as monotherapy in the second-line or third-line setting. Trastuzumab is currently licensed as a weekly treatment, although a 3-weekly schedule could be used conveniently in combination with other cytotoxic agents that are administered on a 3-weekly basis in metastatic breast cancer. PATIENTS AND METHODS: We determined the safety of i.v. trastuzumab (8 mg/kg followed by 6 mg/kg) every 3 weeks in combination with chemotherapeutic agents administered in 3-weekly courses (docetaxel, vinorelbine and capecitabine) in 31 patients with HER2-positive recurrent locoregional and/or metastatic breast cancer. RESULTS: 3-weekly trastuzumab appeared to be as well tolerated as the standard once-weekly schedule. All myelosuppressive adverse events and the majority of non-hematological adverse events were typical and characteristic of the individual concomitant cytotoxic agents. Transient trastuzumab-related infusion reactions occurred in 5 patients and 1 patient developed cardiac dysfunction, which recovered after discontinuation of trastuzumab. Efficacy appeared favourable: 18 clinical responses (3 complete and 15 partial) and 8 disease stabilizations gave an overall response rate of 58% (70% in the 20 patients receiving first-line therapy). Median progression-free and overall survival times were 9.9 months (95% CI: 6.3-13.5) and 23.1 months (95% CI: 19.2-27.0), respectively. CONCLUSIONS: These findings will likely encourage further evaluation of this more convenient 3-weekly trastuzumab regimen in patients with HER2-positive metastatic breast cancer.     

Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: A randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie

IntroductionHuman epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC.Materials and methodsPatients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1–21 plus capecitabine (CAP) 2000 mg/m² on days 1–14 of a 21-day cycle or LAP 1500 mg monotherapy day 1–21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms.Results37 pts were enrolled (18 to LAP + CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP + CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37–34.7), both in the LAP + CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38–61) days in the LAP group and 83 (95% CI: 42–86) days in the LAP + CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP + CAP (61%; 95% CI: 35–83) compared to 26% (95% CI 9–51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]).DiscussionLapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP + CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).     

The trichotomy of HER2 expression confers new insights into the understanding and managing for breast cancer stratified by HER2 status

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that plays a carcinogenic role in breast cancer (BC) through gene amplification, mutation, or overexpression. Traditional methods of HER2 detection were divided into positive (immunohistochemistry (IHC) 3+/fluorescence in situ hybridization (FISH) amplification) and negative (IHC 2+/FISH−, IHC 1+, IHC 0) according to the dichotomy method. Anti-HER2-targeted therapies, such as trastuzumab and pertuzumab, have significantly improved the prognosis of HER2-positive patients. However, up to 75% to 85% of patients remain HER2-negative. In recent years, with the rapid development of molecular biology, gene detection technology, targeted therapy, and immunotherapy, researchers have actively explored the clinicopathological characteristics, molecular biological characteristics, treatment methods, and HER2 detection methods of HER2-low/zero breast cancer. With the clinical efficacy of new anti-HER2 targeted drugs, accurate classification of breast cancer is very important for the treatment choice. Therefore, the following review summarizes the necessity of developing HER2 detection methods, and the clinicopathological and drug treatment characteristics of patients with HER2-low/zero, to light the dawn of the treatment of breast cancer patients with HER2-low/zero expression.     

Third-Line Chemotherapy in Small-Cell Lung Cancer: An International Analysis

IntroductionSmall-cell lung cancer is an aggressive disease for which the mainstay of treatment is chemotherapy. Despite good initial responses most patients will relapse. Some will receive second-line therapy with clinical benefit, but for third-line chemotherapy there is little evidence to guide treatment decisions and the benefits of treatment are unknown. This study investigated the treatment of SCLC in the third-line setting.Patients and MethodsAn international, multicenter retrospective analysis of patients who received at least 3 lines of chemotherapy for their SCLC was performed.ResultsFrom 2000 to 2010, 120 patients were identified from 5 centers: median age 61, 40% (n = 72) limited stage, and 79% (n = 95) Eastern Cooperative Oncology Group performance status of 0 to 1. Only 22% of these patients received 3 distinct lines of chemotherapy. The remainder were rechallenged with a chemotherapy regimen used at least once previously. Six percent received platinum-based chemotherapy in all 3 lines. In third-line, response rate was 18% and median overall survival was 4.7 months. Factors associated with longer survival included normal baseline LDH levels and response to second-line chemotherapy. On multivariate analysis only normal baseline LDH retained statistical significance. Thirty-five patients went on to receive chemotherapy beyond the third line.ConclusionFew SCLC patients receive 3 chemotherapy lines. Most patients were rechallenged with a similar regimen at least once. Response and survival in the third-line setting are modest. Lack of response to second-line chemotherapy and elevated baseline LDH level might predict lack of benefit from third-line treatment. This data set does not include patients receiving fewer lines for comparison.