Central nervous system metastases in a cohort of metastatic breast cancer patients treated with trastuzumab

Background  Several analyses suggest an increase of brain metastases in HER2 over-expressing breast cancers treated with trastuzumab as compared to historical series of unselected patients. Patients and methods  We analyzed the incidence of central nervous system (CNS) metastases in 78 patients with HER2 over-expressing breast cancer treated with trastuzumab between July 2000 and June 2006 at the Oncology Department of University Federico II in Naples. We also characterized and compared patients with and without CNS involvement. Results  The median follow-up was 35.3 months (95%CI 26.3–44); median overall survival was 56 months (95%CIs 46-nr); 5 patients showed CNS involvement before trastuzumab therapy while 31 developed CNS metastases during trastuzumab treatment. The median overall survival after CNS metastases was 25.4 months (95%CIs 15.2-nr); patients with CNS lesions showed worse overall survival than patients without CNS lesions (39.1 vs. 75 months, p = 0.005). Conclusion  CNS metastases are common events in patients with metastatic HER2 over-expressing breast cancer treated with trastuzumab; the impact on survival is detrimental even if survival after CNS metastases is longer than historical reports. Appropriate investigation of the role of CNS imaging screening and the prophylactic treatment strategies for CNS represents a priority research in this setting. E. Montagna and G. Cancello have contributed equally to this work.     

Brain metastases from breast cancer: proposition of new prognostic score including molecular subtypes and treatment

To develop a specific prognostic score for patients with brain metastases (BM) from breast cancer (BC), including the BC molecular subtype and treatment parameters, we analyzed the outcome of 130 patients with BM from BC who received whole-brain radiotherapy. We identified hierarchical risk groups for estimated survival by using recursive partitioning analysis (RPA). Seven prognostic factors, namely performance status, age, trastuzumab-based therapy for HER-2-overexpressing tumors, a triple-negative phenotype, Scarff-Bloom-Richardson grade, the serum LDH level and the lymphocyte count at BM diagnosis, were incorporated in the RPA. The final RPA nodes were grouped according to the survival time. The RPA tree showed that survival was best (median 19.5 months) among patients with HER2-overexpressing tumors who received trastuzumab-based therapy. The worst survival (median 3.5 months) was observed among patients who did not receive trastuzumab and who had lymphopenia at BM diagnosis, or KPS <70 and age over 50 years, or KPS ≥70 and a triple-negative tumor (HR− & HER-2−). The other patients had a median survival of 12.5 months (P < 0.001). This 3-class specific prognostic score successfully predicted the outcomes of a heterogeneous group of patients with brain metastases from BC.     

HER2-positive Breast Cancer Brain Metastases: Multiple Responses to Systemic Chemotherapy and Trastuzumab—a Case Report

Brain metastases from metastatic breast cancer typically occur in 10–15% of patients and are associated with survival of 3–6 months. Recent series have shown that women with HER2-postive metastatic breast cancer receiving the drug trastuzumab develop brain metastases more frequently than this, but also that continuation of trastuzumab after diagnosis of brain metastases in such patients is associated with extended survival. Authors have speculated that this is due to improved systemic control of disease; however, a possibility is that trastuzumab may have a beneficial effect on cerebral metastases themselves. We report the case of a woman with HER2-positive metastatic breast cancer who developed multiple brain metastases while on trastuzumab, in whom the addition of systemic chemotherapy to continued trastuzumab has produced multiple treatment responses associated with prolonged survival. This is the first report of its kind.     

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood–brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.     

Management of patients with brain metastases receiving trastuzumab treatment for metastatic breast cancer

Background: With the more effective control of visceral metastases in patients with metastatic breast cancer (MBC), an increasing number of patients face brain metastases (BM). The aim of this retrospective analysis was to investigate the incidence and factors affecting the prognosis of patients with BM under trastuzumab treatment for MBC. Patients and Methods: A total of 75 HER2positive patients treated with trastuzumab for MBC were included. Results are discussed in the context of the current literature. Results: Patients who developed BM (n = 29) had longer median progression-free survival (PFS) during first-line chemotherapy and longer overall survival (OS) after diagnosis of MBC than 46 patients without BM (PFS: 27 vs. 14 months, p = 0.039; OS: 46 vs. 18 months, p = 0.067). Median survival of patients with continuation of trastuzumab after diagnosis of BM was longer than survival of patients with discontinuation of trastuzumab treatment after BM (18 vs. 3 months, p = 0.006). Survival of patients who were treated with surgery and radiotherapy for BM was better compared with radiotherapy alone (9 vs. 5 months, p = not significant) or best supportive care (9 vs. 2 months, p = 0.049). Conclusions: Continuation of trastuzumab treatment as well as resection of BM seem to give further benefit in the treatment of patients with HER2-overexpressing MBC.     

Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab

We aim to investigate the incidence, patterns and timing of brain metastases in advanced breast cancer patients who have previously received trastuzumab. Eighty-seven patients who had received trastuzumab for advanced breast cancer from November 1999 to September 2003 at the Royal Marsden Hospital were assessed. With a median follow-up period of 11 months from commencing trastuzumab, 23 patients developed brain metastases (30% at 1 year; 95% CI 58-82%). Among 57 patients who had clinical benefits on trastuzumab, 12 (21%) patients developed first disease progression in brain with 75% of them had isolated CNS progression. Moreover, among patients who received trastuzumab as first line treatment, isolated brain metastases were the initial site of progression in 17% patients. Nearly all patients developed parenchymal brain disease. This study shows brain metastases are common phenomenon in HER2 positive advanced breast cancer patients receiving trastuzumab and also may implicate the brain as a sanctuary site for early relapse in this patient cohort.     

Triple-negative breast cancer with brain metastases: a comparison between basal-like and non-basal-like biological subtypes

The aim of this study was to divide the group of triple-negative breast cancer patients with brain metastases into basal-like and non-basal-like biological subtypes in order to compare clinical features and survival rates in those two groups. A comprehensive analysis of 111 consecutive triple-negative breast cancer patients with brain metastases treated in the years 2003–2009 was performed. In 75 patients, immunohistochemistry was used as a surrogate of microarray in order to evaluate the expression of three basal markers: cytokeratin 5/6 (CK 5/6), EGFR/HER1 and c-KIT. The basal-like (ER/PgR/HER2-negative, CK5/6positive and/or HER1-positive) and non-basal-like (ER/PgR/HER2-negative, CK5/6-negative, HER1-negative) subsets were selected. Clinical features and survivals were compared in both groups. In the group of 111 triple-negative breast cancer patients, median DFS, OS and survival from brain metastases were 20, 29 and 4 months, respectively. In 75 patients who were evaluable for basal markers, median DFS, OS and survival from brain metastases were 18, 26 and 3.2 months, respectively. In the basal-like subtype, the survival rates were 15, 26 and 3 months, respectively, and in the non-basal-like subtypes, they were 20, 30 and 2.8 months, respectively. No statistically significant differences in survivals were detected between the basal-like and non-basal-like biological subtypes. Factors influencing survival from brain metastases were: Karnofsky performance status (KPS), the status of extracranial disease and age. Biological markers differentiating triple-negative group into basal-like and non-basal-like subtype (CK 5/6, HER1, c-KIT) had no influence on survival. In patients with triple-negative breast cancer and brain metastases, well-known clinical, but not molecular, features correlated with survival.     

Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study

BACKGROUND: The optimal trastuzumab-based chemotherapy regimen for HER2-overexpressing, metastatic breast cancer is not known. The trastuzumab and vinorelbine or taxane (TRAVIOTA) study was a prospective, multicenter, randomized trial that was designed to compare these regimens. METHODS: Eligible patients had HER2-overexpressing, metastatic breast cancer and had received no prior chemotherapy for advanced disease. Patients were randomized 1:1 to receive either trastuzumab with weekly vinorelbine therapy or weekly taxane therapy (paclitaxel or docetaxel at the investigator's choice). Originally planned for 250 patients, the study was closed because of poor accrual with 81 evaluable patients, including 41 patients who received vinorelbine and 40 patients who received taxane. RESULTS: Response rates were 51% and 40% for the vinorelbine/trastuzumab arm and the taxane/trastuzumab arm, respectively (Fisher exact test; P = .37). The median time to disease progression was 8.5 months and 6.0 months for the vinorelbine- and taxane-based arms, respectively (log-rank test; P = .09). Treatment with either regimen generally was well tolerated, yielding comparable rates of neurologic and gastrointestinal toxicity. Vinorelbine-based treatment was associated with more anemia and neutropenia and with 2 episodes of cardiotoxicity. Taxane-based therapy was associated with more dermatologic toxicity, myalgias, and fluid retention. CONCLUSIONS: Both vinorelbine/trastuzumab and taxane/trastuzumab treatments were active as first-line therapy for HER2-positive, metastatic breast cancer and had comparable rates of efficacy and tolerability. The toxicities observed were the result of recognized side effects associated with each of the chemotherapy agents and schedules. These data can inform treatment decision making in this clinical setting.     

Defining prognosis for women with breast cancer and CNS metastases by HER2 status

BackgroundThe purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease.MethodsFive hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics.ResultsIn the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.ConclusionIn our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.     

Phase 2, Multicenter,Single-Arm Study of Eribulin Mesylate With Trastuzumab as First-Line Therapy for Locally Recurrent or Metastatic HER2-Positive Breast Cancer

BackgroundThe aim of this study was to assess efficacy and safety of eribulin with trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ breast cancer.Patients and MethodsIn this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2+ breast cancer received eribulin mesylate at 1.4 mg/m² intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary end point was ORR, and secondary end points included PFS, TTR, DOR, and safety.ResultsFifty-two patients were enrolled. Fifty-one patients (98.1%) had metastatic disease, 25 (48.1%) with liver metastases, 24 (46.2%) with lung metastases, and 19 (36.5%) with bone metastases. Patients received a median of 10.0 cycles of eribulin and 11.0 cycles of trastuzumab. The ORR was 71.2% (n = 37) with median TTR of 1.3 months, DOR of 11.1 months, and PFS of 11.6 months. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 20 (38.5%) patients, peripheral neuropathy in 14 (26.9%; all Grade 3) patients, fatigue in 4 (7.7%) patients, and febrile neutropenia in 4 (7.7%) patients.ConclusionsBecause of the high ORR, prolonged median PFS, and acceptable safety profile, combination eribulin/trastuzumab is an acceptable treatment option for locally recurrent or metastatic HER2+ breast cancer.     

Biological subtypes and survival outcomes in breast cancer patients with brain metastases (study of the anatolian society of medical oncology)

Background: The aim of this study is to determine the relationship between the survival outcomes and biological subtype in breast cancer patients with brain metastases. Methods: We retrospectively evaluated clinical data from 422 breast cancer patients with brain metastases between 2001 and 2011 from referral centers in Turkey. The study population was divided into four biological subtypes according to their hormone receptor status and HER2 expression. Results: Systemic treatment prolonged median overall survival (OS) after brain metastases in the entire group (14 vs. 3.2 months, p < 0.001). It also prolonged median OS after brain metastases in the triple negative (7.5 vs. 1.6 months, p = 0.010) and luminal A (14.3 vs. 7.1 months, p = 0.003) subgroups. The median OS for untreated patients, chemotherapy and/or hormonal therapy receiving patients, and chemotherapy and/or hormonal therapy plus targeted therapy receivers was 2, 5.8, and 17.7 months, respectively (p < 0.001), in the HER2-overexpressing subgroup. In the luminal B subgroup, it was 3.7, 5.3, and 15.4 months, respectively (p = 0.003). Conclusions: The use of systemic therapy improves OS after brain metastases in all biological subgroups. Targeted therapies also improve OS after brain metastases in HER2-positive patients. The combined use of targeted therapies and lapatinib are superior to single use and trastuzumab, respectively, in these patients.     

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.     

Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes

Purpose  The purpose of this study was to investigate the activity of capecitabine and trastuzumab in patients with HER2-overexpressing metastatic breast caner resistant to both anthracyclines and taxanes. Method  From June 2003 and May 2006, 40 female patients with measurable or assessable metastatic breast cancer were enrolled and data from 38 patients were reviewed extramurally and analyzed. Patients were treated with weekly trastuzumab given at a dose of 2 mg/kg/day over 90 min (4 mg/kg/day on the first infusion) and capecitabine given at a dose 1,657 mg/m²/day during 21 days with a subsequent pause of 7 days. This cycle was repeated every 28 days. The primary endpoint was overall survival and secondary endpoints were progression-free survival and response rate. Result  A median of 4.5 cycles (range 1–9 cycles) were delivered. The median age was 53 (range 30–69 years). Median overall survival and progression-free survival was 22.3 and 4.1 months, respectively. Survival rate at 1 and 2 year was 81.6 and 47.4%, respectively. Response rate was 18.4% (95% CI, 7.7–34.3%). All evaluable patients have responded with two CR (5.3%), 5 PR (13.2%), 20 SD (52.6%), 8 PD (21.1%) and 3 NE (7.9%). Regarding the hematological toxicities, grade 1/2/3 neutropenia, grade 1/2 anemia, grade 1 thrombocytopenia and grade 1/2 liver dysfunction were also common. No treatment-related death was reported. Conclusion  The combination of capecitabine and trastuzumab is active and well-tolerated in patients with HER2-overexpressing breast caner resistant to both anthracyclines and taxanes.     

A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients

Background

It is known that one third of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) treated with trastuzumab will develop brain metastases. As the development of brain metastases is fatal, controlling its progression is clinically meaningful. However, effective therapy for MBC patients with brain metastasis after cranial radiation is limited. The international clinical study in which six Japanese patients participated indicated the antitumor activity of lapatinib against brain metastases of HER2-overexpressing breast cancer.

Methods

The efficacy, safety, and pharmacokinetics of lapatinib 750 mg given twice daily to Japanese HER2-overexpressing MBC patients with brain metastases were assessed as part of the international clinical study.

Results

Of six Japanese patients treated in this study, two patients had shown volumetric reduction >20 % in their central nervous system (CNS), one of whom had >50 % reduction. Three patients, including two of these patients, had shown >20 % volumetric reduction in non-CNS lesions. Frequently reported adverse events were diarrhea and rash, all of which were controllable. The AUC_0–12 of lapatinib on day 28 was 1.74 times higher than that on day 1.

Conclusion

These results suggest that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with brain metastases after cranial radiation.     

Prognostic factor analysis in patients with brain metastases from breast cancer: how can we improve the treatment outcomes?

Purpose  We conducted this study to analyze clinicopathologic features and treatment outcomes for various treatment modalities in breast cancer patients with brain metastases. Patients and methods  Retrospective analysis was performed using medical records of patients who were diagnosed with metastatic brain tumors from breast cancer. The treatment modalities applied included whole-brain radiotherapy (WBRT), surgical resection, stereotactic radiosurgery (SRS) and systemic treatments such as chemotherapy and endocrine therapy. Results  Among 125 female breast cancer patients with brain metastases, 87.2% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2. The median overall survival (OS) was 6.6 months (95% CI 3.9–9.2). A multivariate analysis using the Cox-regression test identified three risk factors; poor PS (P = 0.023), HER2 positivity (P = 0.013), and no additional systemic treatment (P = 0.006). Those patients who had no risk factors showed outstanding outcome (median OS 49 months). On the contrary, the patients who had all risk factors (poor PS with HER2 positive and did not receive additional systemic chemotherapy) showed dismal prognosis (median OS 2 months). Conclusions  Our new classification according to the suggested risk factors for patients with metastatic brain tumor from breast cancer reflects particular characteristics of each subset of the patients with good prognostic capacity. B.-B. Park and J. E. Uhm contributed equally to the work.     

Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery

AimsStereotactic radiosurgery (SRS) is an alternative to surgery or whole brain radiotherapy for the control of single or multiple brain metastases in patients with breast cancer. To date, there is no clear consensus on factors that might predict overall survival following SRS. The aim of this study was to assess the overall survival of breast cancer patients with brain metastases treated with SRS at a single centre and to examine the factors that might influence survival.Materials and methodsA retrospective analysis of consecutive patients with breast cancer and brain metastases, considered suitable for SRS by the regional neuro-oncology multidisciplinary team. All patients were treated at a single National Health Service centre.ResultsIn total, 91 patients received SRS between 2013 and 2017, of whom 15 (16.5%) were alive at the time of analysis. The median overall survival post-SRS was 15.7 months (interquartile range 7.7–23.8 months) with no significant effect of age on survival (67 patients ≤ 65 years, 16.3 months; 26 patients > 65 years, 11.4 months, P = 0.129). The primary tumour receptor status was an important determinant of outcome: 31 oestrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2–) patients had a median overall survival of 13.8 months, 14 ER+/HER2+ patients had a median overall survival of 21.4 months, 30 ER–/HER2+ patients had a median overall survival of 20.4 months and 16 patients with triple negative breast cancer (TNBC) had a median overall survival of 8.5 months. A larger total volume of tumour treated (>10 cm³), but not the number of individual metastases treated, was associated with worse survival (P = 0.0002) in this series. Patients with stable extracranial disease at the time of SRS had improved overall survival compared with those with progressive extracranial disease (30 patients stable extracranial disease overall survival = 20.1 months versus 33 patients progressive extracranial disease overall survival = 11.4 months; P = 0.0011). Seventeen patients had no extracranial disease at the time of SRS, with a median overall survival of 13.1 months.ConclusionsThis single-centre series of consecutive patients with brain metastases from breast cancer, treated with SRS, had a similar overall survival compared with previous studies of SRS. TNBC and ER+/HER2– histology, metastatic volumes >10 cm³ and progressive extracranial disease at the time of SRS were associated with worse survival.     

A systematic review of trastuzumab and lapatinib in the treatment of women with brain metastases from HER2-positive breast cancer

Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the blood–brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies in the treatment of brain metastases in breast cancer. We searched PUBMED for all human studies published 1998–2012 using the following search terms: breast neoplasm/cancer, human epidermal growth factor receptor 2/HER2, ErbB2, trastuzumab, lapatinib, brain/cerebral neoplasm/metastases and blood–brain barrier. We identified few and mostly small clinical studies. Study designs were very heterogeneous making comparisons on endpoints difficult. Overall survival for patients treated with trastuzumab varied from 8 to 25 months and 5.5 to 11 months for patients receiving lapatinib. The majority of studies were retrospective thus possibly biasing data. Only three studies were identified comparing trastuzumab to lapatinib. Conclusively, no solid data exist on how to treat patients with HER2-positive disease and brain metastases. Although continuous HER2-blockade is recommended by international consensus guidelines, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur. The choice of chemotherapy to accompany the blockade is not obvious and we do not know if dual is better than single blockade. Further clinical trials are urgently needed.     

Central nervous system metastases in women with HER-2 positive metastatic breast cancer after treatment with trastuzumab

Background: Historically, central nervous system (CNS) metastases have been reported to occur in 10–16% of women with metastatic breast cancer (MBC) with a median survival of less than 1 year after diagnosis of CNS disease. A higher rate of CNS metastases has been described in women with metastatic breast cancer (MBC) over‐expressing HER‐2 who receive trastuzumab therapy. Aims: The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with trastuzumab, CNS metastases occurred (i) more frequently than historical controls, and (ii) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 consecutive patients with MBC over‐expressing HER‐2 and treated with trastuzumab and chemotherapy was performed. Results: A total of 22/25 (88%) patients who initially responded to trastuzumab had progressed within a median of 11.2 months after starting trastuzumab therapy. Central nervous system metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) had controlled systemic disease (CR = 2, PR = 6, SD = 1). There were trends for patients with CNS metastases to have greater than one site of metastatic disease at the commencement of trastuzumab therapy (P = 0.06), and to be hormone receptor negative at initial diagnosis (P = 0.14). The median time to diagnosis of CNS metastases after the commencement of trastuzumab therapy was 12 months (range 6–19 months). The median survival after diagnosis of CNS metastases was 12 months (range 2–22 months). Conclusions: This study demonstrates a high rate of CNS metastases (39%) in HER‐2 positive MBC patients treated with trastuzumab. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was 1 year. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration.     

Possible available treatment option for early stage,small, node-negative,and HER2-overexpressing breast cancer

Trastuzumab is known for its clinical activity in women with HER2-overexpressing breast cancer. Randomized clinical trials have shown significant improvement in disease-free and overall survival with trastuzumab administered in conjunction with adjuvant chemotherapy for early-stage HER2-positive breast cancer. However, there is no direct evidence of clinical benefit from adjuvant trastuzumab in patients with node-negative, HER2-overexpressing, small (T1a-b) breast cancers. Previous literature shows that most breast cancers with node-negative small tumors have a good prognosis, but HER2-overexpressing disease might still be worse in this population. Some recent retrospective studies showed that an adjuvant trastuzumab-based regimen has a better prognostic effect, even in patients with node-negative, HER2-overexpressing, small breast cancers, although absolute survival differences were small. On the basis of the available literature, we believe that trastuzumab should be considered for patients with minimal HER2-overexpressing disease, although tools for accurate selection of patients at risk of relapse still need to be developed.     

Risk factors for brain relapse in HER2-positive metastatic breast cancer patients

Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0–81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6–13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03–2.33, P = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; P = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47–1.77, P = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07–2.44; P = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse. Presented in part in oral form at the 2007 European Cancer Conference, Barcelona, Spain.