Absolute lymphocyte count predicts efficacy of palbociclib in patients with metastatic luminal breast cancer.

BACKGROUND: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. METHODS: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/µL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. RESULTS: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0-9) and 1 (range, 0-7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). CONCLUSION: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer.

Cost of Pegfilgrastim for the Prophylaxis of Chemotherapy-induced Febrile Neutropenia in Patients with Breast Cancer Receiving Perioperative Chemotherapy in Daily Practice in Japan: A Posthoc Analysis in a Single-center Retrospective Study.

This study aimed to estimate the medical costs associated with febrile neutropenia (FN) prophylaxis with pegfilgrastim and evaluate its impact on survival outcomes in daily practice in Japan. In this single-center retrospective study, we obtained data from 296 Japanese patients with breast cancer receiving fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 chemotherapy; the patients were divided into the pegfilgrastim and non-pegfilgrastim groups. We analyzed the median costs of chemotherapy, drugs for all adverse events (AEs) and FN, and hospitalization due to FN. We also assessed the survival outcomes. The pegfilgrastim group showed a significantly higher median total cost (JPY 872320.0 vs. JPY 466715.0, p<0.001). This difference was associated with the prophylactic use of pegfilgrastim. The median costs of the drugs for all AE treatments were JPY 9030.4 and JPY 24690.6, with the non-pegfilgrastim group showing a significantly higher cost (p<0.001). In 11 patients hospitalized for FN management, no significant difference in hospitalization cost was observed between the pegfilgrastim and non-pegfilgrastim groups (JPY 512390.0 vs. JPY 307555.0, p=0.102). No significant difference in the 3-year overall survival was observed between the pegfilgrastim and non-pegfilgrastim groups (79.9% vs. 88.3%, p=0.672). In this study, although the total medical cost in daily practice increased because of primary prophylaxis with pegfilgrastim, the 3-year overall survival was not impacted by the use of pegfilgrastim. Our study data suggested that the primary prophylaxis pegfilgrastim should be used during FEC-100 chemotherapy based on the patient-related FN risk factors, instead of routine use.

Case series of Li-Fraumeni syndrome: carcinogenic mechanisms in breast cancer with TP53 pathogenic variant carriers.

BACKGROUND: Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67-83%) to develop HER2 + breast cancer than noncarriers (16-25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype. METHODS: We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS. RESULTS: We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR - /HER2 + . The median age at the onset of breast cancer was slightly younger in HR - /HER2 + tumors than in HR + /HER2 - tumors (31 years and 35.5 years, respectively). CONCLUSIONS: The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16-25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers.

Availability of genome-matched therapy based on clinical practice.

BACKGROUND: Comprehensive genomic profiling (CGP) provides new opportunities for patients with advanced cancer to receive genome-matched therapies, but the availability rate of these remains low. We reviewed our CGP cases and suggested possible strategies to improve the current status from a clinical perspective. METHODS: Druggable genomic alterations and barriers to accessing genome-matched therapies were investigated in 653 patients with 30 various types of cancers who underwent CGP. RESULTS: While the availability rate of genome-matched therapies as a whole was 9.5%, CGP was useful in some cancer types. Patients with thyroid cancer and lung cancer harbored druggable genomic alterations at high rates, while sarcoma rarely harbored these alterations (100%, 76%, and 15.2%, respectively). In contrast, the availability rate of genome-matched therapies was highest in patients with sarcoma and head and neck cancer (HNC) (60% and 40%, respectively). One hundred thirteen patients (63.5%) had multiple barriers to accessing genome-matched therapy. Of 178 patients, 21 patients (11.8%) could not be considered for genome-matched therapies solely because of the deterioration of their performance status. CONCLUSION: This study demonstrated the usefulness of CGP for patients with sarcoma and HNC in addition to lung cancer in clinical practice. Performing CGP at the front line has the potential to improve the availability of genome-matched therapy.

[Overview of Clinical Application of Whole Genome Analysis for Cancer].

Cancer genomic medicine in Japan began in earnest with the implementation of gene panel testing covered by national health insurance in June 2019. However, the information obtained from this testing is limited to less than 0.1% of the entire genome. To enhance the effectiveness of therapy, understand the intricate biology of cancer, and develop new therapeutic drugs, it has become essential to promote the analysis of the whole genome. In Japan, the Action Plan for Whole Genome Analysis(Version 1)was released in December 2019. In 2021, AMED project"the full-scale operation of cancer whole genome analysis"was launched. The Action Plan for Whole Genome Analysis 2022 set a goal to return the information promptly to patients and citizens. Project Implementation Preparation Office was organized in April 2023 for acceleration of the system development for the clinical whole genome analysis. This paper introduces the current efforts and discuss the future perspectives of cancer genome medicine in Japan.

Prognostic impact of cancer genomic profile testing for advanced or metastatic solid tumors in clinical practice.

Cancer genomic profile (CGP) testing, which is covered by the national health insurance system in Japan, has been introduced as a routine clinical practice. However, the effects of CGP testing on prognoses remain unclear. Drug accessibility rates and prognoses after CGP testing were retrospectively investigated in 713 patients who underwent CGP testing examined by our molecular tumor board between November 2019 and October 2022,. Overall survival (OS) was examined using the log-rank test and the Kaplan-Meier method. The median age of patients (326 males and 387 females) was 58 years (12-85 years). CGP testing revealed one or more gene mutations in 681 cases (95.5%), among which actionable gene mutations were detected in 439 (61.6%). Although treatment options were recommended for 285 cases (40.0%) by the molecular tumor board, only 45 received treatment based on their gene mutations. During the median observation period of 8.6 months, 351 (49.2%) patients died of the exacerbation of existing diseases. No significant differences were observed in OS between patients treated with and without genomically matched therapy (p = 0.285). According to clinical responses to treatment based on gene mutations, median OS was significantly longer in patients who achieved partial response and stable disease (26.5 months; 95% CI 14.4-38.6) than in those with progressive disease and not evaluated (9.8 months; 95% CI 5.8-13.8, p = 0.013). Responses to treatment based on gene mutations may improve prognoses, and it is important to increase the drug accessibility rate after CGP testing.

Evaluation of an inflammation-based score for identification of appropriate patients for comprehensive genomic profiling.

Performance status (PS) is widely used as an assessment of general condition in patients before performing comprehensive genomic profiling (CGP). However, PS scoring is dependent on each physician, and there is no objective and universal indicator to identify appropriate patients for CGP. Overall, 263 patients were scored using the modified Glasgow prognostic score (mGPS) from 0 to 2 based on the combination of serum albumin and c-reactive protein (CRP): 0, albumin ≥ 3.5 g/dl and CRP ≤ 0.5 mg/dl; 1, albumin < 3.5 g/dl or CRP > 0.5 mg/dl; and 2, albumin < 3.5 g/dl and CRP > 0.5 mg/dl. Overall survival was compared between mGPS 0-1 and mGPS 2 groups. The prognosis of patients with PS 0-1 and mGPS 2 was also evaluated. Thirty-nine patients (14.8%) were mGPS 2. Patients with mGPS 2 had significant shorter survival (14.7 months vs 4.6 months, p < 0.01). Twenty-eight patients were PS 0-1 and mGPS 2, and their survival was also short (5.6 months). Evaluation of mGPS is a simple and useful method for identifying patients with adequate prognosis using CGP.

Druggable gene alterations in Japanese patients with rare malignancy.

Without a current standard of care, patients with rare malignancy are subjected to precision oncology with next-generation sequencing to identify a course of treatment. We sought to establish the clinical relevance of comprehensive genomic profiling (CGP) among patients with rare malignancy. Rare malignancy was defined using the Rare Cancers in Europe definition (<6 cases per 100,000 individuals). We analyzed gene mutations, fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Level A gene alterations, categorized using Clinical Interpretations of Variants in Cancer and MD Anderson Knowledge Base for Precision Oncology, were considered druggable. Rare malignancy accounted for 149 (45%) cases, with female genital cancers (32%) most common. Among the rare malignancy cases, we identified a lower frequency of mutation in TP53 (41% vs. 60%, P<0.001), KRAS (13% vs. 43%, P<0.001) and APC (3% vs. 25%, P<0.001), and a higher frequency of ARID1A mutation (14% vs. 6%, P=0.03), as compared with common malignancies. TMB-high and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 37 patients with rare malignancy; this percentage tended to be higher than that for patients with common malignancies (25% vs. 17%, P=0.08). Common druggable alterations were BRAF V600E, ERBB2 amplification, PIK3CA E542K, and BRCA1/2 variant. Five of the 37 patients with druggable alterations received genome-driven treatment. There was no significant difference in overall survival between the rare and common malignancy groups. Our results provide clues for future clinical development and treatment success among Japanese patients with rare cancers.

Assessment of a cancer genomic profile test for patients with metastatic breast cancer.

Comprehensive cancer genomic profile (CGP) tests are being implemented under Japanese universal health insurance system. However, the clinical usefulness of CGP test for breast cancer patients has not been evaluated. Of the 310 patients who underwent CGP testing at our institution between November 2019 and April 2021, 35 patients with metastatic breast cancer whose treatment strategy was discussed by our molecular tumor board within the study period were investigated after exclusion of 2 cases that could not be analyzed. The turn-around time, drug accessibility, and germline identification detection were evaluated. The subtype was luminal in 20 patients (57.1%), triple-negative in 12 patients (34.3%), and luminal-HER2 in 3 patients (8.6%). Actionable gene mutations were detected in 30 patients (85.7%), and 7 patients (20.0%) were recommended for clinical trial participation, with the drug administered to 2 patients (5.7%). Three patients (8.6%) died due to disease progression before the test results were disclosed. We report the results of an initial assessment of the utility of CGP testing for patients with metastatic breast cancer under Japanese universal health insurance system. Conducting CGP tests at a more appropriate time could provide patients with greater benefit from treatments based on their specific gene mutations.

Serial circulating tumor DNA monitoring of CDK4/6 inhibitors response in metastatic breast cancer.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression-free survival and have become the standard therapy for estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection and repeated biopsy genomic profiling is not clinically feasible. Serial circulating tumor DNA (ctDNA) analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n = 178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of 12 patients (61%) responding to CDK4/6i who eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with an average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (progressive disease at first radiological assessment, 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% variant allele frequency), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small-sized target lesions), as well as detecting acquired genetic alterations linked to CDK4/6i resistance in the G1 to S transition phase. Circulating tumor DNA analysis was more sensitive than carcinoembryonic antigen or cancer antigen 15-3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings indicated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real-time monitoring of CDK4/6i response.

Trastuzumab and fulvestrant combination therapy for women with advanced breast cancer positive for hormone receptor and human epidermal growth factor receptor 2: a retrospective single-center study.

BACKGROUND: Trastuzumab and fulvestrant combination therapy is one of the treatment options for patients with hormone receptor- and human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer; however, there are limited studies evaluating the efficacy of this combination therapy. METHODS: We retrospectively reviewed the data of women with hormone receptor- and HER2-positive metastatic breast cancer who received trastuzumab and fulvestrant combination therapy between August 1997 and August 2020 at the Cancer Institute Hospital. The primary endpoint of this study was progression-free survival, and the secondary endpoints were response rate, overall survival and safety. RESULTS: We reviewed the data of 1612 patients with recurrent or metastatic breast cancer, of which 118 patients were diagnosed with hormone receptor- and HER2-positive breast cancer. Of these, 28 patients who received trastuzumab and fulvestrant combination therapy were eligible for this study. The median treatment line for advanced breast cancer was 6 (range, 1-14), the median progression-free survival was 6.4 months (95% confidence interval [CI], 3.46-8.17), and the median overall survival was 35.3 months (95% CI, 20.0-46.7). Of the 28 patients, partial response was observed in 1 (4%), stable disease in 17 (61%), and progressive disease in 10 (36%) patients. The disease control rate was 64%. Adverse events of grade ≥ 3 were not observed. CONCLUSIONS: Trastuzumab and fulvestrant combination therapy showed moderate clinical efficacy and no severe toxicity after standard anti-HER2 treatment, which is a reasonable treatment option for patients with hormone receptor- and HER2-positive metastatic breast cancer. These data contribute to understanding the efficacy of trastuzumab and fulvestrant combination therapy as control data for further development of anti-HER2 agents plus hormone therapy.

A phase II study of sequential treatment with anthracycline and taxane followed by eribulin in patients with HER2-negative, locally advanced breast cancer (JBCRG-17).

PURPOSE: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC. METHODS: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative. RESULTS: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%). CONCLUSION: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.

Clinical significance of gene mutation in ctDNA analysis for hormone receptor-positive metastatic breast cancer.

PURPOSE: In this study, we aim to investigate the mutation spectrum of circulating tumor DNA among hormone receptor-positive metastatic breast cancer (HR-MBC) patients using ultradeep targeted resequencing. In addition, we also evaluate the correlation of mutations detected from this study with progression-free survival (PFS). MATERIALS AND METHODS: A total of 56 HR-MBC patients were enrolled. Cell-free DNA (cfDNA) was extracted from plasma and sequenced by using Oncomine Breast cancer cfDNA assay in this study. RESULT: Concentration of cfDNA is correlated with a number of metastatic organs and serum CEA levels (Spearman's rank correlation p = 0.0018, p = 0.0015 respectively). Cases with high cfDNA levels (≥ 2.6 ng/µl of plasma) showed worse progression-free survival (PFS) and overall survival compared with cases with low cfDNA levels (p = 0.043 and 0.046, respectively). Among these patients, 29 patients (51.7%) have TP53 mutations, 12 patients (30.3%) have PIK3CA mutations, and 9 patients (16.0%) have ESR1 mutations. Acquisition of ESR1 mutation increased according to the lines of hormone therapy. In addition, patients with ESR1 mutation showed shorter PFS than those without mutation (log-rank p = 0.047). In the multivariate analysis, ESR1 mutation and cfDNA concentration were significant for PFS (p = 0.027 and 0.006, respectively). In conclusion, assessment of ESR1 mutation and cfDNA concentration could be useful in predicting prognosis for HR-MBCs.

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel.

BACKGROUND: Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). METHODS: Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/µL, 2, and 250, respectively. RESULTS: PFS was significantly improved in patients with ALC ≥1500/µL compared to those with ALC 1000-, <1500/µL or ALC < 1000/µL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/µL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735-0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/µL was observed irrespective of visceral metastasis or chemotherapy regimen. CONCLUSIONS: Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. TRIAL REGISTRATION: UMIN000012375 , registration date: 21NOV2013, and UMIN000006838 , registration date: 6DEC2011.

Pattern of Tumor Shrinkage during Neoadjuvant Chemotherapy Is Associated with Prognosis in Low-Grade Luminal Early Breast Cancer.

Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P < .001 and P < .001, respectively). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .001) and OS (P = .009) rate. In the validation set, the median follow-up period was 56.9 months. Recurrence was observed in 20 patients (16.5%) and eight (6.6%) deaths were related to breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P ≤ .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion The CS pattern as revealed at MR imaging during NAC had the only significant independent association with prognosis in patients with low-grade luminal breast cancer. © RSNA, 2017.

The early onset of peripheral neuropathy might be a robust predictor for time to treatment failure in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel.

BACKGROUND: Paclitaxel plays a central role in chemotherapy for breast cancer. Peripheral neuropathy, a well-known toxicity with paclitaxel, may be of interest in predicting the efficacy of paclitaxel therapy for patients with metastatic breast cancer. We performed a retrospective analysis assessing whether the early occurrence of peripheral neuropathy (EPN) was a predictive marker for better efficacy in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel. PATIENTS AND METHODS: Between January 2000 and August 2008, we examined the records of 168 patients with metastatic breast cancer treated with paclitaxel in our hospital. EPN was defined as a symptom of Grade 2 or more during first three months of treatment. The overall response rate (ORR) and time to treatment failure (TTF) in each group were analyzed retrospectively. RESULTS: Of 168 patients with metastatic breast cancer who were treated with paclitaxel, EPN was documented in 101 patients (60.1%). The clinical benefit rate (CR, PR, and SD ≥ 6 months) was 72.3% in the EPN group and 49.3% in the non-EPN group (p = 0.002). The TTF of the EPN group (median 11.2 months, 95% CI: 9.5-12.9) was significantly longer than that of the non-EPN group (5.7 months, 95% CI: 4.6-6.8) (p<0.001). Multivariate analysis demonstrated that EPN (p<0.001), dose intensity of less than 70% (p<0.001), and the history of microtubule agents (p = 0.001) were the significant favorable prognostic factors for TTF. CONCLUSION: The early onset of peripheral neuropathy might be a robust predictor for TTF in patients with metastatic breast cancer treated with paclitaxel.

Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer: A Case Report and Literature Review.

We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy.

A Case of Recurrent Breast Cancer Identified by Pulmonary Tumor Thrombotic Microangiopathy.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, cancer-related, pulmonary complication that causes hypoxia and pulmonary hypertension. We report on a 42-year-old woman who was diagnosed with recurrent breast cancer that was detected due to the presence of PTTM. Eleven months after surgery for heterochronous bilateral cancer of the left breast, she developed progressive dyspnea but computerized tomography showed no pulmonary thromboembolism, and a transthoracic echocardiography revealed mild pulmonary hypertension. She was diagnosed with PTTM by cytology from pulmonary artery catheterization and perfusion lung scintigraphy. Also, the patients complained of back pain after admission, bone scintigraphy showed multiple bone metastases. Despite the early diagnosis of PTTM, her platelet count decreased, her performance status rapidly deteriorated, and her dyspnea worsened. Thus, we could not treat her with chemotherapy. She died due to respiratory failure 19 days after admission. To the best of our knowledge, this is the first report of recurrent breast cancer identified by the manifestation of PTTM. Although PTTM is a rare phenomenon, it should be considered in the differential diagnosis of acute dyspnea or pulmonary hypertension in patients with breast cancer. Furthermore, upon diagnosis, the patient should be referred to a cardiologist as soon as possible.

First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer.

BACKGROUND: The efficacy and safety of continuing multiple anti-HER2 therapies in advanced breast cancer (ABC) patients remains unclear. This study investigated eribulin in combination with pertuzumab and trastuzumab for both taxane- and trastuzumab-pretreated HER2-positive ABC patients. METHODS: In a single-institute, single-arm, open-label, phase II trial, HER2-positive ABC patients who had previously received taxanes and trastuzumab were treated with eribulin in combination with pertuzumab and trastuzumab. The pharmacokinetics of eribulin in this combination were assessed in 6 patients. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was objective response rate (ORR). RESULTS: A total of 30 patients (median age, 58 years; range, 31-76) were enrolled, with a median number of previous chemotherapy regimens of 3.5 (range: 1-9) in the metastatic setting. Pharmacokinetic parameters of eribulin in this combination were similar to previous reports of eribulin monotherapy. ORR was 34.8% (95% CI: 16.4-57.3, n = 23), and median progression-free survival was 42.6 weeks (95% CI: 20.3-51.9, n = 30). Clinical benefit rate was 60.9% (95% CI: 16.4-57.3). The most common grade 3/4 adverse event was neutropenia in 20 patients (66.7%). A dose reduction of eribulin was required in 27 patients due to adverse events, particularly grade 3 neutropenia. CONCLUSIONS: Eribulin in combination with pertuzumab and trastuzumab was well tolerated in heavily pretreated patients. Eribulin may be a viable treatment option when used in combination with pertuzumab and trastuzumab for HER2-positive ABC patients (UMIN Clinical Trial Registry identification number, UMIN000012375).

Imatinib could be a new strategy for pulmonary hypertension caused by pulmonary tumor thrombotic microangiopathy in metastatic breast cancer.

INTRODUCTION: Pulmonary tumor thrombotic microangiopathy (PTTM) is rare, cancer-related pulmonary complication leading to hypoxia, pulmonary hypertension, and heart failure. The standard treatment for PTTM is not established. However, imatinib, a tyrosine kinase inhibitor of the PDGF receptor, may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM. CASE DESCRIPTIONS: We report two cases of PTTM who received an anti-PDGF agent of imatinib for PTTM developed during chemotherapy for metastatic breast cancer. Case 1: 61-year-old woman who underwent resection of the left breast and axillary lymph node dissection and received adjuvant chemotherapy (CAF followed by docetaxel), then endocrine therapy for 5 years. Twelve years after surgery, multiple bone and mediastinal lymph node metastases occurred. She was under treatment with eribulin for one year but admitted because of rapid progressing dyspnea. Case 2: 45-year-old woman with metastatic breast cancer in multiple bones was under treatment for 5 years. Receiving capecitabine, she suffered from dyspnea for 2 months, she was admitted to our hospital with diagnosis of severe hypoxia. In both cases, the wedged pulmonary arterial blood cell sampling revealed cytologically malignant cells which confirmed the diagnosis of PTTM. They were treated with imatinib, which alleviated pulmonary hypertension. However, they died due to progression of metastatic breast cancer. DISCUSSION AND EVALUATION: Single use of imatinib did not showed sufficient efficacy. It is necessary to conduct a well-designed clinical trial using chemotherapies combined with imatinib for PTTM. CONCLUSIONS: Imatinib, which alleviated pulmonary hypertension, could be a new strategy for pulmonary tumor thrombotic microangiopathy in patient with metastatic breast cancer.