BRCAness of brain lesions reflects a worse outcome for patients with metastatic breast cancer.

PURPOSE: Breast cancer often metastasizes to the central nervous system. Although the prognosis of brain metastases from breast cancer has been considered poor, and systemic therapy has not contributed to an improved prognosis, newer agents are expected to be more effective. BRCAness is defined as the status of homologous recombination deficiency (HRD) in tumor tissue, regardless of the presence of pathogenic germline BRCA1/2 variants. A study employing next-generation sequencing analysis showed that HRD was found relatively frequently in brain metastases of breast cancer patients. However, there have been no studies evaluating BRCAness in brain metastases of breast cancer with more efficient, rapid, and cost-effective methods. METHODS: We retrospectively investigated 17 brain metastases of breast cancer that were surgically resected at our hospital from January 2007 to December 2022. Of these, samples from 15 patients were evaluable for BRCAness by employing multiplex ligation-dependent probe amplification (MLPA) assay. RESULTS: Of the 15 patients, five patients (33%) had tumors with BRCAness. Clinicopathological factors of patients with brain metastases with BRCAness were not statistically different from those of patients who possessed tumors without BRCAness. Patients with brain metastases with BRCAness had shorter overall survival compared to those without BRCAness (BRCAness, median 15 months (95% CI 2-30) vs. non-BRCAness, median 28.5 months (95% CI 10-60); P = 0.013). CONCLUSION: In this study, we evaluated BRCAness in brain metastases of breast cancer with the MLPA method, and found that about one-third of patients had BRCAness-positive tumors. The analysis of BRCAness using MLPA has the potential for practical clinical use.

Efficacy of radiation therapy in Japanese patients with positive margins after breast-conserving surgery.

BACKGROUND: Additional surgical resection is recommended after breast-conserving surgery if the surgical margin is pathologically positive. However, in clinical practice, radiation therapy is sometimes used instead for several reasons. Irradiation may be appropriate for some patients, but real-world data is still insufficient to establish it as standard treatment. We retrospectively investigated the status of local control in patients who received irradiation for positive margins. METHODS: We investigated 85 patients with positive margins after curative partial mastectomy who were treated with irradiation instead of additional excision during the period 2006-2013. The patients received whole-breast irradiation (43.2-50 Gy) using photon beams and additional tumour-bed boost (8.1-16 Gy) using electron beams. Intrabreast tumour recurrence was defined as secondary cancer within the ipsilateral conserved breast. Surgical margin was defined as positive if tumour cell exposure was pathologically confirmed on the margin. RESULTS: Seven patients (8.2%) developed intrabreast tumour recurrence during a mean observation period of 119 months. As to components of positive margin, 76 cases were positive for an intraductal component, of which seven (9.2%) developed intrabreast tumour recurrence. Meanwhile, all nine cases positive for an invasive component were free from intrabreast tumour recurrence. Two of the intrabreast tumour recurrence cases seemed to develop new lesions rather than recurrence, considering tumour location. The cumulative incidence of intrabreast tumour recurrence over 10 years was 6.1%. Limited to true recurrence, intrabreast tumour recurrence incidence was 4.9%. CONCLUSION: Our real-world data supports irradiation as an alternative to additional surgical intervention for positive margins after breast-conserving surgery and offers a basis for further research.

High platelet-to-lymphocyte ratios in triple-negative breast cancer associates with immunosuppressive status of TILs.

BACKGROUND: Rating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately. METHODS: We investigated the relationship between TILs and the peripheral blood markers, PLR and NLR, in the same patients, using surgical specimens from 502 patients with invasive breast carcinoma without preoperative chemotherapy. For analysis of triple-negative breast cancer (TNBC) patient outcomes, 59 patients who received preoperative chemotherapy were also examined. For immune cell profiling, multiplexed fluorescent immunohistochemistry (mfIHC) of CD3, CD4, CD8, FOXP3 and T-bet, was conducted. RESULTS: A positive correlation between PLR and TIL was observed in TNBC (P = 0.013). On mfIHC, tumors in patients with high PLR and NLR contained more CD3+CD4+FOXP3+ T-cells (P = 0.049 and 0.019, respectively), while no trend was observed in CD8+ T-cells. TNBC patients had different patterns of outcomes according to TIL and PLR, with the TIL-high/PLR-low group having the lowest rate of disease relapse and death, and the longest distant metastasis-free and overall survivals, while the TIL-low/PLR-high group had the shortest survivals. CONCLUSIONS: Our data suggest that the combination of PLR with TIL assessment may enable more accurate prediction of patient outcomes with TNBC.

Absolute lymphocyte count decreases with disease progression and is a potential prognostic marker for metastatic breast cancer.

PURPOSE: Peripheral blood parameters such as the neutrophil-to-lymphocyte ratio (NLR) are prognostic markers for breast cancer patients. For instance, patients with a high NLR have a poor prognosis. Meanwhile, high absolute lymphocyte count (ALC) is reportedly a predictive factor for some chemotherapies. However, the underlying mechanisms behind how these markers relate to patient outcomes and how these markers change during the clinical course of patients with metastatic breast cancer (MBC) remains unknown. METHODS: We retrospectively investigated 156 patients who were treated for MBC and eventually transitioned to best supportive care (BSC) at our hospital between January 2017 and December 2021. Changes in peripheral blood parameters during MBC treatments and their association with patient outcomes were examined. RESULTS: From the time of MBC diagnosis (baseline) through to the transition to BSC, ALC became significantly lower, while the NLR and platelet-to-lymphocyte ratio (PLR) became significantly higher (p < 0.001 for all). This association was independent of hormone receptor status. Cox proportional hazard modeling found patients with hormone receptor-negative and a lower baseline ALC had a significantly shorter overall survival (p = 0.030 and p = 0.019, respectively). CONCLUSION: We observed that peripheral blood markers gradually changed with MBC disease progression. Our data suggest that baseline ALC may be a potential prognostic marker after recurrence.

Eribulin improved the overall survival from the initiation of first-line chemotherapy for HER2-negative advanced breast cancer: a multicenter retrospective study.

BACKGROUND: Eribulin methylate (eribulin) improved the overall survival (OS) of eribulin-treated patients with HER2-negative advanced breast cancer (ABC) in prospective and retrospective studies. However, the effect of eribulin on OS as first-line chemotherapy and the characteristics of the patients who benefited from eribulin remain unclear. METHODS: Between January 2011 and December 2016, 301 patients with HER2-negative ABC who started first-line chemotherapy at 3 institutions were retrospectively evaluated for OS from the initiation of first-line chemotherapy. RESULTS: We identified 172 patients (119 estrogen receptor-positive [ER+], 47 ER-, 6 unknown) who received eribulin (eribulin group) and 129 patients (92 ER+, 31 ER-, 6 unknown) who did not receive eribulin (non-eribulin group). The median OS from the initiation of first-line chemotherapy in the two groups was not statistically significant (869 vs. 744 days, P = 0.47, log-rank); however, in patients who received eribulin in later lines (≥3rd-line) and who had a history of perioperative chemotherapy with anthracycline- and/or taxane-based regimens, the median OS improved (1001 vs. 744 days, P = 0.037; and 834 vs. 464 days, respectively P = 0.032, respectively; Wilcoxon). Multivariate analyses revealed that a history of perioperative chemotherapy with anthracycline- and/or taxane-based regimens was a predictive factor (hazard ratio, 0.39; 95% confidence interval, 0.21-0.70) for OS. CONCLUSIONS: This study successfully identified subgroups of HER2- ABC patients with improved OS by eribulin therapy. Selecting patients according to their background and line of treatment will maximize the efficacy of eribulin therapy.

Leptomeningeal Metastasis in ER + HER2- Advanced Breast Cancer Patients: A Review of the Cases in a Single Institute Over a 15-year Period.

PURPOSE: While leptomeningeal metastasis (LM) from estrogen receptor-positive, HER2-negative advanced breast cancer (ER + HER2-ABC) has a poor prognosis, the details of ER + HER2-LM are unclear. We therefore retrospectively investigated patients with LM from ER + HER2-ABC. METHODS: ER + HER2-ABC patients who received any therapy at Shizuoka Cancer Center between October 2002 and December 2017 were retrospectively analyzed. Patients with central nervous system (CNS) metastases were divided into three groups: brain metastasis (BM) only (B group); BM with LM (BL group); and LM only (L group). RESULTS: Among 369 patients, 102 developed CNS metastases: 70 (68.6%), 13 (12.8%), and 19 (18.6%) in the B, BL, and L groups, respectively. The L group showed a later onset, poorer performance status, more symptoms, and more skull metastasis than the other groups. Radiotherapy as the initial treatment was introduced to 13/13 (100%) and 15/19 (78.9%) in the BL and L groups, respectively. Subsequent systemic therapy excluding best supportive care was introduced to 5/13 (38.5%) and 5/19 (26.3%) in the BL and L groups, respectively. The median overall survival from the diagnosis of CNS lesions was 295.0, 146.0, and 99.0 days in the B, BL, and L groups, respectively, and worsening of CNS lesions was the major cause of death in the BL and L groups. Multivariate analyses showed that concurrent soft tissue metastasis (hazard ratio, 4.620) and subsequent systemic therapy (hazard ratio, 0.063) were prognostic for the L group. CONCLUSION: Management of LM from ER + HER2-ABC remains challenging, so a multimodal approach with novel systemic therapy is warranted.

Evaluation of Breast Edema Findings at T2-weighted Breast MRI Is Useful for Diagnosing Occult Inflammatory Breast Cancer and Can Predict Prognosis after Neoadjuvant Chemotherapy.

Background Prediction of occult inflammatory breast cancer (IBC) and breast cancer prognosis based on breast edema findings on T2-weighted MRI scans, even for patients without clinical signs of IBC, would be useful in both pretreatment planning and prognosis and may elucidate the underlying biologic mechanisms. Purpose To evaluate whether classification of breast edema on T2-weighted MRI scans is useful for predicting the prognosis of patients with breast cancer treated with neoadjuvant chemotherapy (NAC). Materials and Methods A retrospective evaluation was performed of women with breast cancer who underwent breast MRI and were treated with NAC between January 2011 and December 2018. Breast edema on T2-weighted images was scored on a scale of 1 to 4, as follows: (a) breast edema score (BES) 1, no edema; (b) BES 2, peritumoral edema; (c) BES 3, prepectoral edema; and (d) BES 4, subcutaneous edema (suspicious for occult IBC). Clinically evident IBC was classified as BES 5 (without MRI). The log-rank test was performed, and hazard ratios were calculated using the Cox hazard model to evaluate associations between BES and progression-free survival (PFS) and overall survival (OS). PFS rate at 100 months after initiation of therapy was also evaluated. Results Of 408 patients (median age, 53 years; range, 28-80 years), 65 (16%) had a recurrence and 27 (7%) died. The log-rank test revealed differences in PFS for BES 4 versus 1, BES 5 versus 1, BES 5 versus 2, and BES 5 versus 3 (adjusted P < .05 for all). PFS rates for BES 1-5 were 0.92, 0.85, 0.80, 0.62, and 0.58, respectively, and the corresponding OS rates at 100 months were 0.98, 0.91, 0.92, 0.77, 0.86, respectively. Conclusion Classification of breast edema findings on T2-weighted MRI scans using a breast edema score was related to the prognosis of patients after neoadjuvant chemotherapy. © RSNA, 2021 Online supplemental material is available for this article.

Is the presence of edema and necrosis on T2WI pretreatment breast MRI the key to predict pCR of triple negative breast cancer?

PURPOSE: Given that a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is an important prognostic factor, evaluating pretreatment imaging findings is important. Outcomes for triple negative breast cancer (TNBC) vary with the histological classification, indicating that this classification is clinically significant. In this study, we focus on the most common histological subtype of TNBC, invasive carcinoma of no special type (NST), to evaluate whether intramammary edema (intra-E) and intratumoral necrosis (intra-N) on T2-weighted magnetic resonance imaging (T2WI) is a useful predictor of pCR. METHOD: We retrospectively included patients with biopsy-diagnosed TNBC-NST who received NAC between January 2014 and December 2017. Intra-E and intra-N were evaluated on T2WI before NAC. We grouped intra-E into no edema, peritumoral edema, prepectoral edema, and subcutaneous edema, and we defined intra-N as water-like signal intensity without enhancement on T2WI. We also evaluated tumor size, Ki-67 expression, and histological/nuclear grade, as well as their correlation with intra-E and intra-N. RESULTS: Fifty-seven patients with TNBC-NST were enrolled. There was no correlation with the rate of pCR and the presence of either intra-E or intra-N before NAC. Only intra-E and tumor size showed a positive correlation. CONCLUSIONS: In patients with TNBC-NST, intra-E and intra-N did not correlate with pCR, but intra-E did positively correlate with tumor size. NST may exhibit a greater response to NAC, regardless of whether intra-E or intra-N is present or not on the pretreatment MRI. KEY POINTS: • Pathological complete response in TNBC-NST had no correlation with intramammary edema or intratumoral necrosis. • NAC may be justified in TNBC-NST even in the presence of edema or necrosis. • The extension of edema correlated with tumor size of TNBC-NST.

A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients.

BACKGROUND: NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer. METHODS: Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215. RESULTS: A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001). CONCLUSIONS: The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01644890.

Impact of race on dose selection of molecular-targeted agents in early-phase oncology trials.

BACKGROUND: We examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia. METHODS: We searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan. We pooled and compared the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and efficacy between these populations. RESULTS: 17 MTA were approved in NA/EU and Asia from 2001 to 2015. Recommended phase 2 doses (RP2D) were identical across races in 14 of 17 (80%) studies and differences were not clinically meaningful. FAD were identical across all regions. 42 and 27 patients from US and Japan, respectively, were enrolled in the phase I studies of DS-7423. Despite differences in race, body weight, and body mass index, the RP2D were 240 mg/day with no differences in toxicities, PK, PD, or efficacy. CONCLUSIONS: Conducting separate clinical trials of single-agent MTA in Caucasian and Asian populations may be redundant.

Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis.

PURPOSE: Though advanced and metastatic epidermal growth factor receptor 2 (HER2)-positive disease is not curable, a small proportion of patients with HER2-positive metastatic breast cancer remain in prolonged complete remission with anti-HER2 treatment. We hypothesized that some cases of HER2-positive metastatic breast cancer may be curable. In this large, multicenter retrospective study, we aimed to assess the long-term outcomes for patients with a durable response to trastuzumab. METHODS: We retrospectively evaluated the data of patients diagnosed with HER2-positive metastatic breast cancer who received trastuzumab for more than 2 years as the first-line treatment. Patients diagnosed between April 1, 2001 and December 31, 2014 at 19 institutions in Japan were included in the analysis. From 124 potential subjects, 16 were excluded and 108 were evaluated. RESULTS: The median follow-up length was 7.7 years. Disease progression occurred in 44/108 (40.7%) patients and 13/108 (12%) patients died. The median progression-free survival was 11.2 years, and as more than 80% of patients were alive 10 years after metastatic breast cancer diagnosis. Of the 108 patients, 57 achieved a clinical complete response. Trastuzumab therapy was interrupted for 27 (47.4%) of these patients (based on the doctor's recommendation for 19 patients, owing to adverse events for 4 patients, owing to unknown reasons for 3 patients, and at the request of 1 patient). Disease progression occurred in 4 of the 27 patients after the interruption of trastuzumab treatment. The median duration of trastuzumab therapy for all 27 patients was 5.1 years (0.9-9.3 years). CONCLUSION: We found that some patients showed no evidence of disease after the interruption of trastuzumab therapy. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while awaiting a global collaborative effort for a randomized trial.

[A Case of Long-Term Survival of the Pancreatic Tail Cancer with the Concomitant Small Liver Metastasis].

We hereby report a case of long-term survival of the pancreatic tail cancer with a synchronous small liver metastasis. A 62- year-old male with pancreatic tail cancer was incidentally diagnosed with single tiny metastasis in the left medial section of the liver duringthe distal pancreatectomy. The lesion was also resected together with primary lesion. Since then, systemic chemotherapies such as gemcitabine(GEM)plus S-1 combination therapy, GEM alone therapy and S-1 alone therapy had been given to escape from recurrence. However, the recurrences were found in the liver at 21 months after surgery. Left hepatectomy was performed for metastatic lesions. Afterwards, proton radiation therapy was twice performed for the metastatic lesions in the liver which were unable to be removed by surgery alone. Partial resection of transverse colon was also needed to be performed for the bowel obstruction caused by recurrence on the surgical margin of the liver. Systemic chemotherapies includingS -1 therapy, FOLFIRINOX therapy and GEM plus nab-paclitaxel therapy have been continued throughout his entire treatment history after recurrence. He has been keepingin good physical condition with these multidisciplinary therapies, even though 51 months have passed since the first evidence of liver metastasis was diagnosed.

[A Case of Long-Term Survival of Metastatic and Recurrent Duodenal Gastrointestinal Stromal Tumor Treated with Multimodality Managements].

We hereby report a case of long-term survival of metastatic and recurrent duodenal gastrointestinal stromal tumor(GIST) treated with multimodality managements. A 59-year-old man was diagnosed with duodenal GIST and underwent surgical resection of a primary lesion of the duodenum. Since the pathological findings on mitotic rate indicated its high risk of recurrence, the systemic treatment by imatinib mesylate was given shortly after the surgery. Six months later, metastatic lesions being considered to be imatinib-resistant were observed in the remnant liver. Since there were no other drugs available for GISTs in clinic at that time, surgery of central bisegmentectomy with partial resection of the liver was performed to eliminate all metastatic lesions. However, recurrences had been repeatedly diagnosed afterward. In response to them, four more surgery for recurrent liver or peritoneal tumors, two transcatheter arterial chemoembolizations(TACE)and one radiofrequency ablation(RFA)were performed on the basis of its resectability. Sunitinib malate had been given since it was approved for imatinib-resistant GISTs in clinic. Eventually, as long as 99 months had passed since we observed the first evidence of the resistance to imatinib mesylate when he died from the GIST.

Randomized phase II study of nab-paclitaxel as first-line chemotherapy in patients with HER2-negative metastatic breast cancer.

Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5-11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4-13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel.

Clinical pattern of primary systemic therapy and outcomes of estrogen receptor-positive, HER2-negative metastatic breast cancer: a review of a single institution.

PURPOSE: In the management of estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (ER+HER2-MBC) patients, endocrine therapy (ET) is preferred to chemotherapy (CT) as a primary systemic therapy (PST) when tumor burden is not high. However, there are no definite criteria for choosing a PST, transitioning from ET to CT or using maintenance ET subsequent to CT. METHODS: We reviewed the medical records of 311 ER+HER2-MBC patients who underwent CT from September 2002 to December 2016 and assessed their outcomes. RESULTS: Of the 311 patients, 178 (57%) received ET as a PST (ET-first group), and 133 (43%) received CT prior to ET (CT-first group). The ET-first group showed a median overall survival (OS) from the diagnosis of MBC (OSMBC) of 1593 days, and the median OS from the initiation of CT (OSCT) was 938 days. Patients with visceral involvement, liver metastasis, soft tissue metastasis, ≥3 organ involvement, or primary advanced BC at the MBC diagnosis showed a significantly higher tendency to be assigned to the CT-first group (P < 0.01 for any visceral involvement, P < 0.05 for all others). Maintenance ET was available in 74 (55.6%) patients in the CT-first group, who showed a significantly better OSMBC and OSCT than patients without maintenance ET (median OSMBC 1423 and 867 days, respectively, P < 0.0001; median OSCT 1350 and 637 days, respectively, P < 0.0001). CONCLUSION: Our findings suggest the possibility for changing the treatment paradigm of patients with ER+HER2-MBC, so a randomized prospective study is warranted to determine the optimum sequence of systemic therapies.

Brain metastasis in patients with metastatic breast cancer in the real world: a single-institution, retrospective review of 12-year follow-up.

PURPOSE: The data of 589 metastatic breast cancer (MBC) patients in a single institution were reviewed to determine the outcomes of patients with brain metastasis (BM) and assess the efficacy of BM screening. METHODS: The patients with BM among the 589 MBC patients who underwent treatment at Shizuoka Cancer Center (Shizuoka, Japan) from 09/2002 to 03/2014 were retrospectively analyzed. RESULTS: During the study period, BM developed in 187 (31.7%) patients. The tumor subtypes were as follows: luminal (hormone receptor [HR]+, HER2-), 44.9%; luminal-HER2 (HR+, HER2+), 14.9%; HER2 (HR-, HER2+), 21.3%; and triple-negative (TN), 16.0%. BM was detected in 48.6% of the patients by screening MRI. While 137 of 187 patients underwent local therapy, whole-brain irradiation was the most frequently applied therapy (63.5%). The median overall survival from the diagnosis of BM was as follows: luminal, 7.0 months (M); luminal-HER2, 13.3 M; HER2, 17.7 M; TN, 4.2 M. The HER2 status (hazard ratio [HR]: 0.58, 95% confidence interval [CI] 0.38-0.88) and nonprogressive extracranial lesion(s) (HR: 0.45, 95% CI 0.29-0.71) were identified as prognostic factors in a multivariate analysis. When limited to HER2-overexpressed MBC patients, the multivariate analysis revealed that non-progressive extracranial lesion(s) (HR: 0.20, 95% CI 0.088-0.47) and stereotactic irradiation (STI) as an initial treatment (HR: 0.18, 95% CI 0.061-0.56) were prognostic factors. CONCLUSIONS: Our retrospective review showed that early detection of BM by screening MRI, followed by STI, improved the prognosis of HER2-overexpressed MBC patients with BM. A further prospective randomized study is needed to confirm our findings.

Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial.

PURPOSE: The randomized phase III JO21095 trial compared the efficacy and safety of low-dose capecitabine plus docetaxel combination therapy (XT) versus single-agent administration of docetaxel in anthracycline-pretreated HER2-negative metastatic breast cancer. METHODS: Patients were randomized to either low-dose XT (capecitabine 825 mg/m2 twice daily, days 1-14; docetaxel 60 mg/m2, day 1 every 3 weeks) or docetaxel (70 mg/m2, day 1 every 3 weeks). The primary objective was to demonstrate superior progression-free survival (PFS) with low-dose XT versus single-agent docetaxel. Overall survival (OS) and safety were secondary endpoints. RESULTS: In total, 162 patients were treated. Median PFS was 10.5 months with low-dose XT and 9.8 months with single-agent docetaxel (hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.40-0.97]; p = 0.03). The OS HR was 0.89 (95% CI 0.52-1.53; p = 0.68). Grade ≥3 treatment-related toxicities occurred in 74% of XT-treated patients and 76% of docetaxel-treated patients. The main differences in grade ≥3 treatment-related toxicities were hand-foot syndrome (7.3% of XT-treated patients vs 0% receiving docetaxel), fatigue/malaise (2.4 vs 10.0%), and peripheral edema (1.2 vs 7.5%). Dose modifications were required in 100% of low-dose XT and 49% of docetaxel patients. Toxicity-related treatment discontinuations occurred in 18 and 33%, respectively. CONCLUSION: The improved PFS with low-dose XT versus docetaxel alone is consistent with higher-dose XT phase III experience, but the safety profile was more favorable and manageable.

Circulating tumor cells as a prognostic marker for efficacy in the randomized phase III JO21095 trial in Japanese patients with HER2-negative metastatic breast cancer.

PURPOSE: Prognostic effects of circulating tumor cells (CTCs) have been reported in metastatic breast cancer (MBC). However, few phase III trials have investigated the potential role of CTCs in treatment selection. We explored potential relationships between CTCs, efficacy, and differential treatment effects. METHODS: Patients with HER2-negative MBC were randomized to receive either concurrent capecitabine plus docetaxel (XT) or sequential single-agent docetaxel followed by single-agent capecitabine at progression (T â†’ X). Blood samples were collected at baseline, on day 1 of cycles 2 and 3, and at progression. CTCs were counted using the CellSearch® System. The relationship between baseline CTC count and outcomes was investigated using a pre-defined threshold of 2 CTCs/7.5 mL. RESULTS: At screening, 44% of the 148 enrolled patients had positive CTC score. In multivariate analyses of pooled treatment arms, positive baseline CTC and triple-negative disease were strongly associated with worse progression-free survival (PFS) and overall survival (OS). Patients with positive CTC score at the baseline had worse OS, irrespective of change in CTC (decreased versus remaining positive) at cycle 2. The prognostic effect of baseline CTC count on OS appeared slightly less pronounced in XT-treated pts. compared with T â†’ X. CONCLUSIONS: A baseline CTC count ≥2 CTCs/7.5 mL was associated with worse prognosis. However, some improvement in PFS and OS was shown with concurrent XT, thus baseline CTC could be a predictive marker. As the current trial was not designed to evaluate a change in chemotherapy according to on-treatment CTC changes, prospective investigation is required.

Safety and effectiveness of eribulin in Japanese patients with locally advanced or metastatic breast cancer: a post-marketing observational study.

Background This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m2) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (≥15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade ≥ 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings.