Predictive factors for response to neoadjuvant chemotherapy: inflammatory and immune markers in triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. However, the TIL level can be determined at a few facilities. By contrast, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily and objectively determined from the results of full blood counts. We conducted a retrospective study to investigate whether TILs, NLR, and PLR predict NAC efficacy and whether NLR and PLR could be surrogate markers for TILs in TNBC. METHODS: Of the 266 patients diagnosed with TNBC between 2013 and 2019, 66 who underwent radical surgery after sequential administration of anthracycline and taxane as NAC were included in the study. TILs, NLR, and PLR were evaluated as predictors of pathologic complete response (pCR) using cutoff values determined from receiver operating characteristic curves. RESULTS: The cutoff values of TILs, NLR, and PLR were 20%, 2.6, and 180, respectively. High TIL level was associated with low NLR (P = 0.01) and low PLR (P = 0.01). High TIL level (odds ratio [OR] 4.28 [95% CI 1.40-13.1]; P = 0.01), low NLR (OR 5.51 [95% CI 1.60-18.9]; P = 0.01), and low PLR (OR 3.29 [95% CI 1.13-9.57]; P = 0.03) were associated with pCR. Low NLR predicted pCR independently (OR 6.59 [95% CI 1.45-30.0]; P = 0.01). CONCLUSIONS: TILs, NLR, and PLR predicted NAC efficacy against TNBC. TIL level was associated with NLR and PLR. NLR was an independent predictive factor and may be a useful surrogate marker for TILs when predicting pCR.

A Comparison of the Oncological Outcomes After Breast-Conserving Surgery With or Without Latissimus Dorsi Myocutaneous Flap Reconstruction for Breast Cancer.

BACKGROUND: There is little information on the oncological outcomes of breast-conserving surgery (BCS) with immediate reconstruction using a latissimus dorsi myocutaneous flap (LDMF) for breast cancer compared with BCS alone. PATIENTS AND METHODS: We conducted a retrospective cohort study from a single institution comparing the margin positivity rates after initial surgery, re-excision rates, and local recurrence (LR) between BCS with immediate LDMF reconstruction (n = 145) and BCS alone (n = 1040) performed from 2012 to 2017 for newly diagnosed stage 0-3 breast cancer. RESULTS: The positive rates of surgical margin after initial surgery were significantly lower in the BCS with LDMF group than in the BCS alone group (4.1 vs. 10.8%; P = .006). There were no marked differences in the re-excision rates between the BCS with LDMF and BCS alone groups (P = .1). At a median follow-up of 61 months, the surgical method (BCS with LD vs. BCS alone) was not associated with the LR-free survival after adjusting for various clinicopathologic factors (P = .8). CONCLUSION: Our findings suggest that BCS with immediate LDMF reconstruction is oncologically safe for breast cancer compared with BCS alone. However, further studies are needed.

Axillary management based on American college of surgeons oncology group Z0011 criteria makes it possible to omit intraoperative diagnosis of sentinel lymph nodes in early breast cancer patients.

The ACOSOG Z0011 trial has resulted in the omission of axillary lymph node dissection (ALND) in early breast cancer patients with one or two metastatic sentinel lymph nodes (SLNs). There has been increasing interest in the necessity of intraoperative assessment of SLNs in patients treated based on the Z0011 criteria. We evaluated the utility of intraoperative assessment in these eligible patients. A total of 1396 patients were treated following the Z0011 criteria from April 2012 to December 2019. We examined the proportion and clinicopathological features of patients who underwent ALND due to three or more metastatic SLNs and the sensitivity of intraoperative assessment. Only 16 (1.1%) patients had three or more metastatic SLNs diagnosed by intraoperative assessment, and they immediately underwent ALND. Of the clinicopathological factors, high clinical tumor stage (p = 0.002) and high Ki-67 labeling index value (p = 0.056) were more likely to be associated with the presence of three or more metastatic SLNs. The major independent risk factor for three or more metastatic SLNs was high clinical tumor stage (OR 3.94 [95% CI 1.42-11.0]; p = 0.009). Intraoperative assessment had low sensitivity (70.5%) and a high false-negative rate (29.5%) in detecting SLN metastases. The main finding of our study was the small proportion of patients who required ALND due to three or more metastatic SLNs according to the Z0011 criteria. The Z0011 strategy enables intraoperative assessment of SLNs to be omitted in early breast cancer patients.

Cerebellar preference of luminal A and B type and basal ganglial preference of HER2-positive type breast cancer-derived brain metastases.

The purpose of the current study was to investigate the hypothesis that the spatial distribution of brain metastases could be affected by the biological subtypes of breast cancer. CT (n=1) or MRI (n=66) images of 67 patients with a total of 437 treatment-naive brain metastases from breast cancer were retrospectively reviewed. Patients were grouped according to the biological subtype of the tumor [luminal A, 28; luminal B, 9; human epidermal growth factor receptor 2 (HER2) positive, 14; triple-negative breast cancer (TNBC), 16]. All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. The distribution pattern of brain metastases after image standardization was analyzed. The cerebellum and the frontal lobe were more commonly affected by breast cancer brain metastases. Brain metastases from luminal A and B types of breast cancer arose more often in the cerebellum. Brain metastases from HER2-positive type breast cancer occurred more often in the putamen and the thalamus and less frequently in the cerebellum than other types (P=0.0057). The subtypes of breast cancer are related to differences in the spatial distributions of their brain metastases. These differences may be utilized to plan different cranial irradiation strategies according to the breast cancer subtypes.

α-Methylacyl-CoA racemase: a useful immunohistochemical marker of breast carcinoma with apocrine differentiation.

Carcinoma with apocrine differentiation is an androgen receptor (AR)-positive subset of triple-negative breast carcinomas. In addition to carcinoma with apocrine differentiation, other AR-positive triple-negative breast carcinomas occur, albeit less frequently. We found that α-methylacyl-CoA racemase (AMACR), also known as P504S, is overexpressed in carcinoma with apocrine differentiation and non-neoplastic apocrine metaplasia. We aimed to evaluate AMACR as a possible marker of carcinoma with apocrine differentiation. We immunohistochemically examined the expression of AMACR in carcinoma with apocrine differentiation and nonapocrine carcinomas and compared it with that of gross cystic disease fluid protein-15 (GCDFP-15). In total, 212 breast carcinomas were evaluated: 39 carcinomas with apocrine differentiation, 28 ductal carcinomas in situ with apocrine morphology (ADCIS), and 145 nonapocrine breast carcinomas. AMACR was expressed in 38 of 39 (97.4%) carcinomas with apocrine differentiation and in 27 of 28 (96.4%) ADCIS, consistent with the expression of GCDFP-15. However, in nonapocrine carcinomas, AMACR expression was observed in 32 of 145 (22.0%) lesions, whereas GCDFP-15 expression was observed in 91 of 145 (62.7%) lesions. For carcinoma with apocrine differentiation, AMACR was as sensitive as GCDFP-15 (both 97.1%) but more specific (77.9% versus 37.2%). In selected cases, AMACR messenger RNA (mRNA) levels were quantitatively determined relative to that of TATA-binding protein mRNA, and they comprised 5.23, 1.33, and 0.60 for carcinomas with apocrine differentiation, nonapocrine carcinomas, and normal breast tissue, respectively. CONCLUSION: Our findings demonstrate that AMACR expression may be used for differentiating carcinoma with apocrine differentiation from nonapocrine carcinomas and indicate that AMACR is a more sensitive carcinoma with apocrine differentiation marker than GCDFP-15.

Prevalence of BRCA1 and BRCA2 mutations in Japanese patients with triple-negative breast cancer: A single institute retrospective study.

Numerous databases for risk assessment of BRCA1/2 gene mutations contain insufficient data about Asians. Furthermore, few studies have reported the prevalence of germline BRCA1/2 mutations in Japanese patients, particularly those with triple-negative breast cancer (TNBC). The present study was a retrospective analysis of data from patients with TNBC who underwent BRCA1/2 mutation testing at Osaka International Cancer Institute (Osaka, Japan) between October 2014 and March 2020. A total of 65 patients with TNBC underwent a test for BRCA1/2 mutations, and 13 (20.0%) had deleterious mutations in the BRCA1 or BRCA2 genes. Furthermore, 12 out of 29 patients with a family history of breast or ovarian cancer had deleterious BRCA1/2 mutations, and only 1 of 34 without a family history had a mutation (41.4 vs. 2.9%; P=0.014). No patients aged >60 years had BRCA1/2 mutations; however, the age of diagnosis was not a significant risk factor for BRCA1/2 mutations (P=0.60). The prevalence of BRCA1/2 mutations in the present cohort of Japanese patients with TNBC was slightly higher than those reported in other larger studies from Europe and North America. Further data from large prospective studies are required to more precisely define the prevalence of BRCA1/2 mutations.

STK11 loss drives rapid progression in a breast cancer patient resulting in pulmonary tumor thrombotic microangiopathy.

We experienced a case of breast cancer in which liver metastases spread rapidly and the patient died of pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is a fatal cancer-associated respiratory complication disease. To reveal genetic alterations of the clinical course, we performed next generation sequencing of the serial specimens using the Ion AmpliSeqTM Comprehensive Cancer Panel and RNA sequencing for transcriptomic data, followed by gene set analysis. The analysis revealed an oncogenic TP53 R213* mutation in all specimens and STK11 loss in tissues sampled after disease progression. Immunohistochemistry with an anti-STK11 antibody confirmed no STK11 expression in the samples after progression. Transcriptome analysis showed a significant downregulation of proteins associated with apoptosis in the specimens with STK11 loss. STK11 loss may have triggered the rapid progression of PTTM from a comprehensive genomic analysis.

[Primary Rhabdomyosarcoma of the Breast in a 16-Year-Old Girl].

We report a case of primary breast rhabdomyosarcoma. A 16-year-old girl noticed tumor of her right breast and consulted a local clinic. From the result of core needle biopsy, breast sarcoma was suspected, so she attended our hospital. Breast ultrasonography showed a mosaic pattern tumor occupying the whole right breast. CT images revealed an axillary node metastasis and no distant organ metastasis. Immunohistochemical staining of the tumor yielded positive results for desmin, MyoD1, and myogenin. Based on reverse transcription polymerase chain reaction(RT-PCR), she was diagnosed as an alveolar rhabdomyosarcoma with PAX3-FKHR(FOXO1)fusion transcripts[t(2;13)(q35;q14)]. She underwent total mastectomy and dissection of axillary lymph nodes. After surgery, the whole-body magnetic resonance imaging(MRI) demonstrated metastases of sacrum and left foot, so she was under systemic chemotherapy.

Current status of endoscopic surgery in Japan: The 14th National Survey of Endoscopic Surgery by the Japan Society for Endoscopic Surgery.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every two years to evaluate the status of endoscopic surgery over time. In 2017, 248 743 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 14th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2016-2017.

Performance of a new system using a one-step nucleic acid amplification assay for detecting lymph node metastases in breast cancer.

One-step nucleic acid amplification (OSNA) for CK19 mRNA is an intraoperative diagnostic procedure for detection of lymph node metastasis. Automated Gene Amplification Detector RD-200 and the LYNOAMP CK19 gene amplification reagent as components of a new OSNA system have been developed. As an improvement over a conventional system, the new system can analyze 14 samples per run, evaluate two lymph nodes in ~ 17 min, and reduce inhibition of reactions. This study was aimed at evaluating clinical performance of the new system by comparing it with performance of histopathological analysis and a conventional OSNA system. A total of 150 lymph nodes in 63 breast cancer patients (T1-3) who underwent sentinel lymph node biopsy or axillary lymph node dissection were examined intraoperatively with the new OSNA system, the conventional system, and histopathological analysis. In comparison with histopathological analysis, sensitivity, specificity, and concordance rate of the new system were 93.9, 98.8, and 96.7%, respectively. In comparison with the conventional system, similar corresponding values were obtained: 96.9, 98.8, and 98.0%, respectively. The results show that clinical performance of the new OSNA system is equivalent to that of histopathological diagnosis and the conventional OSNA system. The new system is superior to the conventional one because of processing of a greater number of samples, shorter testing time, and the absence of inhibited reactions.

Endoscopic surgery in Japan: The 13th national survey (2014-2015) by the Japan Society for Endoscopic Surgery.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, the operative procedure has been standardized, and the safety and usefulness of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less-invasive surgery, the number of endoscopic procedures has been increasing in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. For example, JSES established a technical skills certification system for surgeons to train instructors how to teach safe endoscopic surgery, and the organization performs a national survey every 2 years. In 2015, a total of 211 953 patients underwent endoscopic surgery in all surgical domains, including abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The course of laparoscopic surgery's development and its current status are reported here based on the results of the most recent questionnaire survey conducted by JSES.

Reliability of Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Expression on Breast Cancer Cells Stored in Cellprep® Vials.

OBJECTIVE: The aim of this study was to evaluate the reliability of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) expression levels in Cellprep® (CP). STUDY DESIGN: We evaluated the stability of immunocytochemistry (ICC) of ER and HER2 for primary or recurrent breast cancer samples rinsed in CP vials. Samples were prepared from CP vials stored for 1-30 or 160-240 days. ER and HER2 statuses were determined after 1-30 days (26 and 25 tests, respectively) or 160-240 days (15 and 18 tests, respectively) with the same protocols as immunohistochemistry (IHC), and were compared with the corresponding surgically resected specimens. RESULTS: ER statuses according to CP samples showed perfect agreement (1-30 days: kappa, κ = 1; 160-240 days: κ = 1). HER2 statuses also showed good agreement (1-30 days: κ = 0.79; 160-240 days: κ = 0.64), although there were more equivocal HER2 cases in CP than in the surgically resected specimens. CONCLUSION: ER ICC in CP vials is reliable regardless of the preservation period. HER2 ICC in CP has more equivocal cases than HER2 IHC in surgically resected specimens. Both improvement of the immunostaining protocol and further validation study of in situ hybridization are indispensable for the practical application of ICC in CP.

A prospective feasibility study applying the ACOSOG Z0011 criteria to Japanese patients with early breast cancer undergoing breast-conserving surgery.

BACKGROUND: In patients undergoing breast-conserving surgery and having positive sentinel lymph nodes (SLNs), the ACOSOG Z0011 trial showed equivalent loco-regional outcomes for patients receiving SLN dissection (SLND) alone and those receiving axillary lymph node dissection (ALND). We conducted a prospective single-arm study to confirm the applicability of the Z0011 criteria to Japanese patients with breast cancer. METHODS: Patients meeting the Z0011 inclusion criteria and providing consent to receive no additional ALND were prospectively enrolled at the Osaka International Cancer Institute from April 2012 to December 2016. Cumulative incidence of loco-regional recurrence was estimated and compared to that of the Z0011 study. RESULTS: Among a total of 881 patients who underwent breast-conserving surgery, 189 fulfilling the Z0011 criteria were enrolled and eligible for the subsequent analysis. Adjuvant chemotherapy was given to 113 (59.8%) patients, adjuvant hormone therapy to 170 (89.9%), and whole breast irradiation to 183 (96.8%). The frequency of tumors with positive lymphovascular invasion (p < 0.0001) and macrometastases in SLNs (p < 0.0001) were significantly higher in our study than in the Z0011 study. At the median follow-up of 36 months (range 10-64 months), only 2 of 189 patients (1.1%) experienced loco-regional recurrence. The 5-year cumulative rate of loco-regional recurrences was 1.3% (95% CI 0-3.1%), and the 3-year distant DFS rate was 96.8% (95% CI 94.0-99.6%). CONCLUSIONS: Our prospective study showed that it is feasible to apply the Z0011 strategy to Japanese patients with clinically node-negative breast cancer undergoing breast-conserving surgery with planned whole breast irradiation.

pTis and pT1a Ipsilateral Breast Tumor Recurrence Is Associated with Good Prognosis after Salvage Surgery.

OBJECTIVES: Patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery have a poor prognosis. There is little information regarding the prognostic impact of the tumor size in patients with IBTR. METHODS: A total of 143 patients who had histologically confirmed IBTR without distant metastases and who underwent salvage surgery between 1989 and 2013 in our hospital were included. Distant disease-free survival (DDFS) was calculated according to the invasive tumor size of IBTR. The median follow-up period was 4.6 years. RESULTS: Patients with pT1b or more advanced IBTR have a high (≥20%) 5-year distant recurrence risk. There were significant differences in DDFS between patients with pTis or pT1a and those with pT1b or a more advanced stage (5-year DDFS: 94.4 vs. 70.1%, respectively, p value = 0.006). This significance remained after adjusting for other clinicopathological factors (p value = 0.04). CONCLUSION: Patients with pTis or pT1a IBTR have a good prognosis after salvage surgery for IBTR, and the omission of adjuvant chemotherapy could be considered. Further research and validation studies are needed.

Erratum: A high-salt diet enhances leukocyte adhesion in association with kidney injury in young Dahl salt-sensitive rats.

This corrects the article DOI: 10.1038/hr.2017.31.

Endoscopic surgery in Japan: The 12th national survey(2012-2013) by the Japan Society for Endoscopic Surgery.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and usefulness of endoscopic surgery have been evaluated. With the acceptance of endoscopic surgery as less invasive than open surgery, the number of the endoscopic procedures continues to increase in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has had an important role in the development of endoscopic surgery in Japan. For example, JSES established a technical skills certification system for physicians to train instructors to teach safe endoscopic surgery. Additionally, JSES has performed a national survey every 2 years. In 2013, 178 084 patients underwent endoscopic surgery in all surgical domains, including abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The development and current status of laparoscopic surgery are reported here based on the results of the most recent questionnaire survey conducted by JSES.

Safety for Repeat Lumpectomy Without Radiotherapy for Ipsilateral Breast Tumor Recurrence.

BACKGROUND: There is little information on the local recurrence risk of patients who undergo repeat lumpectomy without radiotherapy after salvage surgery for ipsilateral breast tumor recurrence (IBTR). PATIENTS AND METHODS: Sixty-five patients who underwent repeat lumpectomy without radiotherapy after IBTR were retrospectively analyzed. The risk factors of second IBTR, including the breast cancer subtype of IBTR defined by the estrogen receptor (ER) and HER2 status, were assessed. RESULTS: The median follow-up period was 62 months. The 5-year second IBTR-free survival rate was 83%. Patients with the ER-positive/HER2-negative subtype of IBTR had a significantly better second IBTR-free survival rate than those with other subtypes of IBTR (88% vs. 75%, respectively, p=0.02). Multivariate analysis revealed that the breast cancer subtype of IBTR was a significantly independent predictive factor of second IBTR-free survival (p=0.003). A low-risk group for second IBTR, defined by the breast cancer subtype of IBTR and margin status of primary surgery, was detected (5-year second IBTR-free survival rate: 100%). CONCLUSION: Patients in the low-risk group defined by the breast cancer subtype of IBTR and margin status of primary surgery could safely undergo repeat lumpectomy without radiotherapy for IBTR.

Distant recurrence risk following early ipsilateral breast tumor recurrence.

At present, the risk factors for distant recurrence among patients with early ipsilateral breast tumor recurrence (IBTR) require further investigation. Early IBTR is defined as occurring within 3 years following the initial surgery. In the current study, 40 patients with early IBTR were examined to determine the risk factors for distant recurrence. A node-positive status at the time of primary surgery and the administration of adjuvant chemotherapy following the primary surgery were significantly correlated with poorer distant disease-free survival (P=0.001 and P=0.002, respectively). Multivariate analyses revealed that the nodal status at the time of primary surgery was an independent predictive factor for distant recurrence (P=0.050). Therefore, the results of the current study revealed that the nodal status at the time of primary surgery was an independent predictive factor for distant recurrence among patients with early IBTR.

A high-salt diet enhances leukocyte adhesion in association with kidney injury in young Dahl salt-sensitive rats.

Salt-sensitive hypertension is associated with severe organ damage. Generating oxygen radicals is an integral component of salt-induced kidney damage, and activated leukocytes are important in oxygen radical biosynthesis. We hypothesized that a high-salt diet causes the upregulation of immune-related mechanisms, thereby contributing to the susceptibility of Dahl salt-sensitive rats to hypertensive kidney damage. For verifying the hypothesis, we investigated leukocytes adhering to retinal vessels when Dahl salt-sensitive rats were challenged with a high-salt (8% NaCl) diet using acridine orange fluoroscopy and a scanning laser ophthalmoscope. The high-salt diet increased leukocyte adhesion after 3 days and was associated with a significant increase in mRNA biosynthesis of monocyte chemotactic protein-1 and intercellular adhesion molecule-1 (ICAM-1) -related molecules in the kidney. Losartan treatment did not affect increased leukocyte adhesion during the early, pre-hypertensive phase of high salt loading; however, losartan attenuated the adhesion of leukocytes during the hypertensive stage. Moreover, the inhibition of leukocyte adhesion in the pre-hypertensive stage by anti-CD18 antibodies decreased tethering of leukocytes and was associated with the attenuation of functional and morphological kidney damage without affecting blood pressure elevation. In conclusion, a high-salt challenge rapidly increased leukocyte adhesion through the over-expression of ICAM-1. Increased leukocyte adhesion in the pre-hypertensive stage is responsible for subsequent kidney damage in Dahl salt-sensitive rats. Immune system involvement may be a key component that initiates kidney damage in a genetic model of salt-induced hypertension.

Efficacy and safety of re-induction therapy with bevacizumab and paclitaxel for metastatic breast cancer.

BACKGROUND: In many trials (including E2100), bevacizumab (Bmab) monotherapy has been continued if toxicity of paclitaxel (PTX) becomes unacceptable during combined treatment with Bmab and PTX. When progression occurs on Bmab monotherapy, one possible option is re-induction with the combination of Bmab and PTX (rBP therapy), because PTX was previously stopped due to toxicity rather than progression. However, we have no data about rBP therapy. Therefore, we investigated the efficacy and safety of rBP therapy in this study. METHODS: We retrospectively investigated 46 patients who started Bmab and PTX between October 2011 and April 2013 at our institution. RESULTS: After induction with Bmab and PTX, 19 patients subsequently received Bmab monotherapy and 12 patients received rBP therapy. The overall response rate and clinical benefit rate of rBP therapy was 25 % (3/12) and 58 % (7/12), respectively, while the median time to failure of rBP therapy was 174 days (95 % CI 49-273). The median overall survival time of the 46 patients was 777 days (95 % CI 543-NA). Adverse events of grade 3 or worse associated with rBP therapy were neutropenia (25 %), fatigue (8 %), and gastrointestinal bleeding (8 %). CONCLUSIONS: This is the first report about rBP therapy, which was found to be both safe and effective. The OS of all 46 patients in this study (including 12 patients given rBP therapy) was better than in past reports. Selecting rBP therapy for patients with progression on Bmab monotherapy might have contributed to better overall survival, but a randomized controlled trial will be needed to confirm these findings.