e12601 Background: Based on the Norton-Simon model, dose-dense (dd) chemotherapy with shortened intervals between administrations has been adopted in perioperative chemotherapy for breast cancer. However, the safety and efficacy of dd chemotherapy in neoadjuvant settings have not been thoroughly investigated. Methods: The aim of this study is to evaluate the efficacy and safety of dd versus standard regimen in neoadjuvant chemotherapy. The patients with HER2-negative breast cancer who underwent neoadjuvant chemotherapy (NAC) with anthracycline-taxane were continuously identified between 2014 and 2023. These patients were divided into a triple negative breast cancer (TNBC) cohort with HR < 10% and a luminal cohort with hormone receptor (HR) ≥ 10%, and pathologic complete response (pCR) and relapse-free survival (RFS) were evaluated in each group. Results: A total of 525 patients with HER2-negative breast cancer were identified from 11 institutions in Japan. In the overall cohort, 229 patients were in the dd group and 296 patients were in the standard group, with no significant differences between the two groups in terms of age, nuclear grade (NG), T and N categories. In the dd group, 100% of the cases received dd AC/EC, and 75% of the cases received dd PTX. The pCR rate in the TNBC cohort was 42% in the dd group and 32% in the standard group (p=0.101), and in the subgroup with HR < 1%, it was 39% and 30%, respectively (p=0.167). In the Luminal cohort, the pCR rate for NG3 vs. NG1 or 2 was 27% and 5%, respectively (p=0.005), but in NG3 was 12% in the dd group and 16% in the standard group each(p=0.445). Regarding RFS in the dd group and the standard group, no significant differences were observed in either the TNBC cohort or the Luminal cohort (Logrank P =0.516, 0.946, with median follow up periods of 33 months and 56 months, respectively). The average relative dose intensity of chemotherapy was 96.5% in the dd group, and 95.3% in the standard group. The mean period from the first NAC administration to surgery was 140 days in the dd group and 191 days in the standard group. The incidence of adverse events (AEs) was significantly higher in the standard group compared to the dd group, with a particularly higher incidence of Grade 3 or higher neutropenia and peripheral neuropathy. When analyzed by age, the incidence of neutropenia was significantly higher in the standard group in patients under 65 years of age. Conclusions: This study is the first to demonstrate the safety and efficacy of the dd regimen in NAC for Japanese breast cancer patients. The dd regimen, compared to the standard, showed comparable results in terms of AEs, pCR rate, and prognosis. With a shorter treatment duration, the dd regimen should be considered a preferred NAC regimen for breast cancer. Further evaluation is needed to assess the long-term survival.

β-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases. A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13 weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates. Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89. This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

OBJECTIVE:Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel.METHODS:In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis.RESULTS:One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E.CONCLUSION:Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

Background/Aim: We evaluated the impact of the relative dose intensity (RDI) of neoadjuvant chemotherapy (NAC) on the survival of patients with breast cancer (BC). Patients and Methods: This randomized phase II trial included 188 patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with anthracycline followed by paclitaxel as NAC. We grouped patients using a relative dose intensity (RDI) threshold of 85% and evaluated clinicopathological features and clinical outcomes. Results: The 5-year overall survival rate was 91.2% and 76.3%, when RDI ≥85% and <85%, respectively (p=0.015). Age, tumor, and node status, and the RDI were significantly different on univariate analysis, but not on multivariate analysis. An exploratory subgroup analysis revealed that a low RDI was associated with low overall survival of patients with obesity, T1/2 disease, and lymph node metastases. Conclusion: Maintaining the RDI of NAC is crucial for achieving the survival benefit in selected patients with HER2-negative BC.

Background Breast cancer is well known to tends to invade through the lymphatic chains mainly to the axillary and subclavian nodes or occasionally to the internal mammary nodes. However, inguinal lymph node metastasis from breast cancer is extremely rare. Case presentation We have experienced a case of an 82-year-old woman showing left inguinal lymph node metastases from right breast cancer. Previously, she had received five times abdominal operations and left artificial bone head replacement for metamorphous hip-joint disease. Although the metastases were firstly detected 46 months after the breast surgery, they had already existed at the time of the breast operation, which was retrospectively re-evaluated by CT examination. The progression pattern of inguinal lymph node metastases had much correlated with that of the breast cancer. She underwent inguinal lymph node dissections. Pathological findings revealed them being compatible with breast cancer origin. Conclusions This is the sixth case having been reported in English literature. Besides, this is the first case showing the contralateral spread to the primary breast cancer. One of the causes of this complex metastatic pattern is thought be ascribed to the previously performed prolific abdominal operations.

Background Chyle leakage is a well-known complication after thoracic surgery, such as esophagectomy, cardiac surgery, mediastinal lymph node dissection, and neck surgery. However, chyle leakage is a rare complication after dissections of the lateral or subclavian axillary nodes for breast surgery. It is particularly unusual for chyle leakage to occur after minimally invasive dissection of the axillary nodes. Most cases of chyle leakage subside with conservative management, but some cases require surgery. Case report An 80-year-old woman had invasive lobular cancer of the left breast (cT1 [1.7 cm], cN0, M0) for which she underwent breast-conservative surgery and biopsy of an axillary sentinel lymph node. Because two of the three sentinel lymph nodes tested positive for cancer, seven lateral axillary lymph nodes (level I) were subsequently removed for the additional sampling. On postoperative day 11, the patient visited our outpatient clinic because of swelling in her left axillary region and breast. Centesis of the axilla yielded 670 mL of milky fluid, which suggested chyle leakage. We commenced the conservative management at first; however, the persistent leakage made us perform the surgical management. The operation was not only ligating the opening of the chyle duct but needed total mastectomy because the postoperative pathology report showed invasive lobular carcinoma; the nipple and the caudal surgical margin of the lumpectomy were positive for cancer. The patient agreed to our recommendation of total mastectomy and surgical management of the chyle leakage. Ligation of the opening completely resolved the chylous discharge. Conclusion We here report a case of large-volume leakage of chyle after sampling dissection of the lateral axillary lymph nodes for left breast cancer; the leakage persisted despite the standard conservative therapy but was resolved after surgical treatment. Chyle leakage can occur even after minimally invasive dissection of the axillary nodes.

Background: Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI. Methods: In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated. Results: Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis. Conclusion: In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.

Abstract Background: Eribulin mesylate (ERI) improved the overall survival in metastatic breast cancer (BC) patients. However, the efficacy has not been reported in early breast cancer. We performed the neoadjuvant chemotherapy (NAC) study based on hypothesis that ERI is less toxic, particularly in peripheral neuropathy, and has similar efficacy to paclitaxel (PTX) in patients with operable BC. Methods: This is a multicenter open label randomized phase 2 study (UMIN000012817). Patients were randomly assigned to either ERI (1.4mg/m2, d1 and d8, q21 days, 4 cycles) followed by FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) (ERI-FEC) or PTX (80mg/m2, weekly, 12 cycles) followed by FEC (PTX-FEC) with stratified by ER, HER2, and menopausal status. Trastuzumab was added in patients with HER2 positive disease. Primary endpoint was the incidence of peripheral sensory and motor neuropathy (PSN and PMN) with Grade 1 or higher according to CTCAE ver.4.0. Secondary endpoints were pathological complete response (pCR) rates (ypT0/is/ypN0), clinical response rates (CR+PR), adverse events, disease-free survival (DFS) and patient neurotoxicity questionnaire (PNQ) analysis. Here, we report 3 year’s DFS and PNQ analysis in this study Results: Between December 2013 to March 2016, 121 cases were enrolled and 5 cases were excluded from the primary assessment. One hundred sixteen cases were finally randomized and treated by ERI-FEC in 58 cases and PTX-FEC in 57 cases. A median follow-up time of ERI-FEC and PTX-FEC was 54.2 and 51.4 months, respectively. Three year-DFS rate were 89.7% in the ERI-FEC group (95% CI 51.1 - 57.3) and 86.0% in the PTX-FEC group. (p=0.561). The incidences of PSN and PMN were significantly lower in the ERI-FEC group than the PAX-FEC group at the end of treatments (previously reported). PNQ analysis after treatments is now undergone. Conclusion: DFS was not different between them. Although the pCR rate was lower in ERI-FEC than PAC-FEC as reported at the previous meeting. ERI was more favorable on adverse events than PTX during NAC treatments. Long-term results on neurotoxicity of these two drugs will be presented at the meeting. Citation Format: Takahiko Kawate, Takashi Ishikawa, Daishu Miura, Yoshie Hasegawa, Akihiko Tachibana, Jun Horiguchi, Mitsuhiro Hayashi, Masaru Miyashita, Tomoyuki Kubota, Kazutaka Narui, Masato Suzuki, Kouhei Akazawa, Norio Kohno. Randomized controlled trial of neoadjuvant eribulin mesylate versus paclitaxel in women with operable breast cancer (JONIE-3 study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-07.

BACKGROUND: Anthracycline-containing regimens are standard treatment options in adjuvant and neoadjuvant chemotherapy in breast cancer. Chemotherapy-induced nausea and vomiting (CINV) is experienced frequently in patients receiving these regimens, but the risk factors for CINV are unknown. OBJECTIVE: The aim of this study was to investigate risk factors for CINV in anthracycline-containing regimens retrospectively. METHODS: Data were collected from the JONIE study, which was conducted in order to estimate the efficacy of zoledronic acid in a neoadjuvant setting from March 2010 to June 2012 (UMIN000003261). A total of 180 patients were recruited, and we used CINV data from the first cycle of FEC100 treatment and patient backgrounds. As the protocol regulation allowed the use of antiemetic drugs,in the first cycle of the FEC100 regimen, patients received various types of antiemetic agents, which we classified into four groups: Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3)+neurokinin-1 receptor antagonist (NK1) (DEX+5-HT3+NK1) group; Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3) (DEX+5HT3) group; Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3)+dopamine receptor antagonist (DRA) (DEX+5HT3+DRA) group; and Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3)+neurokinin-1 receptor antagonist (NK1)+ dopamine receptor antagonist (DRA) (DEX+5-HT3+NK1+DRA) group. Risk factors were selected from patient backgrounds and the combinations of antiemetic drugs. In patient backgrounds, the body mass index (BMI) was stratified into 3 categories: Less than 18.5 (underweight group); equal to or more than 18.5 but less than 25 (standard BMI group); and equal to or more than 25 (overweight group). The risks for CINV were analyzed by univariate and multivariate analyses. P values of less than 0.05 were defined as significant. RESULTS: In a univariate analysis of nausea, the body mass index (BMI) was the only significant factor (P CONCLUSIONS: This study revealed that BMI was the most important risk factor for nausea, and that BMI and the combination of antiemetic drugs were risk factors for vomiting. Underweight-patients tend to have CINV in anthracycline-containing regimen. The DEX+5-HT3+NK1 group was the best antiemetic drug combination. These result show that following the CINV guideline treatment is mandatory in order to prevent CINV. Citation Format: Hayashi M, Nakazawa K, Hasegawa Y, Horiguchi J, Miura D, Ishikawa T, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Tanino Y, Yamada K, Kimura K, Akazawa K, Kohno N. Risk analysis for chemotherapy induced nausea and vomiting (CINV) in patients receiving FEC100 treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-07.

BACKGROUND/AIM:Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated.PATIENTS AND METHODS:Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses.RESULTS:In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant.CONCLUSION:BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

Abstract Background: It is well known that the prognosis of non pCR TNBC patients was poor after anthracycline and taxan treatment. For such patients, capecitabine seems to be effective to reduce recurrence based on the HR 0.58 of the CREATE X trial (Masuda, N. et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 376, 2147. 2017) . However, the target of capecitabine is still unclear for TNBC. We classified non pCR tumors as BRCAness and Sporadic using BRCAness test(MRC-Holland, Amsterdam, the Netherlands). The recurrence rate of the BRCAness group was about 70%. Carboplatine is expected to be effective against BRCAness tumors, as it is a DNA damaging agent. In this study BRCAness can be checked just before carboplatin treatment using surgical specimens. Then the efficacy of carboplatin will be directly known to make comparison between DFS in the carboplatin group and that of the observation group. Trial design: This is anopen label, randomized phase III study that will enroll TNBC with residual invasive cancer after surgery with preoperative chemotherapy including both anthracycrine and taxan. Patients are randomly assigned to either the carboplatin group or observation group. The patients in the carboplatin group are treated with carboplatin at AUC 6 and those in the observation group are observed at only 3 years. Eligibility criteria: 1) ER and PgR<1%, HER2 0, 1+ or 2+ with FISH negative on core needle biopsy before the chemotherapy and surgical specimens. 2) Preoperative chemotherapy including both anthracycrine and taxan. 3) Residual invasive cancer on breast tumors or lymph node metastasis in surgical specimens. 4) 20-79 year old women. 5) No chemotherapy within 5 years. 6) Not bilateral breast cancer, without metastasis, no prior breast cancer. 7) No severe bone marrow suppression. Specific aims:Primary objective is DFS (Disease Free Survival). Secondary objectives are overall survival and safety. STATISTICAL METHODS: The 3 years recurrence rate of the observation group was estimated as 40% and hazard ratio at 0.58 based on the CREATE X trial. For both groups, 135 patients are necessary. This study is powered to approximately 80% to test the superiority of carboplatin group at a 2-sided α=0.05 using a stratified log-rank test. Activation Date:22ndMarch 2018. No patients had been enrolled till 3rd July. Citation Format: Tanino H, Suzuki M, Kaise H, Miyashita M, Chishima T, Hayashi M, Miyoshi Y, Futamura M, Ohtani S, Nagahashi M, Ohta T, Kosaka Y, Ishikawa T, Hasegawa Y, Kubota T, Sangai T, Iwatani T, Yamada A, Akazawa K, Kohno N. Phase 3 trial of carboplatin in triple negative breast cancer (TNBC) patients with residual invasive carcinoma after neoadjuvant chemotherapy (JONIE4:J-CAT trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-05-04.

Background: Diagnostic imaging is important for predicting the pathological response to chemotherapy during neoadjuvant chemotherapy (NAC) and for considering the surgical management with appropriate resection after NAC. This study was performed to examine the accuracy of the present radiological imaging for predicting the pathological complete response (pCR). Methods: From 188 patients in our previous JONIE1 Study, a randomized controlled trial comparing chemotherapy with and without zoledronic acid for patients with human epidermal growth factor receptor 2-negative breast cancer, we evaluated 122 patients whose tumor size was examined by magnetic resonance imaging or ultrasound at three points: before NAC; after administering fluorouracil, epirubicin, and cyclophosphamide; and after NAC. The maximum tumor diameter was evaluated by magnetic resonance imaging or ultrasound. Tumor reduction ratios were calculated at the same three points. The association between the radiological clinical response and the pCR was examined. Results: Among the 122 patients evaluated, there were 98 and 24 patients with luminal (Lum) and triple-negative (TN) subtypes, respectively. There were no patients who showed tumor progression after treatment. The radiological size of the tumors was finally reduced by an average of 58.4%. Clinical complete response and pCR were achieved in 22 (18.0%) and 15 (12.3%) patients, respectively. In the overall population (n = 122), the accuracy, sensitivity, and specificity for predicting pCR were 86.1%, 88.8%, and 66.7%, respectively. The negative predictive value and false-negative rate were 45.5% and 11.2%, respectively. According to subtypes, the accuracies were 83.7% and 95.8% in Lum and TN, respectively. Negative predictive value and false-negative rate were markedly different between the Lum (29.4% and 13.5%) and TN subtypes (100% and 0%), respectively. Conclusions: This randomized clinical trial demonstrated that NAC was safe for operable breast cancer patients with appropriate radiological monitoring. Radiological evaluation after NAC may be a reliable method for predicting pathological response in the TN subtype, but not in the Lum subtype. (C) 2017 Elsevier Inc. All rights reserved.

Abstract Background: Although treatment of eribulin mesylate (E) improved overall survival in metastatic breast cancer (BC) patients, little is known about the efficacy in early BC. The hypothesis of this study is that sequential administration of E followed by FEC would have less toxic, particularly peripheral neuropathy, and also have similar effect compared to paclitaxel (P) followed by FEC as primary systemic therapy (PST) for woman with operable BC. Methods: This is a phase II multicenter open label study (UMIN000012817). Patients (pts) were randomly assigned to either E (1.4mg/m2, d1 and d8, q21 days, 4 cycles) + FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) or P (80mg/m2, weekly, 12 cycles) + FEC as PST. HER2+ patients were allowed to receive trastuzumab. Stratification factors were ER, HER2, and menopausal status. Primary endpoint was the incidence of peripheral sensory and motor neuropathy (PSN and PMN) with Grade 1 or higher according to CTCAE ver.4.0. Secondary endpoints were pathological complete response (pCR) rates (ypT0/is/ypN0), clinical response rates (CR+PR), and adverse events. Safety was assessed in all pts who received at least one dose of the study drug. Results: Between 12/2013 to 3/2016, 121 pts were randomly assigned equally to E + FEC and P + FEC. Excluding 5 pts from the primary assessment, 116 pts (58 in each group) were included in the full analysis set. The characteristics of the pts were similar in the two arms. At the end of E or P administration, the incidences of PSN were 55.4% and 92.9% in E and P arm, respectively (p<0.001). The incidences of PMN were 25.9% and 44.9% in E and P arm, respectively (p=0.049). At the end of E or P + FEC, PSN accounts for 38.9% in E arm and 85.2% in P arm (p<0.001), and PMN accounts for 20.7% in E arm and 32.8% in P arm (p=0.201). The pCR rates in E and P arm were 20.7% and 29.8% (p=0.092). The clinical response rates in E and P arm were 82.2% and 91.0% (p=0.108). No statistical significant difference was found in efficacy of PST between E and P. Conclusion: This randomized phase II study revealed that eribulin had favorable peripheral neuropathy profile with modest efficacy in the neoadjuvant setting, compared with paclitaxel. Citation Format: Miura D, Hasegawa Y, Ishikawa T, Tachibana A, Horiguchi J, Hayashi M, Miyashita M, Kubota T, Narui K, Suzuki M, Akazawa K, Kohno N. Randomized controlled trial of neoadjuvant eribulin mesylate versus paclitaxel in women with operable breast cancer (JONIE-3 study) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-15-05.

Abstract Background: Neoadjuvant chemotherapy (NAC) for breast cancer has been improved and pathological complete response (pCR) achieved in about 50% of Her2 positive tumor and over 30% of triple negative tumor. It is possible that not to perform surgery if pCR is diagnosed accurately. This study was performed to examine diagnostic ability of core needle biopsy (CNB) to detect pCR by NAC. (Study registry number: UMIN000012035) Methods: In this multicenter study, we registered histologically proved breast cancer patients who were diagnosed as clinical complete response (cCR) after NAC. The cCR was diagnosed by contrast-enhanced magnetic resonance imaging (MRI) after NAC by radiologists in each facility. Regimens of NAC were not specified by study protocol. A clip marker was not placed in the tumor before NAC. At the operating table, ultrasound-guided CNB is performed before starting the surgery. The CNB was performed with 14 gauge needle without vacuum assistance and requiring three biopsy specimens. The concordance of pathological results between a core needle biopsy and a surgical specimen is examined by pathologists at each facility. The pathological diagnosis was categorized as i) no carcinoma (pCR), ii) carcinoma in situ (CIS) and iii) invasive carcinoma. Results: The study included 86 women from 10 facilities, accrued from December 2013 to March 2017. Median age was 53.5 (31-75) years and median tumor size before NAC was 2.3 (0.9-7.3) cm. Estrogen receptor was positive in 32 (37%). HER2 was positive in 40 (47%). The clinical stage before NAC was stage I 19 (22%), II 48 (56%), III 16 (19%) and IV 3 (3%). All cases were administered cytotoxic agents. Both anthracycline and taxane were given in 70 cases (81%), and trastuzumab was administered in 35 (41%) cases. As for breast surgery, partial resection was performed in 53 cases (62%), whereas 33 cases (38%) underwent mastectomy. Pathological examination on surgical specimen revealed pCR (i) in 41 cases (48%), CIS (ii) in 17 cases (20%) and invasive carcinoma (iii) in 28 cases (32%). Results of pathology of CNB and surgical specimens are shown in table 1. Table 1. Pathological diagnosis of CNB and surgical specimens Surgical specimen No carcinoma (pCR)Residual carcinomaTotalCNBNo carcinoma (pCR)41 (NPV=63%, spec.=100%)24 (FNR=53%, 14 were CIS)65 (76%) Residual carcinoma021 (PPV=100%, sens.=47%)21 (24%)Total41 (48%)45 (52%)86 (100%)CNB: core needle biopsy, FNR: false-negative rate, CIS: carcinoma in situ, NPV: negative predictive value, PPV: positive predictive value, sens.: sensitivity, spec.: specificity. The kappa value was 0.455 which was not enough for accurate diagnosis. In 24 discordant cases, residual tumor was found in surgical specimen but not in CNB, residual disease was CIS in 14 cases. Conclusions: Up to 10% false negative rate of pCR may allow us to proceed to an observational study without performing surgery.This study revealed that the ultrasound-guided CNB for cCR cases by MRI was not accurate enough to omit surgery. Thus, imaging diagnosis and biopsy methods need to be improved. However, it is still possible to consider because the post-operative radiotherapy may compensate for surgery in cases with CIS after NAC. Citation Format: Narui K, Ishikawa T, Hasegawa Y, Kaise H, Kawate T, Yamada K, Suzuki Y, Niikura N, Kohno N, Kimoto T, Sugae S, Yamada A, Kosaka Y, Miyashita M, Okamura T, Shimizu D, Tanino H, Sakamaki K, Tokuda Y. Feasibility study to diagnose pathological complete response by neoadjuvant chemotherapy in breast cancer adding core needle biopsy (KBOG1301 supported by JONIE) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-09.

Background: A randomized phase 2 trial in women with HER2-negative breast cancer has shown that adding zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative (TN) breast cancer patients. We report the data for the secondary end point of disease-free survival (DFS). Methods: Patients were randomly assigned to receive CT or CT + ZOL (CT-Z). All patients received four cycles of FEC100 followed by 12 cycles of paclitaxel weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 wk to the CT-Z group patients. The primary end point was pathologic complete response (pCR). The secondary end points were the clinical response rates, rate of breast-conserving surgery, safety, and DFS. Results: Of the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CT-Z group. DFS and overall survival were analyzed in 92 and 88 patients with the mean times of 5.15 y and 5.38 y, respectively. The 3-y DFS rate was 84.6% in the CT group and 90.8% in the CT-Z group (P = 0.188). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-y DFS period for TN cancer cases (CT versus CT-Z: 70.6% versus 94.1%) but not for postmenopausal cases. Conclusions: ZOL did not improve DFS when combined with CT. However, the improvement of the pCR rate translated to survival outcomes in TN breast cancer. The short-term application of ZOL may not be sufficient to improve the outcome in postmenopausal patients. (C) 2017 Elsevier Inc. All rights reserved.

Abstract BACKGROUND and AIM: Findings from a randomized phase 2 JONIE1 trial in women with HER2-negative early breast cancer have shown that the addition of zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative breast cancer patients. We report the data for the prespecified secondary endpoint of disease-free survival (DFS). METHODS: We enrolled women with HER2-negative early breast cancer and randomly assigned them to receive CT or CT+ZOL (CTZ). All patients received 4 cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 weeks to the CTZ group patients. Definitive surgery was performed 3-4 weeks after the last paclitaxel dose. The primary endpoint was pathological complete response (pCR). The secondary endpoints were the clinical response rates, rate of breast-conserving surgery, safety, and DFS (defined as the time from randomization to disease occurrence or death). The trial is registered as UMIN000003261 (www.umin.ac.jp/english/) with ongoing follow-up. FINDINGS: Of the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CTZ group. The mean (95% CI) DFS time of the CT group was 5.15 years (4.83-5.47) and that of the CTZ group was 5.38 years (5.11-5.66). The 3-year DFS rate was 84.6% (95% CI 77.2-92.0) in the CT group and 90.7% (84.6-96.8) in the CTZ group with no significant difference (p = 0.120). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-year DFS period for triple-negative cancer cases (CT vs CTZ: 70.6% vs 94.1%), but not for postmenopausal cases. CONCLUSIONS: ZOL slightly improved DFS when combined with CT. Although a significant difference was not found in this study, plans are underway for conducting a combined analysis of 3 neoadjuvant CT trials together with ZOL. The improvement of the pCR rate may be associated with DFS in triple-negative cases. Previous studies have shown that ZOL was more efficacious in an estrogen-suppressed condition. However, the short-term application of ZOL in this study may not be sufficient to improve the outcome in postmenopausal patients. Citation Format: Ishikawa T, Akazawa K, Hasegawa Y, Tanino H, Horiguchi J, Miura D, Hayashi M, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Kohno N. Zoledronic acid combined with neoadjuvant chemotherapy for HER2-negative early breast cancer (JONIE 1 trial): Survival outcomes of a randomized multicenter phase 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-10.

Background: We previously reported that the addition of zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) is potentially beneficial in postmenopausal patients with triple-negative breast cancer (BC) in JONIE-1 Study (0% pCR rate in CT versus 50% in CT combing ZOL [CTZ], p=0.029). In order to find biomarkers of response to ZOL, a pilot study was performed using 30 core needle biopsy (CNB) samples at diagnosis from JONIE-1 study. We found that Src activation was highly associated with pCR compared to non-pCR especially in CTZ group. CD8+ TIL was also highly associated with pCR compared to non-pCR. None of CD8+ TIL low patients resulted in pCR in CT group but four out of ten CD8+ TIL low patients experienced pCR in CTZ group. From the result of pilot study, we consider Src activation as a promising biomarker for response to chemotherapy especially in combination with ZOL; however, Src inhibition by ZOL in vivo and the mechanism to explain tumor inhibition is unknown. Because ZOL was effective even in CD8+ TIL low group, the possibility of immune response alteration by ZOL still remains. Not all tumors with Src activation and CD8+ TIL had benefit from ZOL, emphasizing the need for additional markers of response. In the present study, we focused on Src and multiple molecules relating to cancer immune response and analyzed associations with pCR. Patients and Methods: We investigated the relationship between clinicopathological features and tumor shrinkage in Stage IIA-IIIB HER-2-negative BC patients from the JONIE-1 adjuvant phase III trial comparing CT (FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles) versus CT combining ZOL (4mg q3-4w). To access Src activation, HLA class I expression, PD-1 and PD-L1 expression, we performed immunohistochemistry (IHC) and stained slides were evaluated by pathologists. Infiltration of immature dendritic cells, macrophages, cytotoxic T cells, and regulatory T cells in the tumor were assessed by IHC as well. Formalin fixed, paraffin embedded CNB sample at diagnosis and surgical specimen after neoadjuvant CT were processed for HE staining and IHC using primary antibodies as follows; anti-Src Ab (36D10), anti-pan HLA-class I Ab (EMR8-5), anti-CD8 Ab (Clone C8/144B), anti-FOXP3 Ab (Clone 236A/E7), anti-CD68 Ab (Clone PGM1), anti-CD1a Ab (Clone O10). Results: All IHC were successfully performed. Stained slides are now under evaluation by pathologist. Associations between clinicopathological features and the effect of CT with ZOL will be under investigation. Discussion: Src activation was observed in more than 70% of triple negative BC. Multiple cellular functions of Src are mediated by Ras which is the main target of ZOL in osteoclasts. It has been reported that ZOL reverted tumor-infiltrating macrophages (TAM) phenotype from M2 to M1. Moreover, recent study showed that the activation Src and MAPK in melanoma cells promotes PD-L1 expression. Therefore the addition of ZOL might help cytotoxic T cells infiltrate the tumor for inhibiting tumor growth. We will present the results and discuss antitumor effects of ZOL through immunomodulation at the meeting. Citation Format: Sangai T, Sato E, Ishikawa T, Kaise H, Hasegawa Y, Miura D, Takao S, Suzuki M, Tanino H, Horiguchi J, Akazawa K, Yamada A, Kohno N. Exploring immunomodulatory effects of zoledronic acid in breast cancer from clinical trial result of neoadjuvant chemotherapy with zoledronic acid: JONIE-1 study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-25.