Breast cancer

Subtype specific chromosomal aberrations in breast cancer

Author(s)：: Eriko Tokunaga^{1, 2}, Nami Yamashita¹, Kenji Taketani¹, Kimihiro Tanaka, Koji Ando¹, Hiroshi Saeki¹, Eiji Oki¹, Masaru Morita¹, Yoshihiko Maehara¹
Affiliation(s)：: ¹Department of Surgery and Science, ²Department of Comprehensive Clinical Oncology, Graduate School of Medical Sciences, Kyushu University

Background: Breast cancer is a heterogeneous disease and divided into five distinct groups (Luminal A, Luminal B, HER2-enriched, Basal-like, and Claudin-low subtypes) by the gene expression profiles. DNA copy number studies have suggested that the extent of the chromosomal aberrations is different among subtypes. Basal-like, and Claudin-low subtypes are mainly ER-, PR- and HER2- (triple negative: TN). Recent study reported that the basal-like subtype was the most distinct with common losses of the regions containing tumor suppressor genes (TSGs) such as RB1, BRCA1, INPP4B, and the greatest overall genomic instability. On the other hand, Claudin-low tumors showed few copy number changes. Luminal A tumors show fewer chromosomal copy number changes than Luminal B and HER2-enriched subtypes.
Aims: To investigate the extent of the chromosomal aberrations and to evaluate the relationships between chromosomal aberrations and breast cancer subtypes and other clinicopathological characteristics and prognosis.
Methods: Specimens were obtained from 363 invasive breast cancer patients who underwent surgery in our department. These tumors were divided into four subtypes determined by the immunohistochemical analysis of ER, PR and HER2; hormone receptor (HR; ER and/or PR)+/HER2-, HR+/HER2+, HR-/HER2+(HER2) and TN. Loss of heterozygosity (LOH) at the 6 TSGs, BRCA1, BRCA2, TP53, RB1, PTEN and INPP4B, was investigated with microsatellite markers using our microsatellite analysis system. Copy number aberrations (CNAs) were analyzed by SNP-CGH array (Illumina, HumanOmni2.5-8). % Defects, which represents the percent of genome region containing chromosomal aberration, was determined by Karyostudio Software v1.4 (Illumina). The relationships between the incidence of LOH at these TSG loci and CNAs, subtypes, clinicopathological characteristics and prognosis were investigated.
Results: Among informative cases, the incidence of LOH at each tumor suppressor gene locus was BRCA1 113/302 (37.4%), BRCA2 96/282 (34.0%), TP53 159/278 (57.1%), RB1112/267 (41.9%), PTEN 76/295 (25.8%), INPP4B 43/239 (18.0%), respectively. The incidence of LOH was lowest in hormone receptor (HR)+/HER2- subtype, and higher in HER2 and triple negative (TN) subtypes. LOH at these TSGs was associated with high nuclear grade and negativity of ER and PR. LOH at INPP4B locus was significantly associated with TN subtype. Most tumors with LOH at the BRCA1 locus revealed the LOH at the TP53 locus simultaneously. The coexistence of LOH at both BRCA1 and TP53 loci was significantly associated with the aggressive phenotype and gross chromosomal aberrations, and poor prognosis. The impact of LOH at these TSGs on the prognosis was different among subtypes. In HR+/HER2- subtype, the prognosis of the patients with LOH at BRCA1, TP53 and INPP4B was significantly poor. In other subtypes, HR+/HER2+, HR-/HER2+(HER2) and TN, the LOH of these TSG loci was not significantly associated with the prognosis. Many cases with TN subtype reveal gross chromosomal aberrations. However, there are some cases with few chromosomal alterations, whose prognosis was very poor. These tumors were considered to be Claudin-low subtype.
Conclusions: The incidence and biological significance of LOH at TSGs are different among breast cancer subtypes. The coexistence of LOH at both BRCA1 and TP53 loci was associated with the aggressive phenotype, gross chromosomal aberrations and poor prognosis.

MRI-guided quadrantectomy in patients with nonfocal ductal carcinoma in situ of
the breast

Author(s)：: Masahiro Sakakibara MD, Takeshi Nagashima MD, Takafumi Sangai MD, Hiroshi Fujimoto MD, Tiberu-Hiroshi Suzuki MD, Yoshiyuki Okubo MD, Nobumitsu Shiina MD, Kaoru Fujisaki MD, Junta Sakakibara MD and Masaru Miyazaki MD.
Affiliation(s)：: Departments of General Surgery, Chiba University Graduate School of Medicine

Background: We designed magnetic resonance imaging (MRI)-guided quadrantectomy to enable virtual simulation of breast-conserving surgery (BCS) on two-dimensional images reconstructed from MRI, to predict resected volume preoperatively and to directly resect to the planned extent for patients with nonfocal ductal carcinoma in situ (DCIS). This study evaluated the efficacy of our approach for patients with nonfocal DCIS by comparing results to a conventional approach with hooked wires and by comparing the ability to detect DCIS between MRI and mammography.
Patients and Methods: Eighty-six patients were preoperatively diagnosed with nonfocal DCIS based on core-needle biopsy and underwent BCS at our hospital between 2004 and 2009. Thirty-two patients were treated using the conventional approach with hooked wires between 2004 and 2006 (Group 1). Fifty-four patients received our approach with supine MRI and projection onto the breast surface between 2007 and 2009 (Group 2). We used the same indications for BCS of predicted resection volume less than 20% in both Group 1 and Group 2. Supine MRI was performed using 1.5-T scanner units with a flex-M coil. Patients lifted the arm on the affected side and were then fixed in the supine oblique position with use of an oblique board. We performed a virtual simulation of the resection line on the two-dimensional the maximal intensity projection (MIP) image, the resection line was projected onto the breast surface using the linac instruments and quadrantectomy was performed. Surgical outcomes in the two periods were compared histologically. Furthermore, the area of detected lesion on the MIP image from supine MRI, two-dimensional extent of calcifications on specimen mammography and two-dimensional extent of DCIS in the pathological specimen were all calculated using software. We compared differences in detected area among the MRI-detected lesion, extent of calcifications and pathological extent in patients treated using our approach.
Results: Mean lesion size was significantly smaller for patients in Group 1 (3.58 mm) than for patients in Group 2 (4.08 mm; p=0.017). No difference in mean area of the resected specimen was seen between Group 1 (45.8 m2) and Group 2 (37.6 m2; 0.279). In contrast, rate of additional intraoperative resection was significantly lower for patients in Group 2 (9.3%) than for patients in Group 1 (53.1%; p=0.00001). Rate of exposure was significantly lower for patients in Group 2 (3.7%) than for patients in Group 1 (18.8%; p=0.02). In patients treated using our approach (Group 2), mean extent of the MRI-detected lesion, extent of calcifications and extent of pathological DCIS were 8.04 cm2, 5.65 cm2 and 10.37 cm2, respectively. Mean difference between extent of MRI-detected lesion and extent of pathological DCIS was 2.33 cm2, and extent of the MRI-detected lesion was significantly smaller than extent of pathological DCIS (p<0.001). Mean difference between extent of pathological DCIS and extent of calcifications was 4.72 cm2, and extent of calcifications was significantly smaller than extent of pathological DCIS (p<0.001). Mean difference between extent of the MRI-detected lesion and extent of calcifications was 2.39 cm2, and extent of calcifications was significantly smaller than extent of the MRI-detected lesion (p<0.001). These data indicated that MRI-guided quadrantectomy was theoretically superior as a surgical method for DCIS patients compared to hooked wire-guided quadrantectomy.
Conclusion: Due to the strictness of the projection method of image compared to the procedure using hooked wires and the superiority ability to detect DCIS on MRI compared to mammography, MRI-guided quadrantectomy might be useful for patients with nonfocal DCIS.

Different impact on prognosis according to residual tumor status after neoadjuvant chemotherapy in breast cancer subtypes

Author(s)：: Noriaki Wada ¹, Kimiyasu Yoneyama ¹, Chisako Yamauchi ^{1, 3}, Yookija Kang ¹, Toshi Okada ¹, Satoshi Fujii ², Takahiro Hasebe ³, Hirofumi Mukai⁴
Affiliation(s)：: 1. Department of Breast Surgery, National Cancer Center Hospital East,
2. Division of Pathology, Research Center for Innovative Oncology National Cancer Center Hospital East,
3. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East,
4. Department of Breast and Medical Oncology, National Cancer Center Hospital East

Background:
We use various definitions for pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). A purpose of this study was to investigate a prognostic impact according to residual tumor status after NAC in breast cancer subtypes.

Patients and methods:
Data were collected from a prospectively maintained clinical breast cancer database at the National Cancer Center Hospital East. A retrospective search was performed to identify patients treated with NAC between Jun 2002 and Dec 2012. 452 breast cancer patients with stage II-III (T2-4 N0-3 M0) enrolled. All cases were pathologically confirmed invasive component and intrinsic subtypes assessed by immunohistochemistry from core-needle biopsy (CNB) before NAC: Luminal A (LA N=108), Luminal B-HER2 neg (LB-Ki N=89), Luminal B-HER2 pos (LB-HER2 N=38), HER2 pos (HER2 N=77), Triple Negative (TN N=140). All patients were treated with anthracycline and/or taxane based regimens for NAC, 57 patients were concurrently administered trastuzumab. Additional systemic treatment after surgery was scheduled on the basis of patients' tumor prognostic and risk factor status based on St.Gallen consensus meeting. We divided into three groups according to residual cancer in primary tumor: no invasive and no in situ residual (ypT0), no invasive residual and in situ residuals allowed (ypTis), invasive residual (ypTinv). pCR means no residual invasive disease in breast (ypT0 + ypTis) here. Relation between residual tumor status, subtypes and patients' outcome (Overall survival; OS) measures were performed using the Kaplan Meier method and differences tested for significance using the log-rank test. All p-values were two-sided with statistical significance set at p < 0.05.

Results:
Median age was 53 years [26-76 years]. Pretreatment median clinical tumor size was 4.0cm [1.1-15cm]. Overall, number of ypT0, ypTis and ypTinv were 49 (11%), 55 (12%) and 348 (77%), respectively. By subtypes, pCR rate in luminal was very low (2-11%). For non-luminal cohort, rates of ypT0 and ypTis in TN were 19% and 11%, respectively, and rate of ypT0 and ypTis in HER2 were 18% and 36%, respectively. At a median follow-up time of 51 months [6-135month], 5-year survival rate in ypT0, ypTis and ypTinv were 97%, 84% and 80%, respectively. OS curve in ypT0 was significantly superior compared with ypTis and ypTinv by log-rank test (p=0.02 and p=0.02). Although survival curve in ypTis was overlapped with that in ypTinv, OS in ypTis with negative nodes was significantly better than that without positive nodes (p<0.01). Although pCR rates in non-luminal were higher than in luminal, the OS was worse. On the other hand, only ypT0 in non-luminal was associated with excellent prognosis. In ypTinv of each luminal and non-luminal cohort, positive nodes and high Ki-67 after NAC were significantly associated with poor outcome.

Conclusions:
ypT0 defined as no invasive and no in situ residuals after NAC in breast cancer can be a best indicator for an excellent outcome in any subtypes. Impact on the prognosis according to the definition for pCR is different in each subtype．Prognosis of ypTis is equivalent to ypTinv in non-Luminal and it is unfavorable compared to prognosis of ypT0, especially with node positive cases. Patients with LA and LB-Ki could not be considered a candidate for NAC because of not having achieved pCR. Positive node and high Ki-67 in residual invasive cancer after NAC is an indicator for poor prognosis, especially in non-luminal.

Ph III BOLERO-2 study of everolimus plus exemestane: Japanese subgroup analysis

Author(s)：: Norikazu Masuda
Affiliation(s)：: Department of Surgery, Breast Oncology, National Hospital Organization,
Osaka National Hospital, Japan

Background: In BOLERO-2, an international study, mTOR inhibitor everolimus (EVE) + exemestane (EXE) more than doubled progression-free survival (PFS) vs placebo (PBO) + EXE (6.9 months vs. 2.8 months) in patients with hormone-receptor-positive (HR+), HER2-negative advanced breast cancer recurring or progressing on/after nonsteroidal aromatase inhibitors (NSAI) (Baselga J, et al NEJM 2012). Ito et al. reported Japanese patients in the trial treated with EVE + EXE showed similar PFS benefits as the overall population and a manageable safety profile (JSMO 2012). This report presents the updated data including final PFS at 18 months follow-up from the Japanese population.
Methods: The primary endpoint was PFS by local assessment. Secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Eligible patients were randomized (2:1) to EVE, (10mg/day) or PBO, with both arms receiving EXE (25mg/day). Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent.
Results: Of 724 patients from 24 countries enrolled in this study, 106 patients were Japanese (71 EVE+EXE and 35 PBO + EXE). The final PFS in the Japanese population showed the addition of EVE to EXE prolonged median PFS (8.5 months vs 4.2 months; P = 0.012), increased ORR (22.5% vs 0%), and CBR (62.0% vs 25.7%) compared with PBO+EXE. In the EVE + EXE arm, most common adverse events (AEs) were stomatitis (88.7%), rash (54.9%), and dysgeusia (31.0%). Although the incidence of non-infectious lung-related AEs were 31.0% (all grade), which was higher than in the overall population, the majority of these events were grade 1 or 2 (4.2% of grade3 and 0% of grade4) and manageable.
Conclusion: These updated results were consisting with previous report. Therefore, EVE + EXE is a promising new therapeutic option for Japanese women with HR+, HER2-negative advanced breast cancer who have recurred/progressed on or after NSAIs.

Comparative effectiveness of neoadjuvant therapy for HER2 (+) breast cancer

Author(s)：: Tetsu Hayashida, Aiko Nagayama, Koji Okabayashi, Hiromitsu Jinno, Maiko Takahashi, Yuko Kitagawa;
Affiliation(s)：: Department of Surgery, Keio University School of Medicine, Tokyo, Japan

Purpose: The growing number of anti-human epidermal growth factor receptor-2 (HER2) agents has created the need to define the optimal choice of therapy for HER2-positive breast cancer. Network meta-analysis using a Bayesian model assesses indirect comparisons. For example, an indirect estimate of the benefit of A over B can be obtained by comparing trials of A v C with trials of B v C. This study aims to assess the efficacy and safety of neoadjuvant therapy for HER2-positive breast cancer by combining direct and indirect comparisons from a network of trials of multiple treatments.

Methods: The primary endpoint of the study was pathological complete response (pCR) defined as no invasive residual cancer in the breast and nodes. Secondary endpoints were treatment completion, cardiac events and the number of patients with grade 3 or 4 adverse events including diarrhea, neutropenia and skin disorders.

Results: A database search identified 1047 articles, with 10 studies meeting the eligibility criteria. A total of 2247 patients in 7 different treatment arms were assessed. Anti-HER2 agents evaluated included trastuzumab (T-mab), lapatinib, and pertuzumab (P-mab). No significant difference was observed between dual targeting treatment arms (chemotherapy [CT] + T-mab + lapatinib vs. CT + T-mab + P-mab, odds ratio[OR] 1.11 [0.42-2.86], p=0.41); however, lapatinib reduced treatment completion. Patients in dual targeting arms had a significantly higher incidence of pCR than those in other treatment arms (CT + T-mab + P-mab vs. CT + T-mab, OR 2.29 [1.02–5.02], p = 0.02). Surface under the cumulative ranking probability curve indicated that CT + T-mab + P-mab had the highest probability of being the best treatment arm in terms of pCR, followed by CT + T-mab + lapatinib and CT + T-mab.

Conclusions: This study provides evidence that combining 2 anti-HER2 agents with CT is the most effective treatment modality for HER2-positive breast cancer. CT + T-mab showed the well-balanced profile for efficacy, completion and safety.

A Phase Ιb Trial of Trastuzumab Emtansine in Combination with Pertuzumab

Author(s)：: Iwata Hiroji,¹ Horiguchi Jun,² Sato Nobuaki,³ Matsubara Mari,⁴
Kanatani Kazumitsu,⁴ Fujiwara Yasuhiro,⁵
Affiliation(s)：: ¹Department of Breast Oncology, Aichi Cancer Center; ²Department of Breast and Endocrine Surgery, Gunma University Hospital; ³Breast Surgery, Niigata Cancer Center Hospital; ⁴Chugai Pharmaceutical Co. Ltd,; ⁵Department of Breast and Medical Oncology, National Cancer Center Hospital

Background
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1 (a microtubule inhibitor). In EMILIA (TDM4370g/BO21977; N=991), a pivotal phase 3 study of T-DM1 in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane, T-DM1 (n=495) significantly improved progression-free survival (PFS) and overall survival (OS) compared with lapatinib plus capecitabine (n=496) with a PFS hazard ratio (HR) of 0.65 (P<0.001) and an OS HR of 0.68 (P<0.001) (Verma, NEJM 2012). Pertuzumab is a recombinant, humanized monoclonal antibody which targets HER2 at a different epitope from that of trastuzumab. In the phase 3 pivotal study CLEOPATRA (WO20698/TOC4129g; N=808) in patients with previously-untreated HER2-positive MBC, significant improvements in PFS (HR=0.62, P<0.0001) and OS (HR=0.66, P=0.0008) were observed in patients who received pertuzumab, trastuzumab, and docetaxel (n=402) compared with those who received placebo, trastuzumab, and docetaxel (n=406) (Baselga, NEJM 2011; Swain, Lancet Oncol 2013). The combination of T-DM1 and pertuzumab may provide complimentary HER2-targeted activity for the treatment of HER2-positive MBC. In the phase 1b/2 study, TDM4373g (N=67), T-DM1 3.6 mg/kg every 3 weeks (q3w) with the full-dose of pertuzumab (840 mg loading dose, followed by 420 mg maintenance dose q3w) had an encouraging efficacy and safety profile in non-Japanese patients with HER2-positive MBC previously treated with trastuzumab (Miller, ASCO 2010). Here, we report the tolerability and safety of T-DM1 plus pertuzumab in Japanese patients.

Methods
JO22992 is a phase 1b, multicenter, single-arm trial in Japanese patients with HER2-positive MBC. Patients received T-DM1 (3.6 mg/kg) with full-dose pertuzumab (840 mg loading dose, then 420 mg maintenance dose) given q3w until disease progression or unacceptable toxicity. Key eligibility criteria were ECOG PS of 0–2, prior treatment with trastuzumab and chemotherapy, and a left ventricular ejection fraction (LVEF) of ≥50% at baseline (determined by echocardiography or multiple-gated acquisition scanning). The primary endpoints were tolerability and pharmacokinetics; the secondary endpoint was tumor response according to RECIST (version 1.0).

Results
Six patients were enrolled. Median age was 57.5 years (range, 46–68). Median duration of treatment was 11 cycles (range, 1–32). Any grade adverse events (AEs) occurring in ≥50% of patients were diarrhea (n=4), increased levels of AST (n=3), nausea (n=3), chills (n=3), pyrexia (n=3), rash (n=3), headache (n=3), dysgeusia (n=3), muscle spasms (n=3), and rhinorrhea (n=3). There were three grade 3 AEs: increased levels of AST, decreased LVEF, and neutropenia. No grade 4 or 5 AEs were reported. The only dose limiting toxicity (DLT) was the grade 3 decrease in LVEF. This DLT occurred during cycle 1 and LVEF recovered within 30 days of treatment discontinuation. There were 2 serious AEs: grade 2 hemorrhagic gastric ulcer and grade 2 epistaxis. The pharmacokinetic parameters of serum T-DM1 were as follows (mean ± SD): AUCinf, 282 ± 85.0 μg•day/mL; Cmax, 65.0 ± 8.78 μg/mL; and t1/2, 3.73 ± 0.990 day. The serum pertuzumab pharmacokinetic parameters were: AUCinf, 3970 ± 1270 μg•day/mL; Cmax, 301 ± 28.9 μg/mL; and t1/2, 14.1 ± 5.45 day. The pharmacokinetic parameters of T-DM1 and pertuzumab in combination were similar to those seen in single-agent trials. The overall response rate was 50%; the best overall response was a partial response in 3 patients, stable disease in 2 patients, and the response in 1 patient was not evaluable.

Conclusion
The combination of T-DM1 and pertuzumab was tolerable in Japanese patients with HER2-positive MBC; these results support further evaluation of this therapy in this patient population.

Safety of trastuzumab emtansine in patients with HER2-positive metastatic breast
cancer

Author(s)：: Hiroyoshi Doihara,¹ Masahiro Kashiwaba,² Yoshinori Ito,³ Shintaro Takao,⁴ Yoshiaki Rai,⁵ Mari Matsubara,⁶ Kazumitsu Kanatani,⁶ Norikazu Masuda⁷
Affiliation(s)：: ¹Breast and Endocrine surgery, Okayama Univ. Hospital; ²Iwate Medical Univ.; ³Breast Medical Oncology, The Cancer Institute Hospital of JFCR; ⁴Hyogo Cancer Center; ⁵Sagara Hospital; ⁶Chugai Pharmaceutical Co. Ltd; ⁷NHO Osaka National Hospital

Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that selectively delivers the potent microtubule inhibitor DM1 to HER2-overexpressing cells. Like trastuzumab, T-DM1 inhibits HER2 pathway signaling and HER2 shedding, and induces antibody-dependent cellular cytotoxicity. EMILIA, the pivotal phase 3 study of T-DM1 in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane, met both co-primary efficacy endpoints of progression-free survival and overall survival (OS). Patients in the T-DM1 arm had a median OS of 30.9 vs 25.1 months for patients in the control arm of lapatinib + capecitabine (HR=0.68; 95% CI: 0.55–0.85; P<0.001). As for the safety, patients in T-DM1 arm had fewer grade ≥ 3 AEs relative to those in the control arm (Verma, NEJM 2012). Here we describe the safety and efficacy analysis and OS results of an open-label study of T-DM1 in Japanese patients.

Methods: JO22997 is a phase 2 study of T-DM1 3.6 mg/kg every 3 weeks in Japanese patients with previously-treated HER2-positive MBC. Key eligibility criteria were prior treatment with trastuzumab, ≥1 chemotherapies for MBC, and ECOG PS of ≤2. Adverse events (AEs) were graded according to NCI-CTCAE v4.0 and any relationship to the study drug was assessed by the investigator.

Results: Of the 76 enrolled patients, 73 were included in the safety analysis. Median age was 58 years old (range, 36–82 years old). The median number of prior chemotherapy regimens for MBC was 3 (range, 1–8), including lapatinib in 43 (58.9%) patients. Any grade AEs occurred in 70 of 73 patients (95.9%). Grade ≥3 AEs were observed in 41 patients (56.2%). Any grade thrombocytopenia (TCP) and hepatotoxicity (ie, elevated serum levels of liver enzymes, such as AST, GGT) were observed in 27.4% and 34.2% of patients, respectively. Any grade neutropenia and leucopenia were observed in 13.7% and 6.8% of patients, respectively. The total ratio of discontinuation of T-DM1 due to AEs was 19%. TCP and AST increases were the causes of discontinuation of T-DM1 in 1 patient each and in total TCP and hepatotoxicity led to discontinuation of T-DM1 in 6.8% of patients. Asymptomatic decreased left ventricular ejection fraction was observed in 2 patients (2.7%). Neurotoxicity was reported in 16.4% of patients; most of these events were grade 1 or 2 neuropathy. Grade 3 neurotoxicity was observed only 1 patient. There were no reports of alopecia. Any AEs occurring within 24 hours of infusion were observed in 21.9% of patients, all of them grade 1 or 2. The incidences of grade ≥3 AEs did not differ between patients <65 years (n=59) and ≥65 years (n=14) of age. The majority of grade ≥3 AEs occurred after the first or second administration of T-DM1. TCP and transaminase elevations were generally transient, with peak changes occurring around day 8 after therapy and subsequent recovery to grade 1 or less prior to the next cycle. The primary endpoint of ORR by IRC was 38.4% (90% CI, 28.8%-48.6%). In the updated survival analysis, median OS was 30.9 months (95% CI, 25.2-not reached).

Conclusions: In this study, T-DM1 was well-tolerated in Japanese patients with previously-treated HER2-positive MBC, although the incidence of grade ≥3 AEs was higher than that observed in previous studies. The most frequently-observed grade ≥3 AEs (TCP and transaminase elevations) generally occurred in the initial phase of treatment. The safety profile of patients ≥65 years of age was consistent with that of the overall population.

Prognostic significance of progesterone receptor expression and its appropriate cutoff value in patients
with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer

Author(s)：: Kurozumi S¹, Matsumoto H¹, Kurosumi M², Hayashi Y¹, Takei H¹, Ninomiya J¹, Tozuka K¹, Kubo K¹, Tsuboi M¹, Okubo F³, Nagai ES³, Inoue K³, Oba H², Horiguchi J⁴, and Takeyoshi I⁴
Affiliation(s)：: ¹ Division of Breast Surgery, ² Department of Pathology, and ³ Divisions of Breast Oncology, Saitama Cancer Center, Saitama, Japan
⁴ Department of Thoracic Visceral Organ Surgery, Gunma University Graduate School of Medicine, Gunma, Japan

Background:
Recently, breast cancer has been classified into several intrinsic subtypes on the basis of biological characteristics evaluated by microarray clustering analysis. Intrinsic subtypes are routinely determined mainly by the expression of the estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2), as detected by immunohistochemistry. This information can be used to classify breast cancer as the luminal　type (ER and/or PgR positive), HER2-enriched type, and basal-like type (triple negative). Patients with ER-positive and HER2-negative tumors can be further categorized into luminal A and B subtypes according to the Ki67 labeling index; luminal A, low Ki67 index (<14%) and luminal B, high Ki67 index (≥14%). The prognosis of patients with luminal A cancer is known to be significantly better than that of patients with luminal B disease, and Ki67 is considered a significant prognostic marker in ER-positive and HER2-negative breast cancer. On the other hand, PgR expression has also become recognized as a prognostic marker in ER-positive and HER2-negative breast cancer. However, a definite cutoff value for PgR expression has not yet been established. In this study, we investigated the prognostic utility of PgR expression in ER-positive and HER2-negative breast cancer, and sought to determine the most suitable cutoff value for PgR expression.
Patients and Methods:
We enrolled 177 consecutive patients with ER-positive and HER2-negative invasive carcinoma of no special type with invasive lesions larger than 5 mm who were treated in 2000–2001 (median follow-up: 131 months). Immunohistochemical staining for ER and PgR was performed, and the percentages of nuclei stained were calculated. ER positivity was defined as ≥1% positive staining, in accordance with American Society of Clinical Oncology and College of American Pathologists criteria. In addition, the degree of staining of ER and PgR was evaluated using two scoring systems: the Allred score and the J-score (proposed by the Japanese Breast Cancer Society). In the Allred scoring system, proportion scores were defined as 0 (0% staining), 1 (<1%), 2 (1–10%), 3 (10–33%), 4 (33–67%) and 5 (>67%), and intensity scores were defined as 0 (no staining), 1 (weak staining), 2 (intermediate staining), and 3 (strong staining). The total score was determined by adding the proportion score and intensity score, to get final scores of 0 and 2-8. The J-score was defined as 0 (0% staining), 1 (<1%), 2 (1–10%), 3a (10–50%), and 3b (>50%). Recurrence-free survival (RFS) and cancer-specific survival (CSS) were compared between patients divided into two groups according to the degree of PgR staining (scores and percentages). Significant cutoff values for the selection of patients with a poor prognosis were determined using Kaplan-Meier analysis. In addition, multivariate analysis was performed to determine the significance of factors such as PgR expression, pathological tumor stage (pT), pathological regional lymph node category (pN), nuclear grade (NG), menopausal status, and adjuvant chemotherapy.
Results:
With regard to PgR expression, 21 patients (11.9%) showed 0% staining, 4 patients (2.3%) showed 0–1% staining, 18 patients (10.2%) showed 1–10% staining, 23 patients (13.0%) showed 10–20% staining, 9 patients (5.1%) showed 20–33% staining, 48 patients (27.1%) showed 33–50% staining, and 54 patients (30.5%) showed >50% staining. Patients who had a J-score of 3b (>50% staining for PgR expression) survived significantly longer than those with a score of 0–3a (0–50% staining) (RFS: P = 0.0022; CSS: P = 0.0002). Of all the Allred scores (0, 2–8) for PgR status, a score of 6 was the most significant cutoff point for prognosis (RFS: P = 0.0032; CSS: P = 0.0001), and among the proportion scores (score 0–5), a score of 3 (10-33% staining) was the most significant cutoff point (RFS: P = 0.0016; CSS: P = 0.007). Furthermore, PgR positivity of 20% (range, 10–33%) was the most significant cutoff value for predicting differences in survival (RFS: P = 0.0003; CSS: P < 0.0001). Multivariate analysis showed that PgR expression (≥20%) is a significant prognostic marker (RFS: P = 0.0006; CSS: P < 0.0001). In patients with tumors with low proliferation (NG 1, 2), the most significant cutoff value for PgR positivity was also 20% (CSS: P = 0.0016).
Conclusions:
The degree of PgR expression is thought to be a significant prognostic indicator for the evaluation of long-term outcomes in patients with ER-positive and HER2-negative breast cancer. This study suggests that examining the degree of PgR expression allows for the selection of patients with a poor prognosis and that the best cutoff value might be 20%.

A prospective multi-institutional feasibility study of accelerated partial breast irradiation (APBI) using interstitial brachytherapy. Results of the secondary endpoints at 30 months

Author(s)：: Ken Yoshida¹, Naoto Shikama², Toshiaki Saeki², Takushi Dokiya², Iwao Tsukiyama³, Shuji Asahi³, Eisaku Yoden⁴, Kazutaka Nakajima⁴, Yasunari Matsumura⁵, Seiji Tachiiri⁶, Tadayuki Kotsuma⁷, Norikazu Masuda⁷, Yuki Otani⁸, Takayuki Nose⁹, Masahiko Oguchi¹⁰
Affiliation(s)：: 1 Osaka medical college
2 Saitama medical university international medical center
3 Aidu chuo hospital
4 Kawasaki medical school
5 Kyusyu medical center
6 Kyoto city hospital
7 Osaka national hospital
8 Osaka university graduate school of medicine
9 Nippon medical school tama nagayama hospital
10 Cancer institute hospital

Purpose: To report the results of the secondary endpoints (sequelae ratio, local /regional/distant control ratio, and cosmesis) for a multi-institutional feasibility study of accelerated partial breast irradiation (APBI), we evaluated our clinical data of median 30 months' follow-up.　
Materials and Methods: The study group for standardization of high-dose-rate brachytherapy supported by grant-in-aid for cancer research by Ministry of Health, Labour and Welfare implemented a prospective multi-institutional feasibility study of APBI using interstitial brachytherapy (UMIN000001677）. This is the first prospective multi-institutional study of APBI in Japan. Essential eligibility criterion are histological tumor size <= 3 cm, pN0M0, no tumor exposure at surgical margin, positive hormone receptor, age >= 35 years old. Eight institutions participated in the study. From January 2009 through December 2011, 46 patients with early breast cancer were enrolled. For 45 patients, applicators were implanted post-breast conserving surgery setting and for 1 patient as intra-breast conserving surgery setting. A dose of 36 Gy/ 6 fractions/ 3-4 days was delivered at a selected isodose-surface for dose prescription using microSelectronHDR (Chiyoda Technol/ Nucletron an Elekta Company). Follow-up clinical data were collected to the central data center using case report forms from participating institutions. Kaplan-Meier methods were used for sequelae ratio analyses.
Results: As of August 2013, median duration of follow-up was 30 months (range, 18-42 months). No local recurrences or regional/distant metastases were observed. Observed sequelae were as follows: pneumothorax (G0 98 %, G1 2 %), radiation dermatitis (G0 45 %, G1 48 %, G2 7 %), hyperpigmentation (G0 63 %, G1 37 %), hypopigmentation (G0 98 %, G1 2 %), telangiectasia (G0 85 %, G1 15 %), rib fracture (G0 98 %, G1 2 %), soft tissue necrosis (G0 93%, G2 7%), fibrosis (G0 41 %, G1 41 %, G2 11 %, G3 7 %), pain (G0 54 %, G1 37 %, G2 7 %, G3 2 %). As for cosmesis, excellent/good scores were recorded in 100 %, 93 %, and 82 % of patients at pre-implantation, at 12 months, and at 24 months, respectively.
Conclusions: At 30 months of follow-up, local control ratio, regional/distant metastases ratio, sequelae ratio, and cosmesis were within the preceding APBI literature reports, except for G2 dermatitis, G1 hyperpigmentation, G1 pain, and G1/G3 fibrosis ratios. However, these exceptional sequelae results showed only minor difference compared with other reports.

Efficacy of zoledronic acid in postmenopausal women with adjuvant letrozole

Author(s)：: Norio Kohno ¹,Shunji Takahashi ², Takuji Iwase ², Takashi Ishikawa ³, Seung Jin Kim ⁴, Mitsuchika Hosoda ⁵, Jun Horiguchi ⁶, Hideko Yamauchi ⁷, Yasuo Hozumi ⁸, Morihito Okada ⁹, Masao Fukunaga ¹⁰, Shinzaburo Noguchi ⁴
Affiliation(s)：: ¹ Tokyo Medical Univ. Hospital, ² Cancer Institute Hospital, JFCR, ³Yokohama City Univ. Medical Center, ⁴Osaka Univ. Hospital, ⁵Hokkaido Univ. Hospital, ⁶Gunma Univ. Hospital, ⁷St. Lukes International Hospital, ⁸Jichi Medical Univ. Hospital, ⁹Hiroshima Univ. Hospital, ¹⁰Kawasaki Medical School

(Background) We reported 12-month results of upfront zoledronic acid (ZOL) therapy prevented bone loss in postmenopausal Japanese women who were receiving adjuvant letrozole (Takahashi et al. Breast Cancer Res Treat 2012;133(2):685-93). But the examination in the long term of aromatase inhibitor-associated bone loss has not been proved in the Japanese or Asia women.
(Methods) Postmenopausal women with hormone receptor positive early breast cancer (BC) patients receiving adjuvant letrozole with bone mineral density (BMD)≥ young adult mean (YAM)－2.0 SD were randomly assigned to receive either upfront or delayed-start ZOL (4mg intravenously every 6 months) for 5 years. The delayed group received ZOL when lumbar spine (L2-L4) BMD decreased to less than young adult mean -2.0 SD or when a nontraumatic fracture occurred. The primary endpoint of this study was to compare the changes in L1-L4 BMD at month 12 between the groups. Secondary endpoints, measured at other predetermined timepoints, included comparing changes in L1-L4, L2-L4 and total hip (TH) BMD and markers of bone turnover, fracture incidence, and time to disease recurrence. We report the results of 36-month interim analysis.
(Results) At 36 months, mean change in L1-L4 BMD was 10.7% higher in the upfront group than in the delayed group (+6.26% vs. -4.43%; 95% CI, 9.2% to 12.1%; p<0.001), L2-L4 BMD was 10.9% higher (+6.52% vs. -4.57%; 95% CI, 9.3% to 12.5%; p<0.001), and TH BMD was 6.7% higher (+2.78% vs. -4.07%; 95% CI, 5.3% to 8.1%; p<0.001). In the patients of delayed group who started ZOL (n=9), changes of BMD at 36M were -1.49% at L1-4 (p=0.41) and -1.98% at L2-4 (p=0.40). In the upfront group, the patients with normal baseline BMD (> YAM -1.0 SD) remained normal, but in the delayed group, 36.0% of the patients　changed to osteopenic (BMD ≤ YAM -1.0SD and ≥ -2.0 SD) at 36M. 48.3% of osteopenic patients shifted to normal BMD at 36M in the upfront group, but all of oeteopenic patients in the delayed group remained oeteopenic. About bone metabolic markers, serum NTx decreased by -22.5% from basal levels at 12M (p<0.001), but increased to -9.2% (p=0.006) at 36M in the upfront group, but in the delayed group, NTx increased by 21.5% at 6M, then decreased to 5.0% at 36M. Bone alkaline phosphatase (BAP) also decreased by -38.7% at 12M and remain decreased by -52.7% at 36M in the upfront group, whereas increased by 14.6% at 6M then remained increased by 21.3% at 36M in the delayed group. The incidence of fracture was decreased in the upfront group (upfront, 2 (2.0%) vs. delayed, 8 (8.2%), p=0.058). Disease recurrence was reported in 3 upfront (3.1%) and 1 delayed (1.0%) patients. By month 36, 11 patients (11.3%) in the delayed group initiated ZOL therapy. There was no significant difference of adverse events other than fever with ZOL at the first treatment between the two groups.
(Conclusion) Upfront ZOL seems to be the preferred treatment strategy versus delayed administration, as it is significantly and progressively increase BMD in postmenopausal Japanese women with early BC who were receiving adjuvant letrozole for 36 months.

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