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Supplementary Figure S1. 　ER status in breast cancer tissues was associated with Ki-67 response after tamoxifen therapy. (A) Ki-67 response was lower in the tissues in which the proportion of ER-positive cells was less than 2/3 than in the tissues in which the proportion of ER-positive cells was 2/3 or more. (B) In Allred score, a semi quantitative system, that takes into consideration the proportion of positive cells (scored on a scale of 0-5) and staining intensity (scored on a scale of 0-3), tissues with score of 7 or less showed lower Ki-67 response than those with score of 8. Supplementary Figure S2. Correlation between Ki-67 response and tumor response after tamoxifen therapy. No significant tumor response was observed by short-term pre-operative tamoxifen therapy. No correlation was also observed between the tumor response and Ki-67 response (Pearson correlation coefficient; R = -0.12). Tumor response was measured in bi-directional maximum dimension using ultrasound. Supplementary Figure S3. Relationship between Ki-67 response and pathological response after tamoxifen therapy. The breast cancer tissues with no pathological response (Grade 0) showed significantly lower Ki-67 response than those with Grade 1a or more pathological response. Supplementary Figure S4. Association between CYP2D6 genotypes and Ki-67 labeling index in pre-treatment tissue. CYP2D6 genotype was not associated with Ki-67 labeling index in pre-treatment tissue.

Supplementary Table S1 Association between all CYP2D6 genotype and ER status in pre-treatment tissue.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.

Preoperative evaluations of the size of ductal carcinoma in situ (DCIS) extension in invasive breast cancer (IBC) are problematic and markers of the actual size of DCIS remain elusive. This study aimed to quantify DCIS on core needle biopsy (CNB) and investigated its association with degree of DCIS extension on paired resection specimens, instead of with presence or absence of an extensive intraductal component or margin status as in earlier studies. This series examined 150 IBCs diagnosed from paired CNB and resection specimens. The DCIS/invasion ratio was calculated using the sum of each element size from CNB. In resection specimens, cases in which the greatest dimension of DCIS extension was longer than the greatest dimension of invasive size were defined as extended DCIS (Ext-DCIS). DCIS/invasion ratio level correlated positively with the degree of Ext-DCIS (P = 0.003). Using receiver operating characteristic curve analysis, setting cases with the subgroup of DCIS extension with greatest dimension 2.5 times that of the invasive size in the resection specimen (Ext-DCIS 2.5) as the positive class provided the best discrimination ability for DCIS/invasion ratio (0.375). In multivariate analysis, DCIS/invasion ratio 0.375 was significantly associated with Ext-DCIS 2.5 (P = 0.033). In conclusion, DCIS/invasion ratio 0.375 in CNB was identified as a predictor of Ext-DCIS 2.5 in resection specimens, suggesting that an approach combining DCIS/invasion ratio from CNB with preoperative staging may better predict the extent of DCIS and facilitate better surgical planning.

Breast spiradenoma is extremely rare, with only 4 cases reported previously. We describe an instructive case of breast spiradenoma resembling adenoid cystic carcinoma (AdCC). A 71-year-old woman underwent excisional biopsy of a breast mass after a conclusive diagnosis was unable to be obtained from core needle biopsy showing an AdCC-like pattern. Histopathologically, the lesion demonstrated solid and cribriform foci comprising basaloid cells, luminal cells, and eosinophilic hyaline material, reminiscent of solid-basaloid AdCC, alongside convoluted lumens, stromal edema, lymphocytic infiltration, and c-kit negativity. On molecular analysis, neither MYB fusion genes nor CYLD gene abnormalities were identified. These results were supportive of spiradenoma. Salivary gland- and skin adnexal-type tumors are challenging to diagnose due to morphological overlaps. This case, highlighting histopathological and molecular features, shows that breast spiradenoma can be a diagnostic pitfall among the differential diagnoses of AdCC.

While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.

Background:There are several small case series about the omental flap for breast reconstructions. However, the long-term oncological safety and the clinical benefits remain uncertain, especially the flap is used as a part of oncoplastic breast surgery. We retrospectively studied 200 patients who underwent oncoplastic breast surgery using the laparoscopically harvested omental flap. Methods:A retrospective chart review of 200 patients who underwent oncoplastic surgery using the omental flap at our institution from April 2002 to March 2016 was performed. All the omental flaps were laparoscopically harvested, and mainly used as a partial reconstruction immediate after breast-conserving surgery (BCS). Short- and long-term laparoscopy-associated complications, local recurrences and cosmetic outcomes were evaluated. Results:Although 46 cases of nipple-sparing mastectomy or skin-sparing mastectomy were included, most of patients underwent partial breast reconstruction after BCS. The successful rate of laparoscopically harvesting of the omental flap was 99.5% (199 out of 200). The rate of complications was 12.0%. Laparoscopy-associated complications occurred in 4 cases (2.0%). The rate of positive margin was 6.5%. Local recurrence occurred in two cases (1.0%) during medial follow-up period of 78 months. In 24 patients (12.0%), the volume of the flap was insufficient. When applied to nipple-sparing mastectomy or skin-sparing mastectomy, volume luck occurred in 32.6% of patients. Cosmetic outcome was mostly satisfactory. Approximately 80% of patients scored good or excellent evaluated with 4 point scale by 3 health professions. The size of the reconstructed breast basically did not change even after radiation therapy. Donor-site scars were almost negligible just like those of laparoscopic cholecystectomy. Conclusions:The laparoscopically harvested omental flap has minimal donor-site morbidity and deformity. The long-term oncological safety is also promising. Although there is a limit of adaptable volume, the omental flap is an attractive option in partial breast reconstruction after BCS. Citation Format: Abe N, Sagawa N, Unesoko M, Zaha H. 200 experiences of oncoplastic surgery with the omental flap reconstruction [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 P3-13-16.

There are several small case series on use of a laparoscopically harvested omental flap (LHOF) for breast reconstruction. However, the long-term oncological safety and clinical benefits of the LHOF remain uncertain, especially in use of the flap in oncoplastic breast surgery. A retrospective chart review was performed for 200 patients who underwent oncoplastic breast surgery using a LHOF at our institution from April 2002 to March 2016. Laparoscopy-associated complications, local recurrence, and cosmetic outcomes were evaluated. Most of the patients underwent partial breast reconstruction immediately after breast-conserving surgery (BCS). The success rate of laparoscopic harvesting of the omental flap was 99.5%. The rate of complications was 12.0% and laparoscopy-associated complications occurred in four cases (2.0%). The rate of a positive margin was 6.5%. Two cases (1.0%) had local recurrence during a median follow-up period of 90 months. In 24 patients (12.0%), the volume of the flap was insufficient. When applied to total reconstruction, volume insufficiency occurred in 32.6% of patients. Cosmetic outcomes were mostly satisfactory. Approximately 80% of patients were rated as good or excellent by evaluation using a 4-point scale and Breast Cancer Conservative Treatment cosmetic results (BCCT.core) software. Donor-site scars were negligible, as in laparoscopic cholecystectomy. The LHOF has minimal donor-site morbidity and deformity, and oncological safety is promising. There is a limit to the adaptable volume, but the LHOF is an attractive option in partial breast reconstruction after BCS.

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.

As visual quantification of the density of tumor-infiltrating lymphocytes (TILs) lacks in precision, digital image analysis (DIA) approach has been applied in order to improve. In several studies, TIL density has been examined on hematoxylin and eosin (HE)-stained sections using DIA. The aim of the present study was to quantify TIL density on HE sections of core needle biopsies using DIA and investigate its association with clinicopathological parameters and pathological response to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The study cohort comprised of patients with HER2-positive breast cancer, all treated with neoadjuvant anti-HER2 therapy. DIA software applying machine learning-based classification of epithelial and stromal elements was used to count TILs. TIL density was determined as the number of TILs per square millimeter of stromal tissue. Median TIL density was 1287/mm2 (range, 123–8101/mm2). A high TIL density was associated with higher histological grade (P = 0.02), estrogen receptor negativity (P = 0.036), and pathological complete response (pCR) (P 2420/mm2) was significantly associated with pCR (P

The modified round block technique (MRBT) is a level I oncoplastic breast-conserving surgery (OBCS), which contains a very wide glandular flap created by extensive dual-plane undermining that is achieved by entire subcutaneous dissection and approximately 50% dissection of the breast parenchyma from the pectoralis muscle. A retrospective analysis was performed for 100 patients who underwent OBCS using MRBT from February 2009 to October 2017. The incidence of positive margin was 7.0% (seven cases), and there has been no local recurrence during a median follow-up period of 68 months. Short- and long-term complications included fat necrosis (11.0%), infection (4.0%), and hematoma formation (4.0%). When patients were divided into two groups based upon the preoperative mammography findings, fat necrosis occurred in 5.2% of the patients with extremely dense or heterogeneously dense mammography, and in 19.0% of patients with scattered fibroglandular or entire fat mammography, which showed a statistically significant difference. Therefore, in level I OBCS, the extent of dual-plane undermining should be minimized to less than 50% of the total parenchyma in fatty breasts.

Purpose: To evaluate tumor-infiltrating lymphocytes (TILs) quantitatively in breast cancer and to verify the utility of machine learning image analysis in TIL assessment. Methods: Stromal TILs in 105 Human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancers, diagnosed from patients treated with neoadjuvant anti-HER2 therapy, were evaluated by image analysis of hematoxylin and eosin-stained slides from core needle biopsies. TIL level was determined as the number of TILs per square millimeter of stromal tissue. Associations of TIL level with clinicopathological parameters, pathological response, and clinical outcomes were assessed. Results: Median TIL level were 1287/mm2 (range, 123 - 8101/mm2). Higher TIL level was associated with higher histological grade (P = 0.02), estrogen receptor (ER) negativity (P = 0.036), and pathological complete response (pCR) (P< 0.0001). According to analysis of the receiver operating characteristic curve, a threshold TIL level of 2420/mm2 stroma best discriminated pCR from non-pCR. In multivariate analysis, high TIL levels (>2420/mm2) were significantly associated with pCR (P< 0.0001). On Kaplan-Meier analysis, prognosis was not associated with high or low TIL levels. However, high TIL levels tended to be associated with better prognosis in the HER2+/ER+ subgroup (P = 0.131), but not in the HER2+/ER- subgroup. Conclusions: A machine learning image analysis algorithm could assess TIL level as the number of TILs per square millimeter, contrary to semiquantitative evaluation. TIL level derived from this method could offer an independent predictor of pCR. Citation Format: Norie Abe, Hirofumi Matsumoto, Reika Takamatsu, Kentaro Tamaki, Naoko Takigami, Kanou Uehara, Yoshihiko Kamada, Nobumitsu Tamaki, Tokiwa Motonari, Norihiro Nakada, Hisamitsu Zaha, Naoki Yoshimi. Tumor-infiltrating lymphocytes evaluation using machine learning image analysis based on core needle biopsy in HER2-positive breast cancer [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 PD5-04.

A 47-year-old woman received adjuvant chemotherapy for breast cancer. On the 13th day of 4 courses of dose-dense AC therapy, she developed a fever. She was orally administered an antibioticfor febrile neutropenia treatment. She showed no improvement of symptoms and gradually presented with new symptoms, including a non-productive cough and dyspnea. After admission, she underwent a further examination, and was provided a diagnosis of pneumocystis pneumonia. It is reported that patients receiving chemotherapy for solid tumors are less likely to develop opportunistic infections. However, patients receiving dose-dense chemotherapy may have a higher risk for developing opportunistic infections than those receiving conventional chemotherapy.

Purpose: Trastuzumab has been administered to HER2-positive breast or gastric cancer patients as an effective treatment, however, the cardiotoxicity is identified as one of the life-threatening side effects. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a genome-wide association study (GWAS). Experimental Design: We carried out a GWAS using 11 cases (with trastuzumab-induced cardiotoxicity) and 257 controls (showing no sign of trastuzumab-induced cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed smallest P value in GWAS (P = 1.61 x 10-7 -1.97 x 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. Results: The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (chromosome 13q14.3, 4q25, 15q26.3, 17q25.3 and another 15q26.3, Pcombined = 6.00 x 10-6, 8.60 x 10-5, 1.01 x 10-4, 1.07 x 10-4, 1.60 x 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity, using five SNPs which revealed smallest P value at each locus. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was 42.5% (P =8.69 x 10-15) . This scoring system using five candidate loci could be used to predict the risk of the adverse event before administration of trastuzumab. Conclusion: We identified five novel loci, which could be associated with trastuzumab-induced cardiotoxicity. These findings provide new insights into personalized trastuzumab therapy for patients with HER2-positive cancer. Citation Format: Chihiro Udagawa, Mari Hara, Arata Shimo, Yasuyuki Kojima, Reiko Yoshie, Hisamitsu Zaha, Norie Abe, Tokiwa Motonari, Mikiko Unesoko, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Hiroshi Okamura, Taisei Mushiroda, Koichiro Tsugawa, Hitoshi Zembutsu. A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2951.

Breast cancer mortality is gradually increasing in Okinawa. The 1st Okinawa Breast Oncology Meeting was held on 6 July 2012 and discussions on how to curb the rising trend were focused on breast cancer screening, adjuvant treatment, socioeconomic and geographic issues, and the problem of complementary and alternative medicine. The consensus of the 1st Okinawa Breast Oncology Meeting was that ultrasonography screening is an acceptable screening system for Okinawan women because of the geographic disadvantage of having many small islands and rural areas. Educational and economic support is needed for women in rural areas to get correct information, for access to urban areas and to be treated by evidence-based optimal therapy for breast cancer. In addition, new approaches are needed for Okinawan people to successfully educate patients to correctly interpret evidence-based information.