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Background Previously, we reported the clinical outcomes of the combination of anti-PD-1 Ab, cyclin-dependent kinase 4/6 inhibitors, and endocrine therapy (ET) in patients with ER positive/HER2 negative advanced breast cancer in SABCS2020; biomarker analysis has been performed to provide insight into the hepatotoxicy frequently observed in the study. Methods Subjects received 240 mg nivolumab IV on days 1 and 15, 150 mg abemaciclib PO twice daily, and either 500 mg fulvestrant (FUL) on days 1, 15, 29, and every 4 weeks thereafter (FUL cohort) or 2.5 mg letrozole (LET) once daily (LET cohort). The primary endpoint was objective response rate and secondary endpoints included toxicity evaluated in the CTCAE along with an exploratory endpoint as related to the biomarker analysis. Archival tumor tissues were collected before study entry and blood and stool samples were collected at baseline and on cycle3 day1. Tumor tissues were subjected to IHC analysis and RNA sequencing followed by subtyping using NGS. High throughput cytokine analysis using ELISA-based assay were performed with serum samples and cell sorting analysis of PBMC was performed with FACS. Results From June 2019 to December 2019, 17 subjects were enrolled (FUL cohort [n = 12], LET cohort [n = 5]). The study was prematurely closed due to safety concerns such as hepatotoxicity and interstitial lung disease. AEs ≥ Grade 3 were observed in 91.7% and 100% of patients in the FUL and LET cohorts, respectively. The most frequent AEs ≥ Grade 3 were elevated liver function tests (LFT; FUL cohort: 50.0%, LET cohort: 60.0%). Serum cytokine analysis from the subjects with severe hepatotoxicity indicated cytokine storm with elevations of sCD30/TNFRSF8, IL-11, -34, Pentraxin-3, sTNF-R1, -R2, TSLP, which was supported by the findings of reduction of effector regulatory T cells in PBMC. IHC study in liver biopsy from three subjects with the toxicity revealed infiltration of CD8+ T cells and FOXP3+ T reg into the liver, suggesting the immune related liver injury upon the treatment with nivolumab and abemaciclib. HLA typing was performed in the 17 patients but no association between HLA type and ILD or hepatotoxicity were observed. Conclusions The frequent and severe immune related hepatotoxicity induced by the combination of anti-DD-1 and CDK 4/6 inhibitors might have been an immune-boosting therapy as suggested in the preclinical studies. This study was supported by the Ono Pharmaceutical Co., LTD. The registration number of the study is UMIN000036970. Citation Format: Junji Tsurutani, Jun Masuda, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K. Imamura, Sakiko Miura, Toshiko Yamochi, Kenichi Yoshimura, Toshimi Takano, Hidetaka Kawabata. Biomarker analysis of hepatotoxicity in a Phase II study of nivolumab, abemaciclib and endocrine therapy in patients with HR-positive, HER2-negative breast cancer: WJOG11418BTR NEWFLAME_TR [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-08.

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

This file contains Supplementary Figure S1. High PSF expression is positively associated with poor prognosis of breast cancer patients.; Supplementary Figure S2. ESR1 expression is elevated in endocrine resistance model hydroxytamoxifen-resistant OHTR cells and ESR1 knockdown represses OHTR cell proliferation.; Supplementary Figure S3. PSF knockdown represses the proliferation and cell cycle progression of ER-positive T47D breast cancer cells.; Supplementary Figure S4. PSF correlates with estrogen signaling pathway and regulates the expression of estrogen target genes without altering its own mRNA expression.; Supplementary Figure S5. PSF regulates ESR1 expression at the posttranscriptional level.; Supplementary Figure S6. PSF overexpression enhances ESR1 expression and overcomes OHT-dependent cell proliferation inhibition.; Supplementary Figure S7. Mapping of PSF-immunoprecipitated RNAs in the vicinity of known PSF-associated genes or PSF-nonassociated gene and identification of PSF-binding RNAs with RIP-seq.; Supplementary Figure S8. PSF regulates SCFD2, TRA2B and ASPM expression at posttranscriptional level in ER-positive breast cancer cells.; Supplementary Figure S9. PSF knockdown promotes nuclear accumulation of SCFD2 and TRA2B but not ASPM in ER-positive breast cancer cells, whereas high expression of TRA2B and ASPM is significantly associated with shorter survivals of breast cancer patients.; Supplementary Figure S10. High expression of PSF-targeted SCFD2 is associated with shorter relapse-free survival of ER-positive breast cancer patients and SCFD2 knockdown represses T47D cell proliferation.; Supplementary Figure S11. PSF siRNA injection downregulates ER+ expression in xenograft tumors inoculated with tamoxifen-resistant cancer cells without altering mouse body weight and pre-mRNA expression of ESR1 and SCFD2.; Supplementary Table S1. Primers used in this study.; Supplementary Table S2. Association between PSF status and clinicopathological parameters in Shikoku Cancer Center cohort including 73 cases of human ER-positive breast cancers.; Supplementary Table S3. Clinicopathological parameters associated with distant disease-free or overall survival in univariate and multivariate analyses in Shikoku Cancer Center cohort (n = 73).; Supplementary Table S4. Association between PSF status and clinicopathological parameters in Toranomon Hospital cohort including 114 breast cancer cases.; Supplementary Table S5. Clinicopathological parameters associated with overall survival in univariate and multivariate analyses in Toranomon Hospital cohort (n = 114).; and Supplementary Experimental Procedures.

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.Significance:This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.

Background The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence. Methods The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. Results A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years). Conclusion The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy.

Background: Only old evidence exist to back up the use of medroxyprogesterone acetate (MPA) in endocrine therapy. Therefore, this study aimed to explore the factors that influence the time to treatment failure (TTF) of MPA in real world settings as late-line treatment following aromatase inhibitors and fulvestrant. Methods: This was a cohort study that used the database of the Safari study, on estrogen receptor-positive (ER+) post-menopausal advanced breast cancer previously treated with fulvestrant (UMIN000015168). We created Kaplan-Meier curves for TTF treated with MPA. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the TTF of MPA. Results: Fist, we made Kaplan-Meier curves by treatment line for MPA in TTF analysis population 1 (n = 244), excluding HER2+ and HER2 with unknown status. The median TTF for MPA was 8.2 months (95% CI 5.1–14.9) for first- and second-line treatments, 3.0 months (95% CI 2.5–3.9) for third-line treatment, and 4.1 months (95% CI 3.5–5.0) for fourth or later treatment lines. The first- and second-line treatments had significantly longer TTF than the third-line treatment (P < 0.001) and fourth-line or later treatments (P < 0.001). No difference in TTF was observed between the third and fourth or later treatment lines. Similar results were obtained in the analysis population 2 (n = 203) for TTF, excluding cases in which MPA was considered to have been used in palliative care. The median TTF for MPA was 7.9 months (95% CI, 5.1-16.0) for first- and second-line treatments, 3.0 months (95% CI 2.8–4.6) for third-line treatment, and 4.3 months (95% CI 3.7–5.6) for fourth or later treatment lines. The first- and second-line treatments had significantly longer TTF than the third-line treatment (P < 0.001) and the fourth-line or later treatments (P < 0.001). No difference in TTF was observed between the third and fourth or later treatment lines. Second, Table 1 shows the clinicopathological factors involved in the TTF of MPA. In univariate analysis, long DFI (≥ 6 years), small nuclear or histological grade, and the presence of visceral metastases correlated with significantly long TTF (P < 0.05). Whereas PgR, adjuvant chemotherapy, and adjuvant endocrine therapy did not affect the TTF of patients treated with MPA. However, in the multivariate regression analysis, only longer DFI (≥ 6 years) was correlated with a significantly longer TTF. Third, we compared the clinicopathologic factors in the groups that received MPA as the fourth or later treatment lines and achieved a TTF of more than 1 year with those that did not. There were no characteristic clinicopathological factors distinct between the two groups. Conclusion: In actual clinical practice, patients treated with MPA alone as the fourth or subsequent treatment lines showed a TTF of 4 months, suggesting that there is merit in using MPA even in late treatment lines, especially in patients with long DFI and those who are difficult to treat with other antineoplastic agents. Table 1. Univariate and Multivariate analyses to investigate association between clinicopathological factors and TTF of MPA (n=170) Citation Format: Kaho Utsunomiya, Hidetoshi Kawaguchi, Yutaka Yamamoto, Shigehira Saji, Norikazu Masuda, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Toshinari Yamashita, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Retrospective study using database for the effectiveness of medroxyprogesterone acetate in patients with ER-positive/HER2-negative postmenopausal advanced breast cancer: An additional analysis of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-15.

Chemotherapy is often difficult to treat human epidermal growth factor receptor 2 (HER2)-positive metastatic recurrent breast cancer in the elderly, and no standard treatment has been established at this point. We experienced a case in which trastuzumab (Tmab) + anastrozole (ANA) was ineffective (progressive disease; PD) in elderly HER2-positive breast cancer with postoperative multiple liver metastases, but T-DM1 was significantly effective (complete response; CR), and treatment could be continued safely. An 82-year-old woman was referred to our department with a right breast mass. A close examination revealed right breast cancer cT1bN0M0 cStage I, and total mastectomy and sentinel lymph node biopsy were performed. The postoperative pathological result was pT1bN0M0 pStage I (luminal HER2 type). The patient was elderly and had no adjuvant treatment after the operation. Approximately 2 years after the operation, multiple liver metastases were observed, and treatment with ANA and Tmab was started. Four months later, MRI showed that the number of multiple liver metastases increased. The patient was diagnosed with PD, and the anti-HER2 drug was changed from trastuzumab to trastuzumab emtansine (T-DM1). The dose was reduced due to vomiting (grade 3). Two months later, MRI showed that the multiple liver metastases shrank and became obscure after 5 months. After that, T-DM1 was continued, and the disease did not worsen. In elderly people with difficulty in administering chemotherapy, T-DM1 may have a safe and sufficient therapeutic effect by adjusting the dose and managing side effects appropriately.

BACKGROUND: The identification of factors that are related to return to work after surgery for breast cancer could help healthcare professionals accurately identify patients at risk of return to work-related difficulties in order to provide them with appropriate support during breast cancer management. OBJECTIVE: The aim of this study was to identify factors related to return to work in breast cancer patients three months after axillary lymph node dissection. METHODS: Seventy-three women who were working before the surgery were evaluated. Age, body mass index, level of lymph node dissection, marital status, children, co-resident household members, preoperative chemotherapy, postoperative chemotherapy, postoperative hormonal therapy, postoperative radiotherapy, shoulder range of motion, upper limb function (Disabilities of the Arm, Shoulder and Hand; DASH), and work were evaluated. Patients who had returned to work constituted the return to work group, and those who had not returned to work constituted the no return to work group. RESULTS: Of the patients, 36 returned to work at three months. Logistic regression analysis including the five variables showed that shoulder flexion range of motion and DASH were significantly associated with return to work (p

BackgroundOnly old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment.MethodsThis was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan–Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate.ResultsFrom the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer.ConclusionIn actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.

Purpose Scalp cooling during chemotherapy infusion to mitigate alopecia for breast cancer patients is becoming widespread; however, studies regarding hair recovery after chemotherapy with scalp cooling are limited. We conducted a prospective study of hair recovery after chemotherapy with scalp cooling. Patients and methods One hundred and seventeen Japanese female breast cancer patients who completed planned (neo)adjuvant chemotherapy using the Paxman Scalp Cooling System for alopecia prevention were evaluated for alopecia prevention in our prospective study. We evaluated their hair recovery 1, 4, 7, 10, and 13 months after chemotherapy. Primary outcomes were grades of alopecia judged by two investigators (objective grades) and patients’ answers to the questionnaire regarding the use of a wig or hat (subjective grades). Results Of 117 patients, 75 completed scalp cooling during the planned chemotherapy cycles (Group A), but 42 discontinued it mostly after the first cycle (Group B). Objective and subjective grades were significantly better in Group A than in Group B throughout 1 year, and at 4 and 7 months after chemotherapy. When we restricted patients to those with objective Grade 3 (hair loss of > 50%) at 1 month, Group A exhibited slightly faster hair recovery based on the objective grades than Group B. There was less persistent alopecia in Group A than in Group B. Conclusions Scalp cooling during chemotherapy infusion for Japanese breast cancer patients increased the rate of hair recovery and had preventive effects against persistent alopecia.

Background: The Phase III POTENT trial demonstrated an improvement in invasive disease-free survival (IDFS) by the addition of S-1, an oral fluoropyrimidine, to adjuvant endocrine therapy in patients with ER-positive/HER2-negative early breast cancer. Because the trial was terminated at the interim analysis as the primary endpoint was met, the result of the overall survival (OS) remains immature. Methods: This multicenter observational study aimed to investigate the survival outcomes of patients who participated in the POTENT trial, in which patients with stage I to IIIB ER-positive, HER2-negative breast cancer without protocol-defined low-risk features received adjuvant endocrine therapy alone or with S-1 for 1 year. Of the full analysis set (FAS) of the POTENT trial (N=1930), patients who withdrew the consent or whose institutions terminated the contract were excluded from this study. The primary endpoint was OS. Secondary endpoints were IDFS and distant recurrence-free survival (DRFS). Results: A total of 337 patients (17%) in the POTENT study were excluded from this analysis (eight patients withdrew consent and 329 patients for institutions whose contract had been terminated). A total of 1593 patients were included in this study (803 in the endocrine therapy alone group and 790 in the endocrine therapy plus S-1 group). The median follow-up was 77.5 months (IQR: 68.8–86.0). The median duration of endocrine therapy was 71 and 69 months in the endocrine therapy alone and endocrine therapy plus S-1 groups, respectively. The patient characteristics were well balanced between the treatment groups, except for the number of lymph nodes involved. The endocrine therapy alone group included more patients with four or more positive nodes than the endocrine therapy plus S-1 group (12% vs. 9%, P=0.01). 58 (7%) patients in the endocrine therapy alone group and 51 (6%) in the endocrine therapy plus S-1 group died (HR 0.89, 95%CI: 0.61–1.30, P=0.54). The 5-year overall survival estimate was 94.7% (95%CI: 92.9–96.1%) in the endocrine therapy alone group and 95.6% (95%CI: 93.8–96.8%) in the endocrine therapy plus S-1 group. IDFS events were observed in 166 patients (21%) in the endocrine therapy alone group and in 135 patients (17%) in the endocrine therapy plus S-1 group (HR 0.80, 95%CI: 0.64–1.01). DRFS events occurred in 123 patients (15%) in the endocrine therapy alone group and in 91 patients (12%) in the endocrine therapy plus S-1 group (HR 0.74, 95%CI: 0.56–0.97). Conclusions: In this observational study, data from 337 patients (17%) were missing from the FAS of the POTENT trial. Both the endocrine therapy alone group and endocrine therapy plus S-1 groups showed favorable OS, and OS was similar between the treatment groups. The benefit of IDFS and DRFS by the addition of S-1 to endocrine therapy were maintained. Citation Format: Masahiro Takada, Shigehira Saji, Takayuki Ueno, Norikazu Masuda, Hiroshi Ishiguro, Takanori Ishida, Toshiaki Saeki, Shigeru Imoto, Shinji Ohno, Hiroji Iwata, Tomoharu Sugie, Kenjiro Aogi, Hirofumi Mukai, Shin Takayama, Nobuaki Sato, Yuichiro Kai, Masahiro Kitada, Rikiya Nakamura, Yutaka Matsuyama, Masakazu Toi. Adjuvant S-1 plus endocrine therapy for estrogen receptor-positive, HER2-negative, primary breast cancer: updated overall survival analysis from the POTENT trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-01-05.

Background Trastuzumab deruxtecan (T-DXd, DS-8201) is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2 positive metastatic breast cancer (MBC) and supported regulatory approval in the US and Japan. Updated longer-term safety and efficacy results are presented here. Methods All patients were required to have MBC that progressed on or after T-DM1. 253 patients were enrolled and 184 received T-DXd 5.4 mg/kg, representing the primary analysis set. The primary endpoint was ORR. Additional endpoints included duration of response, PFS, and OS. Results Patients had received a median of 6 previous lines of treatment for MBC. In this updated data cutoff (8 June 2020) compared to the prior data cutoff (1 Aug 2019), median duration of follow-up has increased from 11.1 to 20.5 mo; 37 patients (20.1%) remain on treatment. Confirmed ORR was 61.4% (12 CRs) with a median duration of response of 20.8 mo; the disease control rate was 97.3% (95% CI, 93.8-99.1). The updated mPFS was 19.4 mo (95% CI, 14.1 mo-NE). Estimated OS was 85% (95% CI, 79%-90%) at 12 months and 74% (95% CI, 67%-80%) at 18 months. The preliminary mOS is 24.6 mo (estimated at 35% maturity with only 17 patients at risk at 24 months). The safety profile of T-DXd was similar as that previously reported; with an additional 9 mo follow-up, only 3 new cases of T-DXd-related interstitial lung disease (ILD) were reported. Results are summarized in the table below. Conclusion Consistent with prior results, T-DXd demonstrated high rates of durable responses in a heavily pretreated population of patients with MBC. From this single-arm, phase 2 study, the PFS and immature OS results are encouraging; these endpoints will be further evaluated in the ongoing randomized controlled studies of T-DXd. For patients who remained on treatment for this longer duration (double that of the previous report), the rate of discontinuation or ILD did not notably increase. Continued attention to pulmonary symptoms and careful monitoring is warranted. Updated Results for DESTINY-Breast011 Aug 2019 datacut8 Jun 2020 datacutPatients remaining on treatment, n/N (%)79/184 (42.9%)37/184 (20.1%)Median duration of follow-up11.1 months20.5 monthsORR60.9%61.4%CR6.0%6.5%PR54.9%54.9%SD36.4%35.9%Duration of response, median (95% CI)14.8 months (13.8-16.9)20.8 months (15.0-NE)PFS, median (95% CI)16.4 months (12.7-NE)19.4 months (14.1-NE)OSMedian (95% CI)NE (NE-NE)24.6 months (23.1-NE)Point estimate at 12 mo (95% CI)86.2% (79.8-90.7)85% (79-90)Point estimate at 18 mo (95% CI)–74% (67-80)SafetyPatients with a TEAE, n (%)183 (99.5%)183 (99.5%)Grade ≥3105 (57.1%)113 (61.4%)Associated with discontinuation28 (15.2%)34 (18.5%)Associated with death10 (5.4%)10 (5.4%)Drug-related ILD per ILD adjudication committeea25 (13.6%)28 (15.2%)Grade 5 drug-related ILD per ILD adjudication committee4 (2.2%)5 (2.7%)a1 grade 1 and 1 grade 3 event are pending adjudication and are not included. Citation Format: Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Yali Liu, Lin Zhang, Javad Shahidi, Antoine Yver, Jose Baselga, Ian E Krop. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-06.

In this study, we examined whether axillary web syndrome (AWS) in patients with breast cancer following axil-lary lymph node dissection affects range of motion (ROM), upper extremity function, and quality of life (QOL). The risk factors for AWS were also evaluated in a total of 238 consecutive breast cancer patients follow-ing axillary lymph node dissection. At 1, 2, and 3 months after surgery, there were no significant differences between the AWS group and the non-AWS group in upper-limb function or QOL. At 2 months after surgery, shoulder flexion and abduction ROM were significantly higher in the AWS group than in the non-AWS group (p < 0.05). Self-training time at home was not significantly different between the groups at 1, 2, or 3 months. Only age was a significant predictor of AWS at 1 month after surgery (p < 0.05). The AWS group in the present study did not have worse results for shoulder joint ROM, upper-limb function, and QOL than the non-AWS group. Younger age should be useful for predicting the development of AWS in the early postoperative period.

Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [1%]), and fatigue (six [1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Background Male breast cancer (MBC) is rare; however, its incidence is increasing. There have been no large-scale reports on the clinicopathological characteristics of MBC in Japan. Methods We investigated patients diagnosed with breast cancer in the Japanese National Clinical Database (NCD) between January 2012 and December 2018. Results A total of 594,316 cases of breast cancer, including 3780 MBC (0.6%) and 590,536 female breast cancer (FBC) (99.4%), were evaluated. The median age at MBC and FBC diagnosis was 71 (45–86, 5–95%) and 60 years (39–83) (p p p = 0.02). Axillary lymph node dissection was more frequent in MBC cases (32.9 vs. 25.2%, p p p p Conclusion Japanese MBC had an older age of onset, were more likely to be hormone receptor-positive disease, and received less perioperative chemotherapy than FBC.

The Japanese Breast Cancer Society Registry started in 1975; it was transferred to the registry platform of the National Clinical Database in 2012. We provide the annual data and an analysis of the Breast Cancer Registry for 2017. Patients’ characteristics and pathological data of the 95,203 registered Japanese breast cancer patients from 1,427 institutes in 2017 were obtained. Trends in age at diagnosis and pathological stage were determined during the most recent 6 years (2012–2017). The mean onset age was 60.2 years with bimodal peaks at 45–49 years and 65–69 years. A short-term trend of the most recent 6 years of data caused the second, older peak. At diagnosis, 32.4% of breast cancer patients were premenopausal. The distribution of stages revealed that the proportion of early stage breast cancer (stage 0–I) increased up to 60%. At the initial diagnosis, 2.2% of patients presented with metastatic disease. Sentinel node biopsy without axillary node dissection was performed without neoadjuvant chemotherapy (NAC) in 68.8%, and with NAC in 31.1%, of patients. For patients without NAC, lymph node metastasis was less than 3% if the tumor size was less than 1 cm. The proportion of node-negativity decreased to 79.5% when tumor size was 2.1–5 cm. This analysis of the registry provides new information for effective treatment in clinical practice, cancer prevention, and the conduct of clinical trials. Further development of the registry and progress in collecting prognostic data will greatly enhance its scientific value.

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers. Significance: This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.

Scalp cooling during chemotherapy infusion has been recently reported to have moderate efficacy in the mitigation of chemotherapy-induced alopecia; however, there are few reports on Asian patients. We aimed to clarify the effects of scalp cooling in Japanese women. Female Japanese breast cancer patients who planned to receive (neo)adjuvant chemotherapy participated in this prospective study on the efficacy of scalp cooling using the Paxman Scalp Cooling System for alopecia prevention. The primary outcomes were the rates of patients with Grade 3 alopecia (defined as hair loss of > 50%) and the rates of patients who used a wig or hat to conceal hair loss 1 month after the last infusion of chemotherapy. The subjects were given a brief questionnaire regarding headaches, bad mood, fatigue, and chills shortly after each cooling. One hundred and forty-three patients participated in the study and used the cooling cap at least once. The mean and median ages of the subjects were 50.6 and 50, respectively (age range 28–76). One hundred and twenty-nine patients completed the planned chemotherapy of 4 to 8 cycles. Among them (7 patients were not evaluable), 74 patients (60.7%) had Grade 3 alopecia 1 month after chemotherapy. Of 80 patients who used the scalp cooling system throughout the planned chemotherapy (1 patient was not evaluable), 36 patients (45.6%) experienced Grade 3 alopecia. The efficacy of scalp cooling during chemotherapy infusion for hair loss mitigation in Asian women is similar to that in Caucasian women.

Introduction Scalp cooling during chemotherapy infusion to mitigate hair loss for breast cancer patients is becoming popular in European and North American countries. But there is little prospective data regarding hair recovery after chemotherapy with scalp cooling. We reported on the results of hair loss prevention with scalp cooling during (neo)adjuvant chemotherapy with anthracyclines and/or taxanes for 122 Japanese breast cancer patients at the 2018 San Antonio Breast Cancer Symposium. Now we report on the prospective data of hair recovery of our 122 patients. Patients and Methods One hundred and twenty two Japanese breast cancer female patients who completed planned (neo)adjuvant chemotherapy used Paxman Scalp Cooling System for alopecia prevention and were evaluable for hair loss prevention in our prospective study. The scalp cooling was done 30 minutes prior to and during and 90 minutes after each chemotherapy infusion. We evaluated their hair recovery 1, 4, 7, 10, and 13 months after completion of the chemotherapy. We took photographs of the heads of the patients from 5 directions, namely front, back, both sides, and top and asked the patients about the use of a wig or hat to conceal the hair loss using a questionnaire at the times mentioned above. Primary outcomes were grades of alopecia judged by two investigators (defined as Grade 0: 0% of hair loss, G1: 1~25 %, G2: 26~50%, G3: > 50%)(objective grade) and patients' answers to the questionnaire (defined as Grade 0: not at all, G1: sometimes, G2: almost always)(subjective grade). Among 122 patients 79 completed scalp cooling during the whole planned chemotherapy cycles, but 43 discontinued it mostly after the first cycle due to several reasons. We compared the objective and subjective grades of hair loss between the patients who had completed the scalp cooling (79 patients: Group A) and those who had discontinued it (43 patients: Group B). Results Objective grades 1 month after completion of the chemotherapy were Grade 0 in 6 patients (4.9 %), G1 in 13, G2 in 29, and G3 in 74, and subjective grades at 1 month were Grade 0 in 3 patients (2.5 %), G1 in 13, G2 in 105, and unknown in 1. The changes over time in objective grades were as follows; 4 months: G0 55 (47.0 %), G1 52, G2 9, G3 1, unknown 5, 7 months: G0 99 (85.3 %), G1 15, G2 1, G3 1, unknown 6, 10 months: G0 105 (89.7 %), G1 10, G2 1, G3 1, unknown 5, 13 months: G0 104 (92.0 %), G1 7, G2 1, G3 1, unknown 9. On the other hand, the changes in subjective grades were as follows; 4 months: G0 12 (10.3 %), G1 29, G2 76, unknown 5, 7 months: G0 53 (45.7 %), G1 22, G2 41, unknown 6, 10 months: G0 80 (68.4 %), G1 15, G2 22, unknown 5, 13 months: G0 93 (82.3%), G1 7, G2 13, unknown 9. When we compared Group A with Group B, the rates of objective G0 were statistically significantly higher in Group A than Group B, at 4, 10, and 13 months (4 months: 55.7% vs. 28.9%, P = 0.010, 10 months: 96.1% vs. 78.0%, P = 0.006, 13 months: 97.3% vs. 81.6%, P = 0.011) and the rate of subjective G0 was also statistically significantly higher in Group A than Group B at 7 months (53.2 % vs. 30.8 %, P = 0.022). When we restricted the data to those with objective Grade 3 at 1 month, Group A showed tendency of faster hair recovery in the objective grades than Group B. Conclusion It is concluded that scalp cooling during chemotherapy infusion for Japanese breast cancer patients made their hair recovery faster. Citation Format: Shozo Ohsumi, Sachiko Kiyoto, Yuichiro Miyoshi, Mina Takahashi, Seiki Takashima, Kenjiro Aogi, Sachie Shimizu, Miyuki Doi. Prospective study of hair recovery after (neo)adjuvant chemotherapy with scalp cooling in Japanese breast cancer patients [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 P5-14-21.

BACKGROUND: Although long-term prognostic outcomes of primary breast cancer (PBC) patients have been improved remarkably in recent years, the disease recurrence remains a serious problem. We have previously investigated a role for oral fluoropyrimidines in postoperative adjuvant treatments.In this study, we aimed to verify the usefulness of S-1 in combination with adjuvant endocrine therapy for PBC patients having luminal disease. PATIENTS AND METHODS: This open-label, randomized, phase 3 trial was carried out in 139 centers in Japan. StageI-IIIPBC patients, who had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negativestatus and intermediate or higher risk of recurrence were randomly assigned (1:1) to receive standard endocrine therapy alone (control arm) or endocrine therapy plus S-1 (S-1 arm). Recurrence risk assessment was performed using anatomical stage, pathological findings such as histologic grade, and centrally confirmed proliferative marker status. S-1 was administered postoperatively in combination with standard endocrine therapy. For patients who underwent multi-drug postoperative adjuvant or preoperative neoadjuvant chemotherapy, S-1 was administered following the multi-drug chemotherapy. Cases having no residual cancer in the breast and axillary node after the preoperative chemotherapy were excluded from this study. The S-1 dosage was chosen among 80 mg/day, 100 mg/day, and 120 mg/day according to the body surface area of each patient, and S-1 was administered for one year with a 2 weeks on/1 week off administration schedule. The primary endpoint was invasive disease-free survival (iDFS), defined as time from randomization to invasive disease recurrence, occurrence of second invasive cancer event, or death, and was analyzed on an intent-to-treat basis. Secondary endpoints included DFS, distant DFS, overall survival, and safety profile. RESULTS: From Feb 2012 to Feb 2016, 1959 patients were enrolled and 1932 patients were included in the full analysis set (control arm, 973; S-1 arm, 959). The results of the prespecified interim analysis met the primary end point, and this trial was terminated early. Median follow-up was 51.4 months. S-1 significantly reduced invasive events; 153 iDFS events were reported in the control arm and 99 iDFS events were reported in the S-1 arm [hazard ratio, 0.63 (95%CI, 0.49-0.81); p-value, 0.0003]. The 5-year iDFS estimate was 81.5% in the control arm and 86.9% in the S-1 arm. Distant recurrence as the first disease event was observed in 6.8% of patients in the S-1 arm and in 9.5% of those in the control arm. The safety data in patients treated with S-1 was consistent with the known profile of S-1. The S-1 treatment was well tolerated and manageable. CONCLUSIONS: It was concluded that the postoperative adjuvant use of an oralfluoropyrimidine S-1 significantly reduced iDFS events and improved 5-year iDFS estimate in PBC patients having HR-positive and HER2-negative disease, in the combination with standard endocrine therapy, with a feasible safety profile. Funding: This study was funded by the Comprehensive Support Project (CSP) of the Public Health Research Foundation. The research fund was provided to CSP by Taiho Pharmaceutical Co., Ltd. This trial was conducted as a study of ‘Advanced Medical Care,’ the Ministry of Health, Labour and Welfare, Japan. JRCT ID: jRCTs051180057, UMIN000003969 Citation Format: Masakazu Toi, Shigeru Imoto, Takanori Ishida, Yoshinori Ito, Hiroji Iwata, Norikazu Masuda, Hirofumi Mukai, Shigehira Saji, Akira Shimizu, Takafumi Ikeda, Hironori Haga, Toshiaki Saeki, Kenjiro Aogi, Tomoharu Sugie, Takayuki Ueno, Takayuki Kinoshita, Yuichiro Kai, Masahiro Kitada, Yasuyuki Sato, Kenjiro Jimbo, Nobuaki Sato, Hiroshi Ishiguro, Masahiro Takada, Yasuo Ohashi, Shinji Ohno. Addition of S-1 to endocrine therapy in the post-operative adjuvant treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative primary breast cancer: A multicenter, open-label, phase 3 randomized trial (POTENT trial) [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 GS1-09.

Background: There are now many treatment options for estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, there are few reports indicating the optimal treatment sequence for this disease. Information to predict response to treatment is vital for personalized therapy and determining the most beneficial approach for individual patients. In this study, we attempted to determine predictive factors of response to hormonal therapy and survival outcomes using the large-scale databases constructed in the Safari study (UMIN000015168), a retrospective, multicenter cohort study involving 1,072 Japanese patients receiving fulvestrant 500mg for ER+ ABC. We examined the association between clinicopathological factors and time to failure (TTF) of fulvestrant in Japanese ABC patients. Methods: Among 1072 patients, 247 patients were selected for this study. Inclusion criteria was as follows: 1) patients treated with either SERM or AI in the adjuvant setting (AS) with known starting and finishing date of the treatment (patients relapsed on adjuvant treatment were excluded), 2) patients treated with SERM, AI and SERD in the metastatic setting (MS) as the first and the second line treatment. Influence of the adjuvant hormonal therapy on the TTF of the first line and the second line treatment and overall survival (OS) was assessed. Cox proportional hazards model was used for this analysis. Results: Patients treated with SERM in AS had significantly longer TTF of 1st line and 1st+2nd line of hormonal therapy in MS (1st line: HR 1.519, 95% CI 1.04-2.218, p=0.0307, 1st+2nd line: HR 2.372, 95% CI 1.584-3.551, p Conclusions: Interestingly, once AI-treated patients in AS have relapsed, their hormone sensitivity is lower and survival outcomes are worse compared with SERM-treated patients in AS in this cohort. Our results have consistency with the results of ABCSG-12 trial showing a pronounced higher risk of death for anastrozole-treated patients (Annals of Oncology 26: 313–320, 2015). Since it is a cohort of selected patients who were successfully treated with fulvestrant, prospective analysis would be therefore warranted. Citation Format: Takahiro Nakayama, Hidetoshi Kawaguchi, Norikazu Masuda, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Influence of the adjuvant hormonal therapy on hormone sensitivity and survival outcomes in ER+ and HER2−advanced breast cancer: A subgroup analysis of the JBCRG-C06 Safari 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 P5-11-11.

Background: After the CONFIRM trial, fulvestrant 500 mg (F500) became a standard treatment for patients with estrogen receptor positive (ER+) advanced/metastatic breast cancer (AMBC). The JBCRG-C06 Safari study (UMIN 000015168) showed that earlier F500 use, a longer time from diagnosis to F500 use, and no prior chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with ER+ and HER2-negative AMBC (Kawaguchi H, et al. Breast Cancer Res Treat, 2017; Kawaguchi H, et al. Curr Med Res Opin, 2018). We had carried out subgroup analyses on real world data from the Safari study focusing on ER+ and HER2+ AMBC with the objective to examine further on potential interactions between TTF and the following: F500 single treatment or F500 with anti-HER2 therapy; presence or absence of visceral metastasis; progesterone receptor (PgR) status; and prior chemotherapy for AMBC. Material & methods: The Safari study was a retrospective, multicenter cohort study, conducted in 1072 patients at 16 sites in Japan for ER+ AMBC. Patients starting treatment with F500 between Nov 2011 and Dec 2014 were registered. After the data cleaning through the central review, 94 patients (9.6%) has been included in this sub-analysis among the 978 patients in which HER2 status was confirmed by the documentation. The relationship between baseline clinical/pathological factors, treatment line, and TTF (time from start to cessation of F500 treatment for any reason, including toxicity and death) were analyzed using Kaplan-Meier methods. Univariate analysis of TTF data was performed by Cox hazards model using: age, histological type, histological/nuclear grade, visceral-metastases, stage, PgR, period from AMBC diagnosis to F500 use, treatment line of F500, prior chemotherapy. Results: Median age at diagnosis of AMBC was 57.5yrs (33-85); 59(33-85) and 56.5(39-75) for F500 with/ without anti-HER2 therapy. Median age of fulvestrant start was 61yrs (35-96). 21.3% had de novo metastatic disease; 78.7% recurrent disease; 37.2% visceral metastases. All patients’ ER status was positive, and PgR status was positive in 65.9%, negative 25.5% respectively. HER2 IHC 3+ patients accounted for 44.7%, IHC 2+/1+ for 38.3%. In the case of IHC 2+/1+, HER2-positivity was confirmed by FISH. F500 alone was administered in 52 patients, while F500 with anti-HER2 therapy in 42 patients. At median follow up of 3.9 years, median TTF was 4.4m (95% CI: 3.3-5.7); 3.7m (95% CI: 2.9-5.9), 5.1m(95% CI: 3.6-6.4) for the F500 alone group, F500 with anti-HER2 therapy group respectively (p = 0.5973). F500 with/ without anti-HER2 therapy was administered in 1stor 2nd-line in 20 (21.3%), and ≥3rd-line in 74(78.7%) patients. Median TTF was 6.6m (95% CI: 4.6-8.5) and 3.7m (95% CI: 2.8-5.2) in the 1stor 2nd-line and ≥3rd-line respectively (p value:0.0145). Although no statistically significant difference was found, TTF tended to be shorter in the group receiving chemotherapy prior to F500 (median TTF: 3.7m vs 5.5m). No other clinical parameters including age, PgR status, metastatic sites were associated with the effectiveness. The median OS was 7.8-years (95% CI: 5.9-9.5), which had not been influenced by with/ without anti-HER2 therapy. The toxicity profile we observed was similar to that in the registration trial. Conclusions: Our findings suggest that F500 with/without anti-HER2 therapy appears to be effective also in the ER+ and HER2-positive ABMC setting which is consistent with the limited results previously published. Earlier line use of F500 use may be useful in HER2-positive patients as well as HER2-negative patients. Citation Format: Misato Hagi, Hidetoshi Kawaguchi, Norikazu Masuda, Shigehira Saji, Yutaka Yamamoto, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Daisuke Yotsumoto, Satoshi Morita, Masakazu Toi, Shinji Ohno. Outcomes of fulvestrant therapy among Japanese women with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of the JBCRG-C06 safari 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 P5-11-13.

Background: To evaluate the survival risk is an important factor to decide or treatment options for recurrent breast cancer patients with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−), though there are not enough supporting reports from large-scale databases. The Safari study (UMIN000015168) is a newly conducted retrospective, multicenter cohort study including 1072 ER+ advanced breast cancer Japanese patients treated with fulvestrant 500 mg mostly as a second or later line hormonal therapy. The follow-up data of Safari study is evaluated to focus on any relationship between clinicopathological factors and post-recurrence survival (PRS) in ER+ HER2− recurrent breast cancer patients. Methods: PRS was defined as the duration from the date of initial treatment for recurrent breast cancer to death. The Cox hazards model was used to evaluate the relationship between the clinical factors and PRS. We also performed multivariate analysis on PRS using factors that showed a statistical difference (p < 0.15) in univariate analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p-values are described. All tests were two-sided and p Citation Format: Kenjiro Aogi, Hidetoshi Kawaguchi, Norikazu Masuda, Takahiro Nakayama, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari 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 P3-08-55.

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS: In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS: Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS: Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.)

Background Assessing survival risk is important for discussing treatment options with estrogen receptor-positive (ER+) advanced breast cancer (ABC) patients. However, there are few reports from large-scale databases on the survival risk factors in ER+ ABC. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study involving 1072 Japanese patients receiving fulvestrant 500 mg mostly as a second- or later-line endocrine therapy for ER+ ABC. The follow-up data after the Safari study were examined, focusing on any relationship between clinicopathological factors and overall survival (OS) in ER+ ABC patients. Methods OS in patients with ER+ ABC was analyzed by univariate and multivariate analyses with a Cox proportional hazards model in this study. Results A total of 1031 cases were evaluable for OS analysis. Multivariate analysis showed that younger age ( Conclusions In ER+ ABC patients whose treatment history included fulvestrant, younger age, longer time from ABC diagnosis to fulvestrant use, no prior palliative chemotherapy use, PgR−, and lower histological or nuclear grade correlated positively with prolonged OS.

Background Hereditary breast and ovarian cancer (HBOC) syndrome is a susceptibility syndrome for cancers, such as breast and ovarian cancer, and BRCA1/2 are its causative genes. Annual breast-enhanced magnetic resonance imaging (MRI) is recommended for BRCA1/2 mutation carriers aged over 25 years as a secondary prevention of breast cancer. However, breast MRI surveillance is rarely performed in Japan, and only four cases of breast cancer diagnosis triggered by MRI surveillance have been reported. Case presentation At our hospital, MRI triggered the diagnosis of breast cancer in four cancer-free BRCA1/2 mutation carriers. In one of our four cases, although MRI showed only a 3-mm focus, we could diagnose breast cancer by shortening the surveillance interval considering the patient’s high-risk for developing breast cancer. Conclusions Image-guided biopsy, including MRI-guided biopsy, depending on the size of the lesion, and shorter surveillance intervals are useful when there are potentially malignant findings on breast MRI surveillance for cancer-free patients with HBOC.

Occult breast cancer (OBC) is classified as carcinoma of an unknown primary site, and the adequate therapy for OBC remains controversial. This retrospective study aimed to reveal the transition in breast cancer therapy and the frequency of primary breast tumors after resection in clinical OBC (cT0N+) patients using the Japanese Breast Cancer Registry database.We enrolled OBC patients with cT0N+ from the registry between 2010 and 2018. On the basis of the period of diagnosis, OBC patients were divided into the following two groups: 2010-2014 and 2015-2018. We described the transition in treatments and tumor characteristics. After breast resection, the frequency of pathological identification of primary tumors and tumor sizes was assessed.Of the 687,468 patients registered, we identified 148 cT0N+ patients with a median age of 61 years. Of these patients, 64.2% (n = 95) received breast surgery (2010-2014: 79.1%, 2015-2018: 50.0%). Axillary lymph node dissection was performed in 92.6% (n = 137, 2010-2014: 91.6%, 2015-2018: 93.4%). The breast tumor size in the resected breast was 0-7.0 cm (median: 0 cm, 2010-2014: 0-7.0 cm [median: 0 cm], 2015-2018: 0-6.2 cm [median: 0 cm]). The pathological identification rate of the primary tumor was 41.1% (n = 39, 2010-2014: 40.4%, 2015-2018: 42.1%).Breast surgery for cT0N+ decreased between 2010 and 2018. Despite the high identification rate of primary tumors, most tumors were small, and there was no significant change in the identification rate or invasive diameter of the identified tumors after 2010.

We conducted the Neo-LaTH study in which patients were randomized to different lengths of neoadjuvant induction anti-HER2 therapy with lapatinib and trastuzumab followed by weekly paclitaxel plus the anti-HER2 therapy, and in estrogen receptor (ER)-positive patients, with or without concurrent endocrine therapy. The use of endocrine therapy did not affect the response, comprehensive pathological complete response (CpCR) plus ypN0 rate was 57.6% and 30.3% in ER-negative and ER-positive patients, respectively. After surgery, patients received an anthracycline-based regimen based on physician’s choice, followed by trastuzumab for 1 year, and in ER-positive patients, endocrine therapy for 5 years. Here, we report the 5-year survival outcomes. Among the followed-up patients (n = 212), the 5-year disease-free survival (DFS), distant DFS, and overall survival rates were 87.8% [95% confidence interval (CI), 82.5–91.6%], 93.7% (95% CI, 89.3–96.3%), and 95.6% (95% CI, 91.7–97.7%), respectively, with no difference between ER-negative and ER-positive patients. The 5-year DFS rate was significantly higher in patients who had a CpCR plus ypN0 after neoadjuvant treatment than in those who did not (91.7% vs. 85.1%, p = 0.0387). The stratified analysis showed better survival outcomes in patients who had CpCRypN0 than in those who did not after neoadjuvant treatment, regardless of use of adjuvant anthracycline therapy.

Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a HER2 antibody, peptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. In a phase 1 trial, the objective response rate (ORR) was 59.5% (66/111) and median progression-free survival (PFS) was 22.1 mo in subjects with HER2-positive metastatic breast cancer (BC) previously treated with T-DM1 (Tamura, Lancet Oncol, 2019). DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 registration study of T-DXd in subjects with centrally confirmed HER2-positive metastatic BC. Methods Part 1 of this 2-part study was performed in 2 stages (pharmacokinetics and dose finding; T-DXd 5.4, 6.4, 7.4 mg/kg) and served to identify the recommended Part 2 dose (RP2D). In Part 2, subjects were treated at the RP2D. Subjects in Parts 1 and 2a were required to have metastatic BC that progressed on or after T-DM1. Subjects in a small additional cohort (Part 2b) had discontinued T-DM1 for reasons other than progression. The primary endpoint was ORR (complete response [CR] + partial response [PR]) per independent central review (ICR). Additional endpoints included disease control rate (DCR; CR + PR + stable disease [SD]), duration of response (DOR), and PFS. Abstract results represent 6 mo of follow-up from the date the last subject enrolled in the study. Results As of data cutoff (March 21, 2019), 253 subjects were enrolled and 184 received the RP2D (5.4 mg/kg), 4 of which were enrolled in Part 2b. All subjects were female, 55% were white, and 38% were Asian. Median age was 55 y (range, 28-96 y; ≥ 65 y, 24%); 53% were hormone receptor (HR) positive and 45% were HR negative. Median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (100%), T-DM1 (100%), pertuzumab (66%), and other HER2-targeted regimens (54%). The reported best response to T-DM1 before enrollment was 22% CR or PR, 21% SD, and 36% progressive disease (PD); 21% were not evaluable. At data cutoff, 60% of subjects remained on T-DXd treatment; primary reasons for discontinuation were PD (21%) and treatment-related adverse events (TEAEs, 8%). The confirmed ORR by ICR in subjects treated at the RP2D in Parts 1, 2a, and 2b was 60% (111/184 [95% CI, 53%-68%]). ORRs were consistent across subgroups, including those with prior pertuzumab (64%) and those with ≥ 3 prior regimens (59%). The DCR was 97% (95% CI, 94%-99%); only 5 of 184 subjects did not have SD or better at the time of first post-baseline scan. As of the data cutoff, median DOR and PFS had not been reached; median duration of follow up was 7.2 mo (range, 0.7-17.2 mo). In the 184 subjects, the median treatment duration was 6.9 mo (range, 0.7-16 mo); 70% had > 6 mo of treatment. TEAEs occurred in 99% of subjects (grade ≥ 3, 51%); the most common any-grade TEAEs were gastrointestinal (nausea [77%], vomiting [45%], constipation [34%], decreased appetite [29%], and diarrhea [27%]), alopecia (48%), fatigue (48%), and hematologic (decreased neutrophil count [31%] and anemia [26%]). Most common grade ≥ 3 AEs were decreased neutrophil count (17%), nausea (7.6%), anemia (6.5%), decreased lymphocyte count (5.4%), and fatigue (5.4%). 15 subjects (8.2%) had interstitial lung disease (ILD) adjudicated as ILD related to T-DXd by an independent adjudication committee; ILD was primarily grade 1 or 2 (6.0%; no grade 3 or 4; 2.2% grade 5). [Additional follow up and first DOR/PFS data will be presented at the meeting.] Conclusion Overall, T-DXd treatment demonstrated clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic BC. T-DXd had a generally manageable safety profile, with ILD identified as a risk warranting proactive awareness and management. Citation Format: Ian E Krop, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice André, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Shanu Modi. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01) [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 GS1-03.

Background: In this year, anti-programmed death-ligand 1 (PD-L1) antibody has been approved for PD-L1-positive metastatic triple-negative breast cancer by the U.S. Food and Drug Administration. The synergistic effect of the combination of anti-PD-L1 antibody, CDK4/6 inhibitor and endocrine therapy (ET) has been anticipated based on various preclinical data. A Phase Ib study (JPCE, NCT02779751) of abemaciclib plus pembrolizumab demonstrated manageable safety and promising anti-tumor activity in patients with HR-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib and ET (letrozole [LET] or fulvestrant [FUL]) as a first or second-line treatment in patients with HR+, HER2- MBC. Trial Design: This is a multicenter, multi-cohort, nonrandomized, open-label Phase II study to evaluate the efficacy and safety of nivolumab in combination with abemaciclib and ET (LET or FUL) in patients with HR+, HER2- MBC. Since there is no safety data of the combination of nivolumab, abemaciclib and ET, we evaluate safety and tolerability of the combination therapy in the first 6 patients with predefined dose-limiting toxicities. Patients will receive nivolumab 240 mg/body on day 1, 15, abemaciclib 150mg twice daily, and either LET 2.5mg once daily (LET cohort) or FUL 500mg on day1, day15 (FUL cohort) every 4 weeks until disease progression, unacceptable toxicity, or patient refusal. Pre- or perimenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligibility Criteria: Key eligibility criteria for the LET cohort are: postmenopausal HR+, HER2- MBC with ECOG PS≤1, measurable disease, no prior systemic therapy. ET in the adjuvant setting is permitted if the patient has a disease-free interval > 12 months from the completion of ET. Key eligibility criteria for the FUL cohort are: HR+, HER2- MBC with ECOG PS≤1, measurable disease, no more than one ET or any prior chemotherapy for MBC. Patients are required to have a disease that progressed while receiving adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for MBC. Specific Aims: The primary endpoint is the objective response rate (ORR) and key secondary endpoints include progression-free survival, overall survival, and the safety of the protocol treatment. Statistical Design: The threshold and expected ORR of LET cohort are 55% and 75%, respectively, and 16 patients are needed to ensure a statistical power of 80% (α=0.20). The threshold and expected ORR of FUL cohort are 45% and 60%, respectively, and 32 patients are needed to ensure a statistical power of 80% (α=0.20). Target Accrual: A total of 53 patients (LET cohort: 18, FUL cohort: 35) will be enrolled and duration of enrollment will be 1 year and 4 months. This trial opened to accrual in June 2019. Clinical trial information: JapicCTI-194782. Contact Information: Jun Masuda, Toranomon Hospital, Tokyo, Japan, masu-j@toranomon.gr.jp Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Masato Takahashi, Hiroji Iwata, Tsutomu Iwasa, Toru Mukohara, Kenichi Yoshimura, Takayuki Ueno, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial) [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 OT2-04-07.

Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD). We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS). There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p