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Background When considering treatment for metastatic and recurrent breast cancer, it is necessary to select drugs with emphasis on side effects and QOL. In Japan, oral 5-FU drugs have often been used for initial treatment. In the conventional schedule of S-1 for 4-week administration period followed by 2-week rest, the inferiority of S-1 to T has already been proved. In this study, we examined the efficacy and safety of the schedule of S-1 for 2-week administration period followed by 1-week rest, which is considered to have less side effects and better compliance. Methods We enrolled individuals with HER2-negative breast cancer who had not received chemotherapy after diagnosis of metastatic breast cancer. S-1 (40-60 mg, twice daily) was administered consecutively for 14 days followed by 7 days of rest (1 course). The primary endpoint was progression-free survival (PFS); the secondary endpoints were overall survival (OS), time to treatment failure (TTF), response rate (RR), disease control rate (DCR), and adverse events. Results Between September 1, 2013 and August 31, 2016, 32 patients were enrolled. Median PFS was 7.8 months (1.4-35.4 months), and median OS was 25.2 months (4.8-47.8 months). TTF was 9.1 months. RR was 31.3%, and the DCR was 78%. The cumulative rates of the relative total administration dose of S-1 was 95.6%. Incidence of grade 3 side effects were neutropenia (9.4%), leukopenia (3.1%), anorexia (3.1%), ocular symptoms (3.1%), and an increase in total bilirubin levels (3.1%). Conclusions The schedule of 2-week administration period followed by 1-week rest seems to be safe and effective for primary treatment of metastatic and recurrent breast cancer. Legal entity responsible for the study Kobe Breast Cancer Oncology Group. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background The PALOMA2/3 trials demonstrated prominent efficacy of combination therapy of palbociclib (PAL) and endocrine therapy (ET) compared with monotherapy. PAL was approved for metastatic breast cancer in Japan in 2017. We evaluated the efficacy and safety in practice after approval of PAL in Japan. Methods We retrospectively reviewed patients who newly received PAL at Aichi Cancer Center after Dec 2017. The patients were classified by treatment-line and assessed as follows; clinical benefit rate (CBR) defined as the rate of clinical PR, CR and long SD (more than 6 months) based on physician's judgment, time to failure (TTF) defined as the duration time of PAL, prior ET response, and adverse events (AEs). TTFs were figured with swimmer's plot by treatment-line, PAL doses (125, 100, 75mg/day). Results Between Dec 2017 and Oct 2018, 64 patients were eligible. Median age was 62.5 (37-82). Forty-one patients (64%) had visceral metastasis. PAL was administered for 1st to 3rd line (early-line group) in 52% (n = 33), and for more than 4th line (late-line group) in 48% (n = 31). Combination ETs were aromatase inhibitors (n = 27, 42%), fulvestrant (n = 35, 55%), and tamoxifen (n = 2, 3%). Prior ET was sensitive in 59% (n = 33). The dose reduction was needed in 62% (100mg; n = 19, 75mg; n = 21). Twenty-eight patients (43.8%) were continuing PAL. Overall CBR was 38%. By treatment line, CBR was 51.6% in the early-line group, and 22.6% in the late-line group. Median TTF was 4.6 months (0.2-10.2). There were no significant differences of TTF by treatment-line, prior ET response, and PAL doses. The grade 3-4 hematological toxicity, such as neutropenia and anemia, were observed in 83% (n = 53). Stomatitis, nausea, and fatigue were common, but most of them were grade 1-2. No patients discontinued PAL due to AEs. Conclusions In the clinical setting, PAL was given in many late line-patients who were not eligible for the PALOMA2/3 trials. Its efficacy was not sufficient, although it was feasible. [ABSTRACT FROM AUTHOR]

One of 400 to 500 general people has a germ-line pathogenic variant in BRCA 1 or 2, and those with such variants are diagnosed as HBOC. Since women with HBOC have extremely high risk of breast and ovarian cancer, they need to take action to avoid death due to those cancers. But how can we find them? We should screen suspicious people by their personal and family histories. We most frequently use NCCN guidelines to find them. They recommend BRCA genetic testing for all patients with personal history of ovarian, male breast, pancreatic or metastatic prostate cancer, and breast cancer patients with young onset, and/or family history of breast, ovarian, prostate, and/or pancreatic cancer. And after the approval of Olaparib for breast cancer, all HER2 negative metastatic breast cancer patients have become candidates for the BRCA genetic testing to check if Olaparib is usable or not. If we consider patients' ages of breast cancer diagnosis and/or family histories of cancers mentioned above, the positive rate will be high, but if we do the testing for all HER2 negative metastatic breast cancer patients, it will be around 5%. Genetic counseling is quite important to do the BRCA genetic testing in suspicious people and recommend women with HBOC to take cancer surveillance and/or risk-reducing surgery. For now, we have a big problem in genetic counseling in most Japanese hospitals. Specialists in genetics, especially genetic counselors, are expected to play an important role in genetic counseling. But there are only 243 certified genetic counselors in Japan. This number is not only small, but the majority of them are not good at hereditary cancers. Physicians and surgeons are also required to do genetic counseling in medical care of HBOC. To improve their knowledge and skills that are required in performing genetic counseling of hereditary cancer syndromes including HBOC, educational workshops have been held by several societies. I will present them briefly. [ABSTRACT FROM AUTHOR]

Background IMpassion130 is randomized, double-blind, phase III study to evaluate efficacy and safety of atezolizumab (ATZ)+nab-paclitaxel (nPTX) vs placebo (Pla)+nPTX in patients (pts) with treatment-naive locally advanced or metastatic triple-negative breast cancer (TNBC). We report the results of Japanese subgroup. Methods Pts were randomized 1:1 to Pla or ATZ (840 mg, q2w)+nPTX (100 mg/m2, 3 weeks on/1 week off). Progression-free survival (PFS) and overall survival (OS) as co-primary endpoints were assessed in intent-to-treat population and programmed death-ligand 1 positive (PD-L1+) population. Results Among 902 enrolled pts, sixty five pts were from Japan (34 pts with ATZ+nPTX, 12 of them PD-L1+; 31 pts Pla+nPTX, 13 of them PD-L1+). Median PFS was 7.4 months (mo) in ATZ+nPTX, as compared with 4.6 mo in Pla+nPTX [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.25-0.90]. In the PD-L1+ population (n = 25), median PFS was 10.8 mo in ATZ+nPTX, as compared with 3.8 mo in Pla+nPTX (HR, 0.04; 95%CI, <0.01-0.35). Median OS was not reached in ATZ+nPTX, as compared with 16.8 mo in Pla+nPTX (HR, 0.44; 95% CI, 0.16-1.24). In the PD-L1+ population, median OS was not reached in ATZ+nPTX, as compared with 13.3 mo in Pla+nPTX(HR, 0.12; 95%CI, 0.01-0.99). Adverse events (AE) leading to any treatment discontinuation occurred in 5.9% in ATZ+nPTX and in 0% in Pla+nPTX. AE that led to the dose reduction or interruption occurred in 64.7% of ATZ+nPTX and in 56.7% of Pla+nPTX. Adverse event of special interest (AESI) occurred in 61.8% of ATZ+nPTX and in 50.0% of Pla+nPTX. The incidence of typical AESI was hepatitis (20.6% vs 26.7%), hypothyroidism (17.6% vs 3.3%), hyperthyroidism (5.9% vs 0%) and pneumonitis (2.9% vs 0%) in ATZ+nPTX and Pla+nPTX, respectively. The incidence of AESI was similar to that of overall study population. Conclusion The efficacy and safety of ATZ+nPTX as first line therapy in Japanese pts with TNBC were consistent with those of overall study population. [ABSTRACT FROM AUTHOR]

Background Two global phase 3 trials (301 trial of first- or second-line eribulin, EMBRACE of third- or later-line eribulin) were carried out during development of eribulin for breast cancer treatment. In this post marketing observation study in Japan, efficacy and safety of eribulin in metastatic breast cancer patients were examined. Additionally, the results were compared with that of phase 3 trials. Method We conducted a prospective study in patients with inoperable or recurrent HER2-negative breast cancer. We enrolled a similar number of patients receiving eribulin as first- or second-line therapy (early line) and those receiving eribulin as third- or later line therapy (later line), and followed the patients for two years (ClinicalTrials.gov Number: NCT02371174). For the overall survival and time to treatment failure, the estimated value of them were calculated by the Kaplan Meier method. The severity of adverse drug events was determined by CTCAE v 4.0. Results During September 2014 to February 2016, 651cases were registered at 182 facilities. In analysis set, 637 patients (319 patients of early line/317 patients of late line/1 patient of unknown) was median age of 62.7 (30 - 85) years. Performance status 0/1/2/3/4 was seen in 360/234/38/5/0 patients, respectively. Dose reduction were required in 33% of patients. The median overall survival (early line/late line) was 18.8 months/12.6 months, respectively, and median time to treatment failure was 4.4 months/3.8 months, respectively. Major side effects (early line/late line) were neutropenia (51%/56%), leucopenia (55%/57%), peripheral neuropathy (32%/22%). Grade 3≤ peripheral neuropathy was 2%. Conclusion The results of overall survival (18.8 months in early line, 12.6 months in later line) in this study is comparable to those of large phase 3 study (15.9 months in 301 trial, 13.1 months in EMBRACE). The incidence of Grade 3≤ peripheral neuropathy was lower than that of phase 3 trials. [ABSTRACT FROM AUTHOR]

Hyperactivation of PI3K pathway can occur due to PIK3CA mutations, which is present in ∼40% of patients (pts) with HR+, HER2- ABC. In SOLAR-1 (NCT02437318) trial, ALP+FUL significantly extended progression-free survival (PFS) vs placebo (PBO)+FUL in the PIK3CA-mutant (mut) cohort (median 11.0 vs 5.7 months; HR = 0.65; P < 0.001). Here we report efficacy and safety results from the Japanese (JPN) population. Men and postmenopausal women with HR+, HER2- ABC and recurrence/progression on/after prior aromatase inhibitor were randomized (1:1) to ALP (300 mg/day)+FUL (500 mg every 28 days+Cycle 1 Day 15) or PBO+FUL. This trial consisted of the PIK3CA-mut cohort for confirmatory purpose and the PIK3CA non-mutant (non-mut) cohort for proof of concept purpose. Primary endpoint was locally assessed PFS in the PIK3CA-mut cohort. Safety was assessed in the total population. Among 572 pts, 68 pts were enrolled in Japan; 36 pts in the PIK3CA-mut cohort received ALP+FUL (n = 17) or PBO+FUL (n = 19), and 32 pts in the non-mut cohort received ALP+FUL (n = 15) or PBO+FUL (n = 17). In JPN pts, ALP+FUL did not improve PFS in the mut cohort (median 9.6 vs 9.2 months; HR = 0.78). Duration of ALP exposure was shorter (median 1.7 months in JPN vs 5.5 months in overall population). Most frequent all-grade adverse events (JPN vs overall population) were rash (75.0% vs 53.9%), hyperglycemia (68.8% vs 65.8%), gastrointestinal toxicities (65.6% vs 75.4%), hypersensitivity and anaphylactic reaction (25.0% vs 16.5%). Severe cutaneous reactions (i.e. Stevens-Johnson syndrome, erythema multiforme) were observed only in JPN pts (n = 4; 12.5%). Among pts from Japan, ALP+FUL showed no clinically meaningful improvement in PFS for pts with PIK3CA mut status and ALP exposure was much shorter than of the overall population. The incidence of cutaneous reactions was higher in Japanese vs overall population. [ABSTRACT FROM AUTHOR]

The PALOMA2/3 trials demonstrated prominent efficacy of combination therapy of palbociclib (PAL) and endocrine therapy (ET) compared with monotherapy. PAL was approved for metastatic breast cancer in Japan in 2017. We evaluated the efficacy and safety in practice after approval of PAL in Japan. We retrospectively reviewed patients who newly received PAL at Aichi Cancer Center after Dec 2017. The patients were classified by treatment-line and assessed as follows; clinical benefit rate (CBR) defined as the rate of clinical PR, CR and long SD (more than 6 months) based on physician's judgment, time to failure (TTF) defined as the duration time of PAL, prior ET response, and adverse events (AEs). TTFs were figured with swimmer's plot by treatment-line, PAL doses (125, 100, 75mg/day). Between Dec 2017 and Oct 2018, 64 patients were eligible. Median age was 62.5 (37-82). Forty-one patients (64%) had visceral metastasis. PAL was administered for 1st to 3rd line (early-line group) in 52% (n = 33), and for more than 4th line (late-line group) in 48% (n = 31). Combination ETs were aromatase inhibitors (n = 27, 42%), fulvestrant (n = 35, 55%), and tamoxifen (n = 2, 3%). Prior ET was sensitive in 59% (n = 33). The dose reduction was needed in 62% (100mg; n = 19, 75mg; n = 21). Twenty-eight patients (43.8%) were continuing PAL. Overall CBR was 38%. By treatment line, CBR was 51.6% in the early-line group, and 22.6% in the late-line group. Median TTF was 4.6 months (0.2-10.2). There were no significant differences of TTF by treatment-line, prior ET response, and PAL doses. The grade 3-4 hematological toxicity, such as neutropenia and anemia, were observed in 83% (n = 53). Stomatitis, nausea, and fatigue were common, but most of them were grade 1-2. No patients discontinued PAL due to AEs. In the clinical setting, PAL was given in many late line-patients who were not eligible for the PALOMA2/3 trials. Its efficacy was not sufficient, although it was feasible. [ABSTRACT FROM AUTHOR]

One of 400 to 500 general people has a germ-line pathogenic variant in BRCA 1 or 2, and those with such variants are diagnosed as HBOC. Since women with HBOC have extremely high risk of breast and ovarian cancer, they need to take action to avoid death due to those cancers. But how can we find them? We should screen suspicious people by their personal and family histories. We most frequently use NCCN guidelines to find them. They recommend BRCA genetic testing for all patients with personal history of ovarian, male breast, pancreatic or metastatic prostate cancer, and breast cancer patients with young onset, and/or family history of breast, ovarian, prostate, and/or pancreatic cancer. And after the approval of Olaparib for breast cancer, all HER2 negative metastatic breast cancer patients have become candidates for the BRCA genetic testing to check if Olaparib is usable or not. If we consider patients' ages of breast cancer diagnosis and/or family histories of cancers mentioned above, the positive rate will be high, but if we do the testing for all HER2 negative metastatic breast cancer patients, it will be around 5%. Genetic counseling is quite important to do the BRCA genetic testing in suspicious people and recommend women with HBOC to take cancer surveillance and/or risk-reducing surgery. For now, we have a big problem in genetic counseling in most Japanese hospitals. Specialists in genetics, especially genetic counselors, are expected to play an important role in genetic counseling. But there are only 243 certified genetic counselors in Japan. This number is not only small, but the majority of them are not good at hereditary cancers. Physicians and surgeons are also required to do genetic counseling in medical care of HBOC. To improve their knowledge and skills that are required in performing genetic counseling of hereditary cancer syndromes including HBOC, educational workshops have been held by several societies. I will present them briefly. [ABSTRACT FROM AUTHOR]

Two global phase 3 trials (301 trial of first- or second-line eribulin, EMBRACE of third- or later-line eribulin) were carried out during development of eribulin for breast cancer treatment. In this post marketing observation study in Japan, efficacy and safety of eribulin in metastatic breast cancer patients were examined. Additionally, the results were compared with that of phase 3 trials. We conducted a prospective study in patients with inoperable or recurrent HER2-negative breast cancer. We enrolled a similar number of patients receiving eribulin as first- or second-line therapy (early line) and those receiving eribulin as third- or later line therapy (later line), and followed the patients for two years (ClinicalTrials.gov Number: NCT02371174). For the overall survival and time to treatment failure, the estimated value of them were calculated by the Kaplan Meier method. The severity of adverse drug events was determined by CTCAE v 4.0. During September 2014 to February 2016, 651cases were registered at 182 facilities. In analysis set, 637 patients (319 patients of early line/317 patients of late line/1 patient of unknown) was median age of 62.7 (30 - 85) years. Performance status 0/1/2/3/4 was seen in 360/234/38/5/0 patients, respectively. Dose reduction were required in 33% of patients. The median overall survival (early line/late line) was 18.8 months/12.6 months, respectively, and median time to treatment failure was 4.4 months/3.8 months, respectively. Major side effects (early line/late line) were neutropenia (51%/56%), leucopenia (55%/57%), peripheral neuropathy (32%/22%). Grade 3≤ peripheral neuropathy was 2%. The results of overall survival (18.8 months in early line, 12.6 months in later line) in this study is comparable to those of large phase 3 study (15.9 months in 301 trial, 13.1 months in EMBRACE). The incidence of Grade 3≤ peripheral neuropathy was lower than that of phase 3 trials. [ABSTRACT FROM AUTHOR]

In July 2018, olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) was approved for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated advanced or metastatic HER2 negative breast cancer in Japan. BRACAnalysisTM was approved concurrently as a companion diagnostic program of olaparib. PARP inhibitors such as olaparib are proven to have activity in women with a BRCA mutation or with a deficiency in homologous recombination repair. Among many companion diagnostic tools in oncology, BRACAnaylsisTM has some uniqueness as follows; comprehensive germline BRCA gene profiling provided exclusively by Myriad Genetic Laboratories, availability to all women with HER2 negative metastatic breast cancer regardless of family history of breast or ovarian cancer, and implications for their family members. An improved level of genetic literacy will be needed for clinicians, patients and their families. Considerations for incorporating genetic testing into the cancer treatment, clinical management of a patient and relatives, ethical requirements will be discussed. [ABSTRACT FROM AUTHOR]