Evaluation of 95-Gene Classifier of Formalin-fixed Paraffin-embedded Tissues in ER-positive, HER2-negative, and Node-negative Breast Cancer.

BACKGROUND/AIM: A subset of patients with estrogen receptor (ER)-positive, HER2-negative, and node-negative breast cancer experience recurrences. Predicting patients who will have recurrences within 5 years of surgery is essential so that patients can be selected to receive adjuvant chemotherapy. The 95-gene classifier (95-GC) has been validated as a method to differentiate patients into high and low-risk groups for early recurrence. PATIENTS AND METHODS: In this study, we performed 95-GC analysis on 56 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients who underwent surgery for ER-positive, HER2-negative, and node-negative breast cancer and did not receive adjuvant chemotherapy. We associated the obtained high- and low-risk groups with clinicopathological characteristics and recurrence-free survival (RFS). RESULTS: We classified 12 out of 56 patients into the high-risk recurrence group. We found significantly higher KI67 scores in patients in the high-risk group. Other clinicopathological characteristics were not associated with the 95-GC risk groups. Patients in the 95-GC low-risk group had a significantly better prognosis than those in the high-risk group (p=0.0387). The 5-year RFS rate was 97.6% in the low-risk group and 74.1% in the high-risk group, while the 10-year RFS rates were 90.1% and 74.1%, respectively. CONCLUSION: The 95-GC score can accurately predict RFS within 5 years of surgery for ER-positive, HER2-negative, and node-negative breast cancer using FFPE tissue samples. These prediction models could help assign patients to the most effective treatment regimen.

[A case of fibrolamellar hepatocellular carcinoma mimicking a liver abscess].

A 23-year-old woman was presented with fever and epigastric pain. Contrast enhanced computed tomography revealed a 40mm mass in the lateral segment. Blood tests showed the elevation of WBC and CRP. With the diagnosis of liver abscess, the antibiotics were administered, and the clinical findings were promptly improved. One year later, she complained of the same symptoms, and the mass had increased to 50mm in diameter. Percutaneous liver biopsy led to the diagnosis of fibrolamellar hepatocellular carcinoma.

Factors associated with overall survival after recurrence in patients with ER-positive/HER2-negative postmenopausal breast cancer: an ad hoc analysis of the JBCRG-C06 Safari study.

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.

Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties.

The onset of neurodegenerative disorders (NDs), such as Alzheimer's disease, is associated with the accumulation of aggregates of misfolded proteins. We previously showed that chemical knockdown of ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into the central nervous system, where NDs are located. Here, we document the conversion of one of our PROTACs into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic degrons. This conversion decreases the molecular weight and the number of hydrogen bond donors/acceptors. All the developed HyTs lowered the level of mutant huntingtin, an aggregation-prone protein, with potency comparable to that of the parent PROTAC. Through IAM chromatography analysis and in vivo brain penetration assay of the HyTs, we discovered a brain-permeable HyT. Our results and mechanistic analysis indicate that conversion of protein degraders into HyTs could be a useful approach to improve their drug-like properties.

Genetic heterogeneity during breast cancer progression in young patients.

BACKGROUND: Because a number of years may be required for normal cells to develop into carcinoma, genes involved in tumorigenesis and progression might differ among breast cancers in young women and those in older women. The present study sought to analyze subclonality during breast cancer evolution as well as diversity within each individual in our young patients' cohort. METHODS: A total of 13 women aged <35 years at diagnosis with early breast cancer were recruited. Serial sections of breast samples consisting of synchronous invasive carcinoma, adjacent ductal carcinoma in situ (DCIS), normal breast tissue, and metastatic lymph nodes were collected and prepared for immunohistochemical analysis of estrogen receptor, progesterone receptor, HER2, and Ki67, and for extraction of genomic DNA. Germline and somatic gene alterations of genomic DNA were examined by targeted sequencing. RESULTS: Genomic DNA from 13 blood samples and 36 breast tissues consisting of 14 invasive carcinomas, nine adjacent DCIS, 11 normal breast tissues, and two metastatic lymph nodes were successfully sequenced. Germline gene alterations including pathogenic variants and gene alterations that were not yet evaluated for their clinical significance were detected in all patients but one. Somatic gene alterations were identified in eight invasive carcinomas, five DCIS, and one metastatic lymph node. Different somatic gene alterations between invasive carcinoma and DCIS were detected in two patients. Somatic gene mutations were present in non-neoplastic tissues in three patients. No two patients had the same gene alterations. CONCLUSION: Our results reveal diversity within each individual during breast cancer progression.

Risk factor analysis for taxane-associated acute pain syndrome under the dexamethasone prophylaxis.

PURPOSE: Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. METHODS: In total, 143 patients with breast cancer who received docetaxel (75 mg/m2) or paclitaxel (175 mg/m2)-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of ≥ G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. RESULTS: Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of ≥ G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of ≥ G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of ≥ G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. CONCLUSION: Pegfilgrastim co-administration is an independent risk factor for ≥ G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.

Endothelial ganglioside GM3 regulates angiogenesis in solid tumors.

Cancer cells require oxygen and nutrients for growth, making angiogenesis one of the essential components of tumor growth. Gangliosides, constituting membrane lipid rafts, regulate intracellular signal transduction and are involved in the malignancy of cancer cells. While endothelial cells, as well as cancer cells, express vast amounts of gangliosides, the precise function of endothelial gangliosides in angiogenesis remains unclear. In this study, we focused on gangliosides of vascular endothelial cells and analyzed their functions on tumor angiogenesis. In human breast cancer, GM3 synthase was highly expressed in vascular endothelial cells as well as immune cells. Angiogenesis increased in GM3S-KO mice. In BAEC, RNA interference of GM3S showed increased cellular invasion and oxidative stress tolerance through activation of ERK. In the breast cancer model, GM3-KO mice showed an increase in tumor growth and angiogenesis. These results suggest that the endothelial ganglioside GM3 regulates tumor angiogenesis by suppressing cellular invasion and oxidative stress tolerance in endothelial cells.

Safety Evaluation of Initial CT-P6 Administration for 30 min during the Switch from Reference Trastuzumab in Maintenance Infusion: A Multicenter Observational Study.

CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer.

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

The disease sites of female genital cancers of BRCA1/2-associated hereditary breast and ovarian cancer: a retrospective study.

Disease sites of female genital tract cancers of BRCA1/2-associated hereditary breast and ovarian cancer (HBOC) are less understood than non-hereditary cancers. We aimed to elucidate the disease site distribution of genital cancers in women with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+) of HBOC. For the primary disease site, the proportion of fallopian tube and peritoneal cancer was significantly higher in BRCA2+ (40.5%) compared with BRCA1+ (15.4%) and BRCA- (no pathogenic variant, 12.8%). For the metastatic site, the proportion of peritoneal dissemination was significantly higher in BRCA1+ (71.9%) than BRCA- (55.1%) and not different from BRCA2+ (71.4%). With one of the most extensive patients, this study supported the previous reports showing that the pathogenic variants of BRCA1/2 were involved in the female genitalia's disease sites.

Brief collaborative care intervention to reduce perceived unmet needs in highly distressed breast cancer patients: randomized controlled trial.

OBJECTIVES: Our newly developed brief collaborative care intervention program has been suggested to be effective in reducing breast cancer patients' unmet needs and psychological distress; however, there has been no controlled trial to investigate its effectiveness. The purpose of this study was to examine the effectiveness of the program in relation to patients' perceived needs and other relevant outcomes for patients including quality of life, psychological distress and fear of recurrence (Clinical trial register; UMIN-CTR, Clinical registration number; R5172). METHODS: Fifty-nine highly distressed breast cancer patients receiving adjuvant chemotherapy and/or hormonal therapy were randomly assigned either to a treatment as usual group or to a collaborative care intervention, consisting of four sessions that mainly included assessment of the patients' perceived needs, learning skills of problem-solving treatment for coping with unmet needs and psycho-education provided by trained nurses supervised by a psycho-oncologist. RESULTS: Although >80% of the eligible patients agreed to participate, and >90% of participants completed the intervention, there were no significant differences with regard to patients' needs, quality of life, psychological distress and fear of recurrence, both at 1 and 3 months after intervention. CONCLUSION: Newly developed brief collaborative care intervention program was found to be feasible and acceptable. The trial, however, failed to show the effectiveness of the program on patients' relevant subjective outcomes. Further intervention program having both brevity and sufficient intensity should be developed in future studies.

How pregnancy and childbirth affect the working conditions and careers of women surgeons in Japan: findings of a nationwide survey conducted by the Japan Surgical Society.

PURPOSE: To identify the conflicts between a career as a surgeon and pregnancy and childbirth for women in Japan. METHODS: The Japan Surgical Society conducted a nationwide survey on pregnancy and childbirth among its members who are women. The questionnaire included items regarding demography, working styles, and pregnancy and childbirth, including adverse events and harassment. RESULTS: The response rate was 29.9% (1068 responses, median age, 37 years). Among the responders, 61% were married and 47% had children (average number of children, 1.7). Half of the respondents reported having experienced sexual harassment and 62% reported having received unwelcome comments about pregnancy. About 20% had undergone fertility treatment. In total, 51% had pregnancies, with miscarriages in 33% of these. The top answer for the best timing for pregnancy and childbirth was after becoming board-certified. Nearly one-third of first-time mothers experienced adverse events during pregnancy and delivery, and 28% quit or changed their job because of their pregnancy and the birth of their first child. CONCLUSIONS: Japanese women who choose a career as a surgeon face obstacles during pregnancy and childbirth. It is vital to share the findings of this study and understand the issues associated with pregnancy and childbirth regardless of gender. Interventions are essential to ensure that every pregnant surgeon has a safe working environment to allow unobstructed development of her career.

[Interstitial Pneumonia Caused by Olaparib during Treatment of Breast Cancer-A Case Report].

The characteristic adverse events of olaparib, a PARP inhibitor, are nausea, vomiting, and anemia, and interstitial pneumonia is rarely reported. We report a case of interstitial pneumonia following the treatment of a metastatic breast cancer with olaparib. The patient was a 34-year-old woman. In March 2018, she was diagnosed with stage Ⅳ breast cancer(multiple lung metastases). She was treated with epirubicin and cyclophosphamide followed by paclitaxel. In November 2018, brain and spinal cord metastases were detected, and she was treated with radiation. In December 2018, a BRCA1 deleterious mutation was confirmed, and treatment with olaparib was initiated. Six weeks later, olaparib was discontinued due to anemia; it also caused interstitial pneumonia. The interstitial pneumonia resolved following multidisciplinary treatment during hospitalization. Subsequently, she was treated with cyclophosphamide/methotrexate/fluorouracil. It is necessary to consider interstitial pneumonia as an adverse effect of olaparib.

Risk factors for lymph node metastasis of ovarian, fallopian tube and primary peritoneal cancer in hereditary breast and ovarian cancer syndrome.

BACKGROUND: To establish an individualized surgical strategy for lymphadenectomy in ovarian cancer patients with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+), we investigated the clinicopathological characteristics that are involved in the increased risk of lymph node metastasis. METHODS: We retrospectively reviewed the data of Japanese women registered in the database of the Japanese Hereditary Breast and Ovarian Cancer Consortium, who underwent BRCA1 and BRCA2 genetic testing. RESULTS: We evaluated the predictors of lymph node metastasis in all patients with the information of age at the diagnosis, disease site, histological subtype, 2014 FIGO stage, personal breast cancer history and family history; 233, 153 and 32 patients in the BRCA- (no pathogenic variant), BRCA1+ and BRCA2+ groups, respectively. The prevalence of lymph node metastasis was not markedly different between BRCA- (20.0%), BRCA1+ (18.4%) and BRCA2+ (26.2%). Multivariate analysis revealed an absence of a family history of ovarian cancer as an independent predictor for an increased risk of lymph node metastasis in BRCA1+, and the prevalence of lymph node metastasis was 11.7 and 42.0% in the groups with and without a family history of ovarian cancer, respectively. This subgroup without a family history of ovarian cancer did not show any correlation with a particular variant of BRCA1, including two common variants of c.188 T > A and c.2800C > T. CONCLUSIONS: This study suggested that certain genetic factors related to the penetrance of hereditary breast and ovarian cancer syndrome altered the frequency of lymph node metastasis in BRCA1+ ovarian cancer, and family history may be useful to personalize the indication of lymphadenectomy.

[A Case of Male Recurrent Breast Cancer Successfully Treated with Bevacizumab plus Paclitaxel Therapy for Carcinomatous Pericarditis].

We report the case of a 44-year-old male who underwent mastectomy plus axillary lymph node dissection after neoadjuvant chemotherapy for left breast cancer. During adjuvant therapy, multiple bone metastases and pericardial effusion were detected. Pericardial drainage was mandated for the patient, although no malignant cells were found. Despite the change in treatment, pericardial effusion worsened. Based on clinical findings, the patient was diagnosed with carcinomatous pericarditis and was switched to bevacizumab plus paclitaxel therapy. CT at 5 months showed improved pericardial effusion; treatment is ongoing.

Reversible Cancer Therapeutics-related Cardiac Dysfunction Complicating Intra-cardiac Thrombi.

Epirubicin-based chemotherapy carries a risk of inducing heart failure, although the frequency is rare. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been widely used in patients with recurrent breast cancer as a first-line chemotherapeutic agent. Heart failure or arterial thromboembolism has been reported as a rare cardiovascular complication of bevacizumab. We herein report a breast cancer patient with reversible cancer therapeutics-related cardiac dysfunction associated with bevacizumab and epirubicin complicating intracardiac thrombi in the left atrium and left ventricle. This case underscores the importance of tailored medical planning according to the individual status in patients receiving anti-cancer therapies.

HER2 Gene Amplification in ER-positive HER2 Immunohistochemistry 0 or 1+ Breast Cancer With Early Recurrence.

BACKGROUND/AIM: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, standard chemotherapies as well as adjuvant endocrine therapy might not be enough for prevention of early relapse. MATERIALS AND METHODS: We focused on ER-positive, HER2 immunohistochemistry (IHC) 0 or 1+ breast cancer, and retrospectively examined HER2 gene amplification and TP53 mutation in breast cancer tissues in patients with or without early recurrence. Post-relapse survival in patients with early recurrence was also analyzed by mutation status of HER2 and TP53. RESULTS: Surprisingly, amplification of the HER2 gene was found in 15% of patients with early recurrence. None of the patients without relapse had HER2-amplified tumors. Post-relapse survival in patients with HER2 gene amplification and/or TP53 mutation in primary tumors was shorter than that in patients without these mutations, especially among postmenopausal women. CONCLUSION: HER2 gene amplification exists in ER-positive, HER2 IHC 0 or 1+ breast cancer in patients who developed early distant metastasis.

The Impact of Immunofunctional Phenotyping on the Malfunction of the Cancer Immunity Cycle in Breast Cancer.

The cancer-immunity cycle (CIC) is a series of self-sustaining stepwise events to fight cancer growth by the immune system. We hypothesized that immunofunctional phenotyping that represent the malfunction of the CIC is clinically relevant in breast cancer (BC). Total of 2979 BC cases; 1075 from TCGA cohort, 1904 from METABRIC cohort were analyzed. The immunofunctional phenotype was classified as follows: hot T-cell infiltrated (HTI), high immune cytolytic activity (CYT), Cold T-cell infiltrated (CTI), high frequency of CD8+ T cells and low CYT, and non-inflamed, low frequency of CD8+ T cells and low CYT. The analysis of tumor immune microenvironment in the immunofunctional phenotype revealed that not only immunostimulatory factors, but also immunosuppressive factors were significantly elevated and immunosuppressive cells were significantly decreased in HTI. Patients in HTI were significantly associated with better survival in whole cohort and patients in CTI were significantly associated with worse survival in triple negative. Furthers, HTI was inversely related to estrogen responsive signaling. We demonstrated that immunofunctional phenotype not only indicated the degree of anti-cancer immune dysfunction, but also served as a prognostic biomarker and HTI was inversely related to estrogen response.

Current conditions and issues of physicians and working conditions at institutions accredited by the Japanese Breast Cancer Society.

BACKGROUND: In Japan, with the rapid increase of breast cancer patients, there has been increasing demand for breast cancer treatment. As the main workforce for breast cancer treatment, women physicians are thought to be in key positions, since the number of women physicians has recently been increasing. METHODS: To clarify the current statuses and issues of physicians and work conditions at the accredited breast cancer care facilities, a survey was conducted by the Japanese Breast Cancer Society (JBCS). RESULTS: The main workforces engaged in breast cancer care are surgeons, and the number of breast surgeons of all institutions in this survey was 1338 (full time 1124, part time 214). The percentages of women among surgeons, breast specialists accredited by the JBCS, and residents are 22%, 25%, and 38%, respectively. Among breast specialists, more women tended to work at university hospitals and cancer hospitals. Twenty-eight percent of women were married and among those, 76% had at least one child. Many hospitals allow short working hours or exemption from in-house call for women surgeons during pregnancy and child-rearing. In contrast, half of the facilities apply a "single doctor-in-charge system", where the patient's primary physician has to be on-call every day. Many institutions convene conferences for breast cancer treatment planning before or after the scheduled working hours. CONCLUSIONS: Current systems for treatment of breast cancer should be improved so that all surgeons specializing in the breast can develop their career while maintaining their personal life.

Factors associated with prolonged overall survival in patients with postmenopausal estrogen receptor-positive advanced breast cancer using real-world data: a follow-up analysis of the JBCRG-C06 Safari study.

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 (< 60 years), longer time from ABC diagnosis to fulvestrant use (≥ 3 years), no prior palliative chemotherapy before fulvestrant use, and progesterone receptor (PgR) negativity (PgR-) were significantly correlated with prolonged OS (median 7.0 years). For cases with histological or nuclear grade data, lower histological or nuclear grades were also correlated with longer OS. In recurrent metastatic cases, long disease-free interval (DFI) was not correlated with longer OS. 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.