Correlation between postoperative treatment selection and prognosis determined using the Oncotype DX® test data: a retrospective multicenter study in Japan.

PURPOSE: Oncotype DX® is a frequently used multigene assay for hormone receptor-positive breast cancers. However, limited evidence is available regarding its application in Japan owing to the lack of insurance coverage. Therefore, we conducted this large-scale, retrospective study by collecting data from nine Japanese institutes and assessed postoperative treatment choice and prognosis by using Oncotype DX®. METHODS: Six hundred thirty-two patients who underwent breast surgery and whose recurrence score (RS) data were available were included. They were divided into RS 0-25 and RS ≥ 26 groups. The groups were compared in terms of clinicopathological factors, treatment options, and prognosis. RESULTS: After the median follow-up period of 10.1 years, the disease-free survival (DFS) rates were significantly better in the RS 0-25 group (p = 0.02). Per the recurrent event type, there was no significant intergroup difference in locoregional recurrence (p = 0.139). However, a trend toward better distant DFS was observed in the RS 0-25 group (p = 0.08). Overall survival was also significantly better in this group (p = 0.027). Considering chemotherapy use, DFS worsened among chemotherapy-treated patients with an RS of 0-25 and those with an RS ≥ 26 who did not receive chemotherapy (p < 0.001). Seven (1.35%) chemotherapy-treated patients with an RS of 0-25 showed disease recurrence. CONCLUSIONS: This study presents the largest database-derived prognostic data in Japanese patients, utilizing the Oncotype DX® treatment selection. Further studies are needed to determine the impact on treatment choice, considering the clinical risk, and the need for additional postoperative treatment.

Preliminary report on ultrashort perioperative partial-breast irradiation with multicatheter interstitial brachytherapy for early-stage breast cancer.

PURPOSE: Perioperative partial-breast irradiation (PBI) with multicatheter interstitial brachytherapy (MIB) is less invasive and more convenient than postoperative one. This study aimed to compare ultrashort perioperative MIB-PBI (uPBI) and conventional perioperative MIB-PBI (cPBI) performed during the same period of time. METHODS: Inclusion criteria of the study were patients aged ≥ 40 years and those with T0-2 (≤ 3 cm), N0-mi, and negative margins on mammography. The locoregional recurrence (LRR) and toxicity rates were compared between uPBI at a dose of 25.2 Gy in four fractions and cPBI at a dose of 32 Gy in eight fractions. RESULTS: In total, 198 patients (151 with uPBI and 47 with cPBI) were evaluated. At a median follow-up of 20.1 months, one (0.66%) patient in the uPBI group had LRR. The 2-year ipsilateral breast tumor recurrence-free survival rates of the uPBI and cPBI groups were 98.7% and 100%, respectively. The highest toxicity grades were grade 1 in 23 (15.2%) and grade 2 in 2 (1.3%) patients in the uPBI group, and grade 1 in 8 (17.0%) and grade 2 in 1 (2.1%) patient in the cPBI group. None of the patients in the two groups presented with grade 3 and higher toxicities. The toxicity rates between the two groups did not significantly differ. Further, 22 (14.6%) patients in the uPBI group and 8 (17.0%) in the cPBI group, and 3 (2.0%) patients in the uPBI group and 1 (2.1%) in the cPBI had acute and late toxicities, respectively. The timing of toxicity development between the two groups did not significantly differ. CONCLUSIONS: Although this preliminary report included a small sample size and had a short follow-up period, the local control and toxicity rates were similar between the uPBI and cPBI groups. Further research is warranted to investigate the ideal dose schedule of MIB-PBI.

Impact of de-escalating systemic therapy guided by 21-gene assay on locoregional recurrence after partial-breast irradiation.

PURPOSE: Partial-breast irradiation (PBI) has been performed as alternative to whole-breast irradiation (WBI) in breast-conserving therapy (BCT). Recently, the 21-gene recurrence score (RS) was introduced to determine the adjuvant therapy for estrogen receptor (ER)-positive, and human epidermal growth factor receptor 2 (HER2)-negative diseases. However, the impact of RS-based systemic therapy on locoregional recurrence (LRR) following BCT with PBI remains uninvestigated. METHODS AND MATERIALS: Patients with ER-positive, HER2-negative, and node-negative breast cancer who underwent BCT with PBI were examined during May 2012-March 2022. In addition to immunohistochemistry (IHC), RS was available to decide on adjuvant therapy. RESULTS: In total, 431 patients were evaluated with a median followup of 48.6 months. The 4-year LRR-free survival rates were 97.3% and 96.4% in the IHC and RS cohorts, respectively (p = 0.50). Ki67 of >20% was significantly associated with LRR in the multivariate analysis (HR 4.39, p < 0.05). For patients with Ki67 > 20%, 29 of 71 (40.8%) and 46 of 59 (78.0%) patients received only endocrine therapy in the IHC and RS cohorts, respectively (p < 0.0001). For patients with Ki67 >20% who received only endocrine therapy, the 4-year LRR-free survival rates were 91.8% in the IHC cohort and 94.6% in the RS cohort (p = 0.29) CONCLUSIONS: Although the introduction of RS increased the number of patients receiving endocrine therapy alone for Ki67 >20% of disease by two times, the LRR-free survival after BCT with PBI could be maintained. However, further studies from multiple institutions with longer followup data are required.

Computed tomography-guided partial-breast brachytherapy using implanted catheters as fiducial markers versus co-registered magnetic resonance imaging.

PURPOSE: Partial-breast irradiation (PBI) needs accurate cavity delineation with computed tomography (CT). In perioperative PBI using multicatheter-interstitial brachytherapy (MIB), catheters implanted during surgery were enabled as fiducial markers. Magnetic resonance imaging (MRI) can also assist delineation with CT. METHODS: Patients receiving MIB-PBI were analyzed. Cavity visualization scores (CVSs) were categorized with CT. With catheter-based delineation (CBD), the relationship between cavity boundaries and catheters were used to contour the tumor bed. Co-registered MRI delineation (CMD) was also performed. The correlation between cavity volume and the excised tissue weight was compared for the two techniques. RESULTS: The association between CVS and preoperative characteristics in 159 patients showed mammographic breast density (MBD) remained correlated to CVS on multiple regression analyses; CVS = 5.2-0.61 x MBD (p < 0.0001). In 43 patients, the cavity volumes determined with CBD vs CMD were 12.8 ±â€¯6.4 cm3 vs 16.1 ±â€¯12.4 cm3 (p < 0.0001), and their plots with excised weights showed the best fitting lines were 0.29 vs 0.48 (p < 0.0001), respectively. The correlation coefficients for CBD vs CMD were 0.65 vs 0.55 (p = 0.20) in low (CVS 1-3, n = 27) and 0.72 vs 0.58 (p = 0.36) in high visualized cavities (CVS 4-5, n = 16), respectively. CONCLUSIONS: The use of implanted catheters as fiducial markers was associated with smaller cavities and greater correlations with the excised tissue weights than co-registration with MRI. This might be a useful technique, especially for patients with dense breasts on mammography.

Predicting adherence of dose-volume constraints for personalized partial-breast irradiation technique.

PURPOSE: Multicatheter interstitial brachytherapy (MIB) and external-beam (EB) radiotherapy are established partial-breast irradiation (PBI) techniques. Although EB-PBI is widely available, it requires extra irradiated margins for target uncertainties. We examined the impact of EB-PBI on dose-volume constraints as compared to MIB-PBI. METHODS AND MATERIALS: Among 653 patients receiving MIB-PBI between October 2008 and April 2020, consequent 159 patients after September 2018 were examined. Clinical target volume (CTV) included the lumpectomy cavity plus 1.0 cm. Planning target volume (PTV) for EB-PBI was defined as CTV with 1.0-cm expansion. Because the ratio of PTV to breast volume (RPB) was related to cosmesis, <25% of RPB was defined as suitable for the ipsilateral breast constraints. Preoperative breast size was classified as very small (<350 cm3), small (350-699 cm3), and medium or large (≥700 cm3). According to each category, the dose-volume constraints of the organs at risk were compared between the two PBI techniques. RESULTS: Patients including 84 very small, 59 small, and 16 moderate to large breasts were examined. Although RPB was suitable in all patients receiving MIB-PBI, it was achieved in 74 patients (46.5%) receiving EB-PBI (p < 0.0001). The suitable RPB in patients with very small, small, and moderate to large breast was 32.1%, 55.9%, and 100%, respectively (p < 0.0001). Normal-tissue constraints for the other organs could be satisfied in patients with moderate to large breasts. CONCLUSION: Although EB-PBI may be an appropriate option for patients with moderate to large breasts, MIB-PBI could still be a crucial technique, especially for patients with small breasts.

Efficacy of Single-Plane Implant Technique in Partial Breast Brachytherapy in Small-Breasted Patients.

PURPOSE: Partial-breast irradiation (PBI) using multicatheter-interstitial brachytherapy (MIB) has been supported by some randomized trials to date. However, it remains underused in Asian countries because of the population's typically smaller breasts. Single-plane implantation has been recommended in these individuals, but limited data on the clinical efficacy exist. We performed a retrospective chart review to compare the tumor control and long-term cosmesis in patients treated with the single-plane implant technique. METHODS AND MATERIALS: Patients receiving MIB-PBI between October 2008 and December 2018 were evaluated. PBI was initiated on the same day of the surgery via an intraoperative catheter implant, delivering 32 Gy by 8 fractions. Tumor control based on the rate of freedom from ipsilateral tumor recurrence (IBTR), disease-free survival, and long-term cosmesis using the Harvard scale was evaluated to compare between the single- and double-/triple-plane implant techniques. RESULTS: Five hundred sixteen patients with 526 lesions received MIB-PBI with a median follow-up of 53.1 months. Patients treated by single- and double- or triple-plane implant numbered 288 (54.8%) and 238 (45.2%), respectively. The 4-year probabilities of IBTR-free survival and disease-free survival were 97.5% and 96.5% in single-plane implant and 98.6% (P = .42) and 98.0% (P = .18) in double- or triple-plane implant MIB-PBI, respectively. Although young age (P < .05) and positive surgical margins (P < .01) were selected as independent risk factors for IBTR, single-plane implantation was not recognized as a risk factor of IBTR. Sixty-one of 69 single-plane implant patients (88.4%) and 84 of 92 double-/triple-plane implant patients (91.3%) reported excellent to good cosmetic results (P = .73). CONCLUSIONS: Although this was a retrospective study from a single institution and cosmesis was evaluated using a subjective method, this is the first report to validate single-plane implant MIB-PBI for use in small-breasted patients. Further multicenter research is required.

Moving incision for covert breast-conserving surgery may prevent early wound complications in brachytherapy-based partial-breast irradiation.

PURPOSE: Brachytherapy-based partial-breast irradiation (PBI) is a treatment option for breast-conserving therapy. Although intraoperative catheter implantation has been introduced, early wound complications are a concern. Covert operations with a moving incision are widely performed to hide surgical scars and may reduce the incision-site radiation dose. This study aimed to compare complication rates for moving incision and conventional incision in covert breast-conserving surgery. METHODS AND MATERIALS: Between October 2008 and December 2018, the medical records of all patients who underwent PBI using multicatheter interstitial brachytherapy after breast-conserving surgery were examined. Since July 2016, to hide the scar, we have performed a moving incision from above the tumor to an invisible site at our institution. The planning target volume included 1.0-1.5 cm of tissue surrounding the surgical cavity. High-dose-rate interstitial brachytherapy with a dose of 32 Gy in eight fractions was performed. The cumulative incidences of surgical site infections and symptomatic seromas ≤90 days were analyzed. RESULTS: The study included 516 consecutive patients with 526 lesions. Overall, 40 (7.6%) early wound complications were observed, in which 4 (2.6%) involved 152 moving incisions and 36 (9.6%) involved 374 conventional incisions (p = 0.01). On univariate analysis, age, tumor diameter, re-excision, planning target volume, numbers of catheters and planes, and incision type were risk factors for complications. On multivariate analysis, only incision type was a risk factor. Moving incision reduced the early complication rate by 75% (p = 0.01). CONCLUSION: Moving incision in covert breast-conserving surgery reduced the risk of early wound complications.

Catheter-based delineation of lumpectomy cavity for accurate target definition in partial-breast irradiation with multicatheter interstitial brachytherapy.

PURPOSE: In partial-breast irradiation (PBI), accurate lumpectomy cavity (LC) delineation is critical. Seroma-based delineation (SBD) using computed tomography (CT) with clips remains uncertain, causing an expansion of the LC and planning target volume (PTV). In catheter-based delineation (CBD), the implanted catheters were used as reference markers for LC delineation in multicatheter interstitial brachytherapy (MIB). MATERIAL AND METHODS: Between October 2008 and October 2018, 513 patients who underwent MIB-PBI were examined. In CBD, anatomical relations of LC to catheters were recorded. In randomly selected 22 CBD cases, the LC volume and PTV were retrospectively recontoured on SBD, and the relationship between the contribution of CBD and cavity visuality was evaluated. The LC volume and PTV before and after the introduction of CBD were compared. RESULTS: The mean LC volumes based on SBD and CBD were 19.1 cm3 and 14.1 cm3, respectively (p < 0.001). The mean PTVs based on SBD and CBD were 47.9 cm3 and 35.7 cm3, respectively (p < 0.0001). More reductions in the LC volume (5.1 cm3) (p < 0.05) and PTV (7.7 cm3) (p = 0.13) were observed in the poorly visible LC than in the visible LC. The LC volume and PTV before the introduction of CBD (n = 411) were compared with those after introduction (n = 102). Significant reductions were observed in the LC volume (5.9 cm3) (p < 0.0001) after the introduction of CBD; moreover, PTV tended to be reduced (3.9 cm3) (p = 0.17). CONCLUSIONS: CBD may help to establish the standardized procedure for MIB-PBI and prevent unnecessary radiation exposure to the normal breast tissue.

Validating the efficacy of single-stage breast-conserving therapy using multicatheter partial-breast brachytherapy based on updated ASTRO guidelines.

Based on the accumulating evidence for equivalent results of partial-breast irradiation (PBI) and whole-breast irradiation (WBI) in breast-conserving therapy (BCT), the American Society for Radiation Oncology (ASTRO) updated the consensus statement (CS) to expand the range of potential candidates for PBI outside clinical trials. Of the various techniques, PBI using multicatheter interstitial brachytherapy (MCB) is the oldest and has long-term data. In this study, the efficacy of single-stage BCT using MCB-PBI achieved by an intraoperative catheter placement was validated on updated ASTRO guidelines. We retrospectively examined patients undergoing BCT using MCB-PBI or WBI. The updated CS distinguished patients aged 40-49 years with ER+, tumor ≤2 cm, and margin ≥2 mm from unsuitable patients in the previous CS. We compared the ipsilateral breast tumor recurrence (IBTR) rate in MCB-PBI with that in WBI patients with suitable or cautionary (S/C) categories on the updated CS. Between November 2007 and September 2017, 641 patients with 647 lesions underwent BCT (MCB-PBI, 407; WBI, 240). At the median follow-up time of 54.4 months, we observed 8 (1.97%; 95% CI: 0.62-3.31%) and 7 (2.92%; 95% CI: 0.79-5.05%) IBTRs, respectively. Updating the CS increased the S/C patients receiving MCB-PBI from 232 patients (57.0%) to 319 (78.4%). Comparison of clinical outcomes at the 12-month minimum follow-up between 291 MCB-PBI and 103 WBI in S/C patients showed no significant differences in the 4-year rate of IBTR-free (100% vs 98.9%; P = 0.29) and disease-free survival (98.7% vs 95.5%; P = 0.24). Overall, single-stage BCT using MCB-PBI offered similar tumor control rates, compared with WBI, on the updated ASTRO CS.

Efficacy of single-stage breast-conserving treatment using multicatheter partial breast brachytherapy evaluated by GEC-ESTRO phase 3 trial.

PURPOSE: The GEC-ESTRO has reported the equivalent outcomes of partial breast irradiation (PBI) using multicatheter interstitial brachytherapy (MCB) to whole breast irradiation (WBI) in breast-conserving therapy (BCT). We performed single-stage BCT with partial breast brachytherapy by intraoperative catheter placement. After the categorization of patients into inclusion and exclusion criteria on this trial, our databases were evaluated in order to translate it to Japanese patients. MATERIAL AND METHODS: Patients undergoing BCT were retrospectively examined between November 2007 and December 2015. The technique is an open-cavity implant with a dose of 32 Gy in 8 fractions. The 4-year clinical outcomes of MCB-PBI were evaluated in the 2 distinct categories, and the comparison of the outcomes of MCB-PBI with WBI was performed in patients with unfavorable features. RESULTS: Of a total of 501 lesions undergoing BCT, 301 lesions were treated with MCB-PBI and 200 lesions with WBI. At the median follow-up time of 52 months, the 4-year rate of ipsilateral breast tumor recurrence (IBTR)-free, disease-free (DFS), and overall survival (OS) in patients with MCB-PBI and WBI were 98.9% vs. 98.0% (p = 0.56), 97.0% vs. 95.3% (p = 0.78), and 99.6% vs. 98.2% (p = 0.38), respectively. Although in exclusion cohort treated with MCB-PBI, IBTR-free, and disease-free survival were significantly worse than in inclusion cohort, non-significantly worse outcomes was demonstrated than in exclusion cohort with WBI; IBTR-free survival (95.0% vs. 97.2%, p = 0.24), and disease-free survival (95.0% vs. 95.8%, p = 0.31). CONCLUSIONS: Single-stage BCT using MCB-PBI offered similar tumor control rates compering to WBI. However, further research is needed to define the benefit for patients with an exclusion criteria.

Efficacy of reduced dose of pegfilgrastim in Japanese breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide therapy.

BACKGROUND: This retrospective study aimed to evaluate the efficacy of a 3.6-mg dose of pegfilgrastim for primary prophylaxis in Japanese breast cancer patients receiving dose-dense chemotherapy. METHODS: Patients treated with adjuvant or neoadjuvant chemotherapy for early-stage breast cancer at the Tokyo-West Tokushukai Hospital were included in this analysis. Because 6 mg pegfilgrastim has not yet been approved for use in Japan, we compared the outcomes of a dose-dense doxorubicin and cyclophosphamide regimen plus 3.6 mg pegfilgrastim support with a conventional dose epirubicin and cyclophosphamide regimen. The incidence of febrile neutropenia, relative dose intensity, dose delay, dose reduction, regimen change and hospitalization because of neutropenia were assessed. RESULTS: From November 2013 to March 2016, 97 patients with stage I-III invasive breast cancer were analyzed (dose-dense doxorubicin and cyclophosphamide plus 3.6-mg pegfilgrastim group, n  =  41; epirubicin and cyclophosphamide group, n  =  56; median ages, 49.0 and 48.5 years, respectively). Febrile neutropenia occurred during the first chemotherapy cycle in 7 of 56 patients (12.5%) in the epirubicin and cyclophosphamide group and 0 of 41 patients in the dose-dense doxorubicin and cyclophosphamide group (P  =  0.02). The average relative dose intensities were 97.9% and 96.8%, respectively (P  =  0.28), with corresponding dose delay rates of 4.9% (2/41) and 16.1% (9/56), respectively (P  =  0.11) and dose reduction rates of 0% (0/41) and 7.1% (4/56), respectively (P  =  0.16). CONCLUSIONS: Our results indicate the efficacy of a 3.6-mg pegfilgrastim dose for the primary prevention of febrile neutropenia in dose-dense doxorubicin- and cyclophosphamide-treated Japanese breast cancer patients.

Impact of young age on local control after partial breast irradiation in Japanese patients with early stage breast cancer.

BACKGROUND: Partial breast irradiation (PBI) is an alternative to whole breast irradiation (WBI) for breast-conserving therapy (BCT). A randomised phase 3 trial demonstrated that PBI using multicatheter brachytherapy had an equivalent rate of local recurrence, disease-free survival, and overall survival as compared to WBI. However, limited data are available on PBI efficacy for young patients with breast cancer. METHODS: We evaluated consecutive patients with Tis-2 (≤ 3 cm) N0-1 breast cancer who underwent BCT. For PBI, patients received radiotherapy using multicatheter brachytherapy in an accelerated manner with a dose of 32 Gy in eight fractions over 5-6 days. For WBI, patients received an external beam radiation therapy that was applied to the entire breast with a total dose of 50 Gy in fractions of 2 Gy for 5 weeks. Two hundred seventy-four patients with 278 lesions received PBI; 190 patients with 193 lesions received WBI. RESULTS: Patients aged <50 years including 98 women with 99 lesions receiving PBI and 85 women with 85 lesions receiving WBI were selected. Ipsilateral breast tumor recurrence rate was 3.0 and 2.4 % by PBI and WBI, respectively (P = 0.99). There was no significant difference in 4-year probability of disease-free survival (97.6 and 91.4 % for PBI and WBI, respectively; P = 0.87). CONCLUSIONS: This is the first report of PBI efficacy in young patients in Asia. Although it is a nonrandomized retrospective chart review of a small cohort of patients with a relatively short follow-up period, PBI may be a better option than WBI following BCS in some young patients with breast cancer.

Comparison of radiation dose to the left anterior descending artery by whole and partial breast irradiation in breast cancer patients.

PURPOSE: Breast conserving surgery (BCS) followed by whole breast irradiation (WBI) is the standard of care for breast cancer patients. However, there is a risk of coronary events with WBI therapy. In this study, we compared the radiation dose in the left anterior descending artery (LAD) in patients receiving partial breast irradiation (PBI) with WBI. MATERIAL AND METHODS: We evaluated consecutive patients who underwent adjuvant radiotherapy after BCS between October 2008 and July 2014. Whole breast irradiation patients received 50 Gy in fractions of 2 Gy to the entire breast. Partial breast irradiation was performed using multicatheter brachytherapy at a dose of 32 Gy in eight fractions. The mean and maximal cumulative doses to LAD were calculated. The radiotherapeutic biologically effective dose of PBI was adjusted to WBI, and radiation techniques were compared. RESULTS: Of 379 consecutive patients with 383 lesions receiving radiotherapy (151 WBI and 232 PBI lesions), 82 WBI and 100 PBI patients were analyzed. In WBI patients, the mean and maximal cumulative doses for left-sided breast cancer (2.13 ± 0.11 and 8.19 ± 1.21 Gy, respectively) were significantly higher than those for right-sided (0.37 ± 0.02 and 0.56 ± 0.03 Gy, respectively; p < 0.0001). In PBI patients with left-sided breast cancer, the doses for tumors in inner quadrants or central location (2.54 ± 0.21 and 4.43 ± 0.38 Gy, respectively) were significantly elevated compared to outer quadrants (1.02 ± 0.17 and 2.10 ± 0.29 Gy, respectively; p < 0.0001). After the adjustment, the doses in PBI patients were significantly reduced in patients with tumors only in outer quadrants (1.12 ± 0.20 and 2.43 ± 0.37 Gy, respectively; p = 0.0001). CONCLUSIONS: Tumor control and dose to LAD should be considered during treatment since PBI may reduce the risk of coronary artery disease especially in patients with lateral tumors in the left breast.

[Factors affecting adherence of breast cancer patients to adjuvant hormonal therapy and validation of the evaluation method].

BACKGROUND: The long-term use of hormonal therapy is important for the treatment of patients with breast cancer. Therefore, we evaluated the methods used for measuring adherence and examined factors that influence compliance. Our goal was to improve overall adherence to the treatment. METHODS: Retrospective analyses by using electronic medical records and questionnaires were performed on 294 patients with breast cancer. The patients were classified into 2 groups based on the mean number of days when a dose was missed over a period of 28 days: group A(range, 0-3 days, n=272)and group B (range, B4 days, n=22). Factors that may influence adherence, including age, duration of hormonal therapy, the drug administered in hormonal therapy, the surgical method, axillary lymph node dissection, and adjuvant chemotherapy, were compared between both groups. RESULTS: The adherence rates calculated from electronic medical records and questionnaires were similar. The proportion of patients younger than 50 years was 30% in group A and 50% in group B(p<0.05). Additionally, there was a difference in the duration of hormone therapy(752 days vs 981 days in groups A and B, respectively; p< 0.05). Additional factors that are related to low-risk cancer-related procedures, such as breast conserving surgery, may also be linked to poor adherence. CONCLUSION: Young age and long duration of hormonal therapy are possibly related to poor adherence. Therefore, pharmacists should identify and manage these patients to increase adherence.

Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B.

Most known interactions between herbal extracts and drugs involve the inhibition of drug-metabolizing enzymes, but little is yet known about the possible role of transporters in these interactions. In this study, we have examined the effects of herbal extracts used in dietary supplements on the function of organic anion-transporting polypeptide B (OATP-B; OATP2B1), which is expressed on human intestinal epithelial cells and is considered to be involved in the intestinal absorption of various drugs. Specifically, the effects of 15 herbal extracts on uptake of estrone-3-sulfate, a typical OATP-B substrate, by human embryonic kidney 293 cells stably expressing OATP-B were evaluated. At concentration levels considered likely to be attainable in the human intestine, extracts of bilberry, echinacea, green tea, banaba, grape seed, ginkgo, and soybean potently inhibited estrone-3-sulfate uptake by 75.5, 55.5, 82.1, 61.1, 64.5, 85.4, and 66.8%, respectively (P < 0.01). The inhibitory effect of ginkgo leaf extract was concentration-dependent (IC(50) = 11.2 +/- 3.3 microg/ml) and reversible. Moreover, flavonol glycosides and catechins significantly inhibited the function of OATP-B, suggesting that the inhibitory effects of the herbal extracts on OATP-B may be primarily attributable to flavonoids. The extracts of mulberry, black cohosh, and Siberian ginseng moderately (but significantly) inhibited estrone-3-sulfate uptake by 39.1, 47.2, and 49.2%, respectively (P < 0.05). Extracts of barley, Job's tears, rutin, rafuma, and passionflower were ineffective. These results suggest that coadministration of some dietary supplements may decrease the absorption of orally administered substrates of OATP-B.