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Background This meta-analysis aimed to test the hypothesis that the HER2-positive metastatic breast cancer (mBC) patients treated with anti-HER2 antibodies in trial intervention arms have a greater prolongation of overall survival (OS) than of progression-free survival (PFS) and this extra-prolongation of median survival time in OS relates specifically to the anti-HER2 antibody. Methods The NCBI/Pubmed and Cochrane databases were searched systematically for HER2-positive or mBC trials published in English during January 1999–November 2017. Treatment arms with shorter PFS were considered as the “control” arm, whereas those with longer PFS as the “test” arm. The between-treatment drug differences were grouped into nine categories. Groups with or without anti-HER2 antibodies were pooled respectively for comparisons. The interrelationships between PFS and OS hazard ratios (HRs) and median survival time differences were investigated by conducting fixed-effects and mixed-effects linear meta-regression analyses. Results Twenty-eight trials (10,928 patients) from 438 articles were collected, and four with missing data were excluded in meta-regression analysis. Overall median PFS (HR = 0.73, 95% CI: 0.68–0.78) and median OS (HR = 0.82, 95% CI: 0.77–0.87) weakly favored the longer PFS arm with a weak correlation between the PFS and OS HRs. However, the between-treatment drug difference was anti-HER2 antibody, the absolute increment in median OS time was double that of median PFS time (p, Highlights • Our study dissected the overall survival benefit over progression-free survival in HER-2 positive metastatic breast cancer treated with anti-HER2 antibody by meta-analysis. • Use of anti-HER2 antibodies, but not other anticancer drugs, to treat HER2-positive metastatic breast cancer independently predicted the OS compared with PFS. • The design of future clinical trials should consider anti-HER2 antibodies carefully in the treatment armamentarium for HER2-positive metastatic breast cancer.

The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor PIK3CA gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA-mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2– advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies PIK3CA mutation testing upon diagnosing HR+/HER2– advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.

Background: Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis–related complications such as portal hypertension (pHTN). This study compared the outcomes of metastatic breast cancer in patients with imaging-diagnosed pseudocirrhosis with or without pHTN. Methods: The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Clinical pHTN was defined based on endoscopic evidence of esophageal or gastric varices. Results: Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)–positive and human epidermal growth factor receptor 2 (HER2)–negative breast cancer. In total, 81 (76%) had initial metastases in both hepatic lobes, 91 (86%) had 4 or more liver metastases, and 32 (30%) had pHTN. The median overall survival (OS) was 5 and 13 months in patients with and without pHTN, respectively (p = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative breast cancer was 16, 9, and 2 months, respectively (p = .001). Patients with pHTN generally had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with pHTN had OS exceeding 1 year. In multivariate analysis, pHTN (p = .007) and triple-negative breast cancer (p = .013) were associated with poor OS. Conclusions: For patients with pseudocirrhosis, clinical pHTN was associated with liver cirrhosis–related complications and shorter median OS. A few patients with pHTN had prolonged OS with effective systemic treatment and aggressive supportive care.

Historically, the median overall survival of patients with metastatic melanoma was less than one year. The recent advent of immunotherapy has changed the outlook dramatically and made long-term disease control achievable. Nivolumab, a monoclonal antibody to programmed cell death 1 (anti-PD1), has been proved to prolong survival in patients with metastatic melanoma. Vitiligo is a skin disorder characterized by the loss of color, and the postulated mechanism is immune-mediated destruction of melanocytes. Anti-PD1 treatment related to vitiligo has been reported to be associated with a favorable response in patients with melanoma. Here we present the case of a 61-year-old woman who received nivolumab for metastatic melanoma. After 6 months of nivolumab therapy, the patient experienced scattered hypopigmentation on her face, chest, and back. Durable response was noticed according to the follow-up images even after nivolumab was discontinued. Keywords: Immunotherapy, Melanoma, Vitiligo

Background The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is convenient but with uncertain toxicity profiles. A Phase I/II study was designed to understand the tolerability and efficacy of this combination treatment. Method Female MBC patients with HER2 positive were eligible. Lapatinib was given once daily and oral vinorelbine was given on Days 1 and 8 of a 21-day cycle. A 3 + 3 standard dose-escalation rule was applied in the Phase I study. The primary endpoint of the Phase II study was PFS. In the Phase II part, because no DLT was observed in the first 20 patients, vinorelbine dose-escalation was permitted if no significant toxicities after the first cycle was observed. Result From June 2009 to February 2013, 46 patients were enrolled in Phase I (n = 15) and II (n = 31) studies. Median age was 52.8 (range 34.3-84.0); 28 (60.9%) patients were ER positive. In the Phase I study, two patients had DLTs (neutropenia (n = 2), diarrhea (n = 1)). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the Phase II study, 11 patients safely had vinorelbine escalated to 60 mg/m2 on cycle 2. The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) patients had PR; the clinical benefit rate was 38.7%. Six patients had disease control over 2 years. Conclusion Lapatinib 1000 mg and oral vinorelbine 50 mg/m2 were tolerable with manageable toxicities. Escalation to vinorelbine 60 mg/m2 is feasible if no significant toxicities after the first cycle. Clinical efficacy was demonstrated with long-term responders observed.

Introduction: T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. In patients (pts) with HER2-expressing or -mutated solid tumors, T-DXd has demonstrated strong antitumor activity with a manageable safety profile and is approved for treatment (tx) of pts with HER2+ metastatic breast cancer (BC) that has progressed on ≥2 anti-HER2 therapies (US) or after chemotherapy (Japan); ILD is an important identified risk. We further characterize ILD in a pooled analysis of 8 single arm phase 1 and 2 T-DXd monotherapy studies. Methods: Pts who received ≥1 dose of T-DXd monotherapy 5.4 mg/kg or higher across 8 single-arm studies were included (between Aug 28, 2015 and the data cutoff June 08, 2020). Potential ILD cases had imaging and clinical data (baseline through the time of ILD case) retrospectively reviewed by an independent adjudication committee to assess whether the reported ILD event was study drug related; events adjudicated as study drug related are reported. Results: 879 pts were included; 510 with BC, 148 with lung cancer, 107 with colorectal cancer, 78 with gastric cancer, and 34 with other cancers (2 had missing tumor type). Median tx duration was 6.9 mo (range, 0.7-50.1 mo); 139 pts (15.8%) experienced an adjudicated ILD event, most were grade (G) 1/2 (G1/2=108 [12.3%]; G3=9 [1.0%]; G4=1 [0.1%]; G5=21 [2.4%]). Among pts treated with T-DXd 5.4 mg/kg (n=315), 48 (15.2%) experienced an ILD event (G1/2=39 [12.4%]; G3=2 [0.6%]; G4=1 [0.3%]; G5=6 [1.9%]). Additional details on ILD events by dose and tumor type will be presented. Among adjudicated ILD events (any grade), the onset date as assessed by investigator was delayed compared with the adjudication committee-assessed date in 71 cases (median difference in onset date, 49 d [range, 1-288 d]). The majority of ILD events occurred in the initial 12 mo of tx. After 12 mo the risk of new onset of ILD decreased with a conditional probability of developing ILD of 7.0% in pts treated to month 12 without ILD and 1.4% in pts treated to month 18 without ILD, which was likely driven by pts with longer tx duration in the BC cohort; however, additional follow-up is required to confirm these observations. Data on the use of steroids to manage ILD will be presented. Conclusion: Pooled analysis showed that most ILD events were low grade (78% of pts with ILD had G1/2 events) and occurred in the first 12 mo of tx, with lowered risk for pts on tx > 12 mo. The adjudication committee identified ILD earlier than investigators in 48% of cases suggesting opportunity for early detection and intervention. Close monitoring, prompt recognition, and proactive management of ILD using current management guidelines may help to improve ILD outcomes. Citation Format: Charles A. Powell, Shanu Modi, Hiroji Iwata, Shunji Takahashi, Egbert F. Smit, Salvatore Siena, Dwan-Ying Chang, Charles S. Fuchs, Kun Nie, Amy Qin, Jasmeet Singh, Corina Taitt, Sunil Verma, D. Ross Camidge. Pooled analysis of drug-related interstitial lung disease (ILD) in 8 single-arm trastuzumab deruxtecan (T-DXd) studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT167.

Interim Analysis Background: Despite the success of immunotherapy in triple negative breast cancer, no approved immunotherapy is available for HR+, HER2- MBC patients. Among HR+/HER2- patients(pts), luminal subtype B pts who are more resistant to endocrine therapy, demonstrate higher tumor infiltrating lymphocytes, higher immune score, and higher expression of PD-L1 than luminal subtype A pts. In addition, estrogen is known to result in immunosuppressive microenvironment. Exemestane, as a steroidal aromatase inhibitor, provides less than 10% overall response rate in second or third line of endocrine therapy for MBC pts. This pilot study aims to observe the efficacy of a combination of exemestane, leuprolide, and pembrolizumab in pre-/perimenopausal HR+, HER2- locally advanced or MBC pts who failed front-line endocrine therapy. Methods: This single-center, nonrandomized, open-label, phase Ib/II study of exemestane/leuprolide plus pembrolizumab enrolled a cohort of endocrine resistant HR+, HER2-, pre-/perimenopausal, locally advanced or MBC pts who 1) had failed adjuvant endocrine therapy within 12 months, 2) had failed at least 2 lines of prior endocrine therapy for MBC, 3) had failed 1st line endocrine therapy within 6 months or 1st line endocrine therapy+ CDK4, 6 inhibitor within 12 months. No prior chemotherapy for locally advanced or MBC was allowed. Patients received 25mg exemestane orally daily, 3.6mg leuprolide subcutaneous injection every 28 days, and pembrolizumab 150mg IV on day 1/day 15 every 28 days. Primary objective was to estimate the efficacy of the exemestane, leuprolide plus pembrolizumab combination defined by progression-free survival (PFS) rate at 8 months. Secondary objectives included safety, objective response rate (ORR), clinical benefit rate (CBR), and PFS. Results: Of 14 pts enrolled, 6 (42.9%) received 1 line and 8 (57.1%) received 2 lines of prior endocrine therapy in the locally advanced/metastatic setting. Safety of the combination was generally consistent with known side effects of exemestane, leuprolide, and pembrolizumab and was generally manageable. Grade 3/4 adverse events in ≥1 pt included AST increase (4 pts/28.6%), ALT increase (4 pts/28.6), and hypo/hyperthyroidism (1 pt, 7.1%). Nine pts did not progress or die at 8 months (64.3% PFS rate at 8th month). In the 13 evaluable pts, 5 had confirmed partial response [PR] (ORR=38.4%), 6 had confirmed stable disease[SD, 46.2%]. The disease control rate (complete response [CR]+partial response [PR]+stable disease [SD]) was 84.6%. CBR (CR+PR+SD persisting for ≥6 months) was 76.9%. Median PFS of the evaluable pts, PR pts, SD pts, and PD pts were 10.2 months, 15.8months, 10.1 months, and 2.4 months respectively. Conclusions: Combination of exemestane, leuprolide plus pembrolizumab demonstrated a generally tolerable safety profile with numerically higher rate of transaminase elevations than reported for the individual treatments. Compared to historical data for exemestane/leuprolide or for pembrolizumab monotherapy in a similar pt population, a meaningful higher ORR and longer PFS were observed. Citation Format: I-Chun Chen, Ching-Hung Lin, Dwan-Ying Chang, Tom Wei-Wu Chen, Ming-Yang Wang, Wei-Li Ma, Yi-Ting Lin, Shu-Min Huang, Yen-Shen Lu. A pilot study of pembrolizumab and exemestane/leuprolide in premenopausal hormone receptor positive/HER2 negative locally advanced or metastatic breast cancer (PEER) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT028.

Breast cancer (BC) is a common cancer in women worldwide; however, the incidence of BC is increasing in younger women, possibly associated with the environment. Perfluoroalkyl substances (PFAS) are one of endocrine disruptors that accumulate in environment and impact human health. This study aimed to investigate whether the PFAS and BC are associated. We enrolled 120 BCE patients and 119 controls at National Taiwan University Hospital (NTUH) and also collected bio-specimen and questionnaire from 2013 to 2015. All subjects’ plasma PFAS levels were analyzed by ultra-performance liquid chromatography tandem mass spectrometry method with electrospray ionization (UHPLC-ESI-MS/MS). A logistic regression model was used to estimate the association between PFAS and BC. In the ≤50 years age group, the adjusted odds ratio (OR) was 2.34 (95% CI = 1.02, 5.38) for perfluorooctane sulfonate (PFOS) exposure per natural log unit increase. After stratifying the estrogen receptor (ER) status and age group, we obtained a positive association for PFHxS and PFOS concentrations with respect to the risk of ER positive tumors for ≤50 years age group. In conclusion, we found that PFAS were associated with the BC risk of ER positive tumors in young Taiwanese women. Further studies are needed to follow and explore whether these associations are causal.

Background: Anti-HER2 therapies are beneficial for patients with HER2+ gastric or breast cancer (BC). [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody (Ab) conjugated by a peptide-based cleavable linker to a novel exatecan-derived topoisomerase I inhibitor (MAAA-1181a). The phase 1 study (NCT02564900) of T-DXd conducted at study sites in the US and Japan showed a manageable safety profile at the recommended doses for expansion (5.4 and 6.4 mg/kg) and a confirmed objective response rate (ORR) of 59.5% in subjects with HER2+ BC; however, safety and pharmacokinetic (PK) analyses from other Asian populations are lacking. Methods: This is a phase 1, open-label study (NCT03368196) conducted at 2 sites in Taiwan. Eligible HER2+ BC subjects were ≥ 20 years of age and received T-DXd 6.4 mg/kg intravenously once every 3 weeks until unacceptable toxicity, progressive disease (PD), or withdrawal from the study. The primary objective was to assess the safety and tolerability of T-DXd. Secondary objectives included assessment of PK and efficacy and incidence of anti-drug Abs (ADA) against T-DXd. Results: All subjects (N = 12) were Asian and female with HER2+ BC (11 IHC3+; 1 IHC2+); median age was 55 y (range, 36-69 y). Prior HER2-directed treatments included trastuzumab (100%), pertuzumab (50%), T-DM1 (33%), and lapatinib (8.3%). At data cutoff (Sept 14, 2018), the median treatment duration was 20 wk (range, 12-24 wk), and treatment was ongoing in all 12 subjects. The ORR (complete response [CR] + partial response [PR]) among 11 evaluable subjects was 36.4% (95% CI, 10.9%-69.2%; all PR); the disease control rate (CR + PR + SD) was 100% (95% CI, 71.5%-100.0%). By data cutoff, all subjects experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3, 58.3%), none of which led to discontinuation. The most common TEAEs were nausea (58%), decreased platelet count (58%), increased aspartate aminotransferase (50%), decreased white blood cell count (42%), decreased appetite (33%), anemia (33%), and fatigue (25%). One drug-related serious AE (febrile neutropenia) occurred, and 2 TEAEs led to dose reductions (grade 3 febrile neutropenia and grade 4 decreased platelet count). One AE of special interest occurred (grade 1 LVEF decrease). No events of pulmonary toxicity occurred and no deaths were reported. At cycle 1, the mean maximum concentration (Cmax) and area under the curve (AUCtau) of T-DXd were 157 µg/mL (SD, 19.1) and 631 day•µg/mL (SD, 173), respectively; for MAAA-1181a, the Cmax was 11.9 ng/mL (3.79) and the AUC was 36.1 day•µg/mL (9.71). PK parameters of total anti-HER2 Ab were similar to those of T-DXd. Some accumulation of T-DXd (57%) was seen at cycle 3 (Cmax, 163 µg/mL [SD, 19.5]; AUCtau, 991 day•µg/mL [SD, 109]). These PK results were similar to those of T-DXd, total HER2 Ab, and MAAA-1181a reported in other studies in HER2+ BC. All subjects were negative for ADA at all assessments. Conclusions: This is the first report of the efficacy, safety, and PK of T-DXd in Taiwan; T-DXd showed a manageable safety profile with no new safety signals. Despite the small number of subjects, results were similar to those previously reported and provide additional evidence of the clinical benefit of T-DXd in subjects with HER2+ tumors. Citation Format: Dwan-Ying Chang, Chia-Chi Lin, Tom Wei-Wu Chen, Ching-Hung Lin, Jih-Hsiang Lee, Ta-Chung Chao, Chun-Yu Liu, Issei Achiwa, Emi Kamiyama, Yasuyuki Okuda, Caleb Lee, Yee Chao. Safety and pharmacokinetic results from a phase 1, multicenter, open-label study of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with advanced HER2-positive breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C041. doi:10.1158/1535-7163.TARG-19-C041

For anthracycline-naive metastatic breast cancer (AN-MBC), early anthracycline treatment is a common practice. However, with the availability of newer chemotherapies, comparative studies on the efficacy of anthracyclines and non-anthracyclines as early treatments for AN-MBC are lacking. We collected retrospective clinicopathological data from 253 AN-MBC patients treated at National Taiwan University Hospital between 2001 and 2006. Patients were categorised into anthracycline or non-anthracycline groups according to their regimens in the first two lines of chemotherapy. The overall survival (OS, 33.3 vs. 34.2 months, p = 0.179), time to treatment failure of the first two lines of chemotherapy drugs (13.3 vs. 12.7 months, p = 0.104) and best composite response rate (59.5% vs. 61.1%, p = 0.81) were not significantly different between the two groups. Multivariate analysis showed that early anthracycline treatment was not a significant prognostic factor of OS (p = 0.052). Thus, the results of this study show that anthracyclines may not be necessary as an early treatment option for AN-MBC.

Objective: To remind gynecologists of the diagnosis of adenomatoid tumor of the female genital tract, a pathology which is often mistaken for leiomyoma, and in addition to warn of the malignant appearance of adenomatoid tumor. Materials and methods: During the study period from January 1988 to May 1994, the clinical features and pathologic findings of 25 cases of adenomatoid tumor of the female genital tract were reviewed at the National Taiwan University Hospital. Results: The age of the patients ranged from 26 to 55 years with a median of 41 years. Adenomatoid tumor was an incidental finding during the surgical treatment of myoma (16 cases), cervical intraepithelial neoplasm (two cases), invasive cervical cancer (one case), adnexal cyst (five cases), and pregnancy with myoma (one case). Twenty-three cases had tumors in the uterine corpus and two in the fallopian tubes. Twenty percent of the patients had multiple tumors. Their sizes ranged from 1.0 to 8.0 cm. The case with the largest tumor measuring 8 cm in diameter is presented in detail. Its histologic, immunohistochemical and ultrastructural characteristics strongly support the mesothelial origin of adenomatoid tumor. Conclusion: Some different results were obtained than those hitherto reported in the literature, such as younger age, frequency of multiple tumors, and fewer cases accompanied by leiomyomas.

Background. The purpose of this study was to determine the prognostic significance of clinical factors and staging systems for survival of hepatocellular carcinoma (HCC) patients who are candidates for therapeutic clinical trials. Methods. From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into six published phase II trials assessing various therapeutic regimens. Of these, 156 chemotherapy-naive patients with Child-Pugh class A and Barcelona Clinic Liver Cancer stage C disease were included in this analysis. Twenty-seven relevant clinical characteristics were analyzed to identify prognostic factors of survival. Beyond these prognosticators, the predictive ability of eight staging systems (the tumor–node–metastasis, Okuda, Cancer of the Liver Italian Program [CLIP], Chinese University Prognostic Index, Japanese Integrated Staging, Tokyo, National Taiwan University Risk Estimation, and Advanced Liver Cancer Prognostic System [ALCPS] score) were compared using the Akaike information criteria. Results. The median overall survival time was 129 days (95% confidence interval, 111–147 days). Significant predictors of a shorter overall survival time were an Eastern Cooperative Oncology Group performance status score ≥2, the presence of symptoms, ascites, an aspartate transaminase level more than two times the upper limit of normal, and regional lymph node involvement. The ALCPS and CLIP scores were superior to the other systems for predicting survival. Conclusions. The prognosis of patients with advanced HCC who are candidates for therapeutic clinical trials is affected by several factors related to the patient, liver function, and the tumor. The ALCPS and CLIP scores appear to be superior to the other systems for predicting survival.

Background Cryptococcal infection is opportunistic and occurs most commonly in immunocompromised patients. Meningitis is the most frequent manifestation and causes marked morbidity and mortality. Other sites are less common. We report a case of vaginal cryptococcal infection. Case A 72-year-old patient who had undergone resection of the colon for cancer 9 years earlier was noted to have a suspicious lesion on the right vaginal wall after an abnormal Papanicolaou test. Biopsy of the lesion showed findings compatible with cryptococcal infection. Serial examinations revealed no evidence of systemic infection or immunocompromised condition. Empirical treatment was tried with fluconazole. Follow-up colposcopy showed almost complete disappearance of the vaginal lesion, and histologic section and culture of the tissue failed to reveal cryptococcus. Conclusion Cryptococcal infection is rare, especially in a patient with no evidence of an immunocompromised condition. The preliminary result of fluconazole treatment was satisfactory. However, further follow-up and evaluation are needed to confirm the effectiveness of fluconazole in our patient.