bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes of preoperative radiotherapy in locally advanced breast cancer: Analysis of Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Pan Zhe , Yao Zhiyuan , Huang Mingkai , Huang Junfeng , Ao Xiang
Published: May 2020

e12600

Background: Currently the treatment paradigm for locally advanced breast cancer (LABC) is multimodality therapy with neoadjuvant systematic treatment, surgery and postoperative radiation therapy (RT). However, with improving outcomes from systematic therapy, the survival rates remain unpromising, which leads to the investigation of the concept of preoperative RT in LABC due to the potential advantages including a possible tumor downstaging and better cosmetic outcomes. We evaluated the overall survival (OS) and breast cancer specific survival (BCSS) of preoperative versus postoperative RT in LABC patients. Methods: Patients diagnosed with non-inflammatory LABC (defined as T3 N1, T4 N0, any N2 or N3, and M0) who received RT before or after surgery between 2010 and 2015 were identified using the SEER database. OS and BCSS were analyzed using Kaplan-Meier method and multivariate Cox proportional hazards model. Results: Among 19249 patients with LABC, 140 (0.7%) received preoperative RT and 19109 (99.3%) received postoperative RT. Overall, 5-year survival and BCSS are 59% and 63% in the preoperative RT group while 77% and 80% in the postoperative RT group. In all patients, treatment with preoperative RT was significantly associated with poor OS (HR 1.82, 95%CI 1.25 to 2.45, P < 0.001) and BCSS (HR 2.00, 95%CI 1.46 to 2.73, P < 0.001) after adjustment for other clinically relevant factors. However, there were no significant difference in terms of both OS and BCSS in ER+ (OS: HR 1.44, 95%CI 0.91 to 2.27, P = 0.12; BCSS: HR 1.55, 95%CI 0.94 to 2.54, P = 0.08) and HER2+ patients (OS: HR 1.33, 95%CI 0.55 to 3.22, P = 0.53; BCSS: HR 1.64, 95%CI 0.67 to 3.97, P = 0.28). Conclusions: Overall, preoperative RT in LABC may reduce overall survival and breast cancer specific survival. However, OS and BCSS were independent of radiation sequence for ER+ and HER2+ patients. This finding warrants further exploration of potential mechanisms of the disparity and the definitive role of preoperative RT in the multimodality therapy of LABC patients.
The impact of endogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC).
Authors: Yariv Orly , Yerushalmi Rinat , Moore Assaf , Shohat Tzippy , Tsoref Dalia , Goldvaser Hadar
Published: May 2020

e12605

Background: Menstrual and parity history might impact the risk for ER positive breast cancer. Data on the impact of these factors on other tumor characteristics are limited. Methods: A single center retrospective cohort study comprising all women with ER positive, human epidermal growth factor receptor 2 (HER2) negative, EBC whose tumors were sent to OncotypeDX analysis and were treated in our institute between 2005 to 2012. Data on endogenous estrogen exposure were collected including: age of menarche and menopause, number of deliveries and age of first delivery. Subsequently, data on pre-specified clinical and histopathological features were collected including: tumor size, nodal status, ER and progesterone receptor (PR) staining, grade, Oncotype recurrence score (RS), ki67, lymphovascular and perineural invasion. The impact of endogenous estrogen exposure was evaluated by multiple comparisons including: early age of (<12 years) compared to older age of menarche, nulliparity compared to women who had at least one delivery, multiparty (≥5 deliveries) compared to other, late age of first delivery (≥30 years) compared to other and postmenopausal compared to premenopausal. In postmenopausal women the age of menopause was also assessed using early age of menopause (<45 years) and late age of menopause (>55 years). Results: A total of 620 women were included. 79% were postmenopausal, median age of menarche was 13 (range 9-17) and median number of deliveries was three (range 0-14). Post-menopausal women were more likely to have stronger ER intensity (79% vs. 65%, p=0.002) and less likely to have high (≥31) RS (8% vs. 16%, p=0.021), but PR negativity was significantly more frequent (16% vs. 7%, p=0.007. Additionally, early age of menarche was associated with PR positivity (94% vs. 85%, p=0.039).). No other associations were found between endogenous estrogen exposures and tumor characteristics. Conclusions: These findings suggest that premenopausal women with luminal EBC might have more aggressive disease. Large scale studies are needed to elucidate the impact of endogenous estrogen on luminal breast cancer.
Characterization of weakly hormone receptor (HR)-positive, HER- negative breast cancer (BC) and current treatment strategies.
Authors: Poterala Johanna , Wisinski Kari Braun
Published: May 2020

e12621

Background: HR and HER2 status is critical for determining initial management of BC. Current guidelines define estrogen receptor (ER) and progesterone receptor (PR)+ as ≥1%. Previous reports of small cohorts with low HR+/HER2- disease showed similar rates of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) as triple negative BC (TNBC). This study aims to further characterize this group of patients (pts), focusing on modern management and breast/axillary pCR rates following NAC. Methods: Pts with newly diagnosed stage I-III, HR+/HER2- BC from 1/1/2009–4/1/2019 were found using the University of Wisconsin Hospital and Clinics Cancer Registry. Medical records were reviewed for demographics, tumor characteristics with quantification level of ER and PR ( < 33%), treatments including NAC and adjuvant chemotherapy (chemo), endocrine therapy, surgery and radiation, and follow-up clinical data. Results: Data reviewed from 2,905 pts: 2,604 (89.6%) were HR+/HER2-, 282 (9.7%) were ER+/PR-, and 19 (0.7%) were ER-/ PR+. A total of 64 pts [median age 54 (22-87), 100% female] met inclusion criteria. At diagnosis, 23 (36%) were anatomic stage 1, 30 (47%) stage II, and 11 (17%) stage III; 18 (28%) had biopsy (bx) proven nodal disease. 57 (89%) had invasive ductal carcinoma; 9 (14%) were ER+/PR+, 43 (67%) ER+/PR-, and 12 (19%) ER-/ PR+. The majority [51 (80%)] received chemo, ~ half with NAC 30 (48%), 1 pt chemo plan was unknown. NAC regimens included an anthracycline (A) and taxane (T) [26 (41%)], a sole A regimen [1 (1%)], and an A+T and platinum regimen [3 (5%)]. 4 pts received capecitabine after NAC. 50 (78%) pts had a sentinel lymph node bx, but 13 (20%) had an axillary node dissection (ALND). 10 (16%) pts did not receive any endocrine therapy, 28 (44%) got tamoxifen, 22 (34%) an aromatase inhibitor, and 4 (6%) unknown. Of 28 pts who had NAC followed by breast and axillary surgery, 12 (43%) had pCR (ypT0/Tis/ypN0). Of the 12 pts who had bx proven nodal disease at diagnosis and NAC, 7 (64%) pts had pCR at the axilla. One pt had progressive disease on NAC, 1 had local recurrence and 8 (13%) pts had distant recurrence. Median time to recurrence was 13.6 (5.6 – 48.7) months. Only 2 pts with pCR had distant recurrence. Conclusions: BC that are HER2- and weakly HR+ treated with NAC demonstrated an axillary and overall pCR rate more similar to TNBC than breast cancers with strong HR+. Neoadjuvant approaches may reduce need for ALND and pCR may provide important prognostic information. Clinical trials should be developed to focus on this unique patient cohort.
Treatment patterns and clinical outcomes of patients with early triple negative breast cancer at a tertiary medical center.
Authors: Tchou Julia C. , Burkbauer Laura , Goldbach Macy , Malinovitch Angela , Keele Luke
Published: May 2020

e12624

Background: The clinical benefit of neoadjuvant chemotherapy in patients with early triple negative breast cancer (eTNBC), especially those with clinical stage I (cStage I) disease, remains unclear. This study aims to examine the treatment pattern and outcomes of patients with eTNBC treated at a tertiary medical center. Methods: After receiving IRB approval, clinical characteristics, treatment patterns and invasive disease-free survival (iDFS) outcomes of patients with eTNBC treated in 2009-2019 were compared between those who received adjuvant chemotherapy (AC) vs. neoadjuvant chemotherapy (NAC). Inverse probability weighting (IPW) statistical methods were used to adjust for subgroup imbalances including age, race, clinical T and N stage. Results: Study cohort (n=919) was 70% white and 25% black. Median follow-up for AC and NAC was 49+/-26 and 28+/-19 months respectively. The majority, 56% (400/717), in AC had cStage I disease while only 8% (16/202) in NAC had cStage I disease. Other clinical characteristics were summarized in Table. The most common chemotherapy regimen used in AC and NAC groups was AC-T: 58% and 79%; followed by TC: 32% and 4%; and carboplatin: 2% and 5% respectively. pCR was noted in 83 patients (41%). Multivariate analyses using IPW showed that AC conferred an improved iDFS with a gain of 18 months in those with <=cStage IIA compared to NAC with pCR (Table). Conclusions: Despite limitations including our small sample size and retrospective study design, our results showed that NAC appeared to only benefit eTNBC patients with higher disease burden (>=cStageIIB). Future work to elucidate the clinical benefits of emerging novel NAC strategies in eTNBC will be of interest. [Table: see text]
Locoregional recurrence following pathologic complete response in patients with T1-3 N0 breast cancer treated with neoadjuvant chemotherapy, breast conserving surgery and whole breast radiation: Is a trial of omission of radiation warranted?
Authors: Parvez Elena , Muanza Thierry
Published: May 2020

e12625

Background: Pathologic complete response(pCR) after neoadjuvant chemotherapy(NAC) in patients with breast cancer(BC) is associated with decreased recurrence and improved survival. In NSABP B18 and B27, 10-yr locoregional recurrence(LRR) after pCR in patients with Stage I-III BC undergoing breast conserving surgery(BCS) and whole breast RT(WBRT) was 5.2-6.9%. However, LRR may be overestimated as Her2 therapy was not used and only some eligible patients received endocrine therapy. A retrospective study using modern protocols found a 5-yr LRR of up to 2.6%. We hypothesize that LRR in N0 patients is even lower, and de-escalation of therapy should be examined. The study objective is to assess if a prospective trial of omission of WBRT after BCS in patients with N0 BC and pCR after NAC is warranted and to assess feasibility. Methods: Patients with T1-T3 N0 invasive BC diagnosed between Dec 2011-2017 treated with NAC and BCS were identified from a hospital BC registry. Health records were retrospectively reviewed to identify patients with pCR, defined as absence of residual invasive or in-situ disease(ypT0N0). Incidents of locoregional and distant recurrence were recorded. Results: Of 89 patients with T1-3 N0 invasive BC treated with NAC and BCS, 29(32.6%) had pCR. Median follow-up was 61.1 months. Median age was 55 yrs and median tumour size was 2.4cm. Receptor status was 16(55.2%) HR-Her2-, 4(13.8%) HR-Her2+, 7(24.1%) HR+Her2+ and 2(6.9%) HR+Her2-. NAC protocols consisted of an anthracycline and/or a taxane in 27(90%) patients, and 6 patients were treated on NAC trials. All patients with Her2+ disease received Her2 targeted therapy. Adjuvant endocrine therapy was taken by 8 of 9 patients with HR+ disease. All patients received WBRT without nodal RT. RT plan was available for 26(86.7%) patients. RT dose ranged from 40-50Gy, and all but 4 received tumour bed boost. There were no local or regional recurrence events at last follow-up. One patient developed brain metastases at 15.7 months. Conclusions: Over 6 years, 29 patients were identified that would be eligible for a prospective trial evaluating omission of WBRT after pCR in N0 patients treated with NAC and BCS. At median 5-yr follow-up, there were no locoregional recurrences in our cohort, demonstrating that the absolute benefit provided by WBRT is likely small. Our results indicate a prospective trial is warranted and will require multi-institution participation to accrue.
Comparing efficacy and toxicity profile of weekly paclitaxel to dose-dense paclitaxel (every two weeks) in treatment of breast cancer: A meta-analysis and systematic review.
Authors: Khan Usman , DeRosa Antonio , Xu Jiaqiong , Patel Tejal Amar
Published: May 2020

e12634

Background: Neoadjuvant and adjuvant chemotherapy includes anthracyclines and taxanes has been used in early stage breast cancer. Studies have demonstrated superiority of weekly and dose dense Paclitaxel when compared with every 3 week regimen. Both weekly and dose dense administration of paclitaxel is an acceptable treatment as they are thought to have similar disease free and overall survival. The two regimens have clearly different toxicity profile but not many studies have compared them against each other. We conducted this analysis to compare efficacy of both regimens in terms of pCR if used in neoadjuvant setting and compared both regimen in terms of grade 3-4 neurotoxicity. Methods: Systematic literature searches were conducted in four databases for randomized controlled trials published in English. The databases searched were: (1) MEDLINE (2) Embase, (3) The Cochrane Library, and (4) Scopus. 18 studies were included in pCR data analysis. Total of 38 studies were included in this meta-analysis for the toxicity analysis. Results: Our analysis showed no significant difference in the rate of pathological complete response between weekly paclitaxel and dose dense paclitaxel (p=0.266). Meta-analysis showed the overall estimate proportion for weekly paclitaxel causing neurotoxicity was 0.04 (95% CI: 0.02-0.06) and for the dose dense paclitaxel 0.10 (95% CI: 0.05-0.17). The test for heterogeneity between two sub-groups in toxicity analysis was p=0.042. Conclusions: Our analysis showed no significant difference in rate of pCR between two regimens however rate of grade 3-4 neurological toxicity was more in dose dense paclitaxel as compared to weekly paclitaxel. This difference in neurological toxicity with no corresponding difference in rate of pathological complete response can be an important factor in deciding the chemotherapy regimen for our patients.
Correlation between HER2 amplification level and response to neoadjuvant treatment with trastuzumab and chemotherapy in HER2 positive breast cancer.
Authors: Antolin Silvia , García-Caballero Lucía , Reboredo Cristina , Molina Diaz Aurea , Mosquera Joaquín , Vázquez-Boquete Angel , Gallego Rosalía , Santiago Maria Paz , Concha Angel , Perez Maria EVA , Calvo Lourdes , García-Caballero Tomás
Published: May 2020

e12641

Background: HER2 targeted therapy in combination with chemotherapy have changed the aggressive natural history of HER2-positive tumors. To select patients to be treated with this type of agents, determination of HER2 status is usually carried out by immunohistochemistry, followed by in situ hybridization in equivocal cases (2+). There are contradictory data in literature regarding correlation between level of HER2 amplification determined by FISH and early and long-term treatment benefits. Objectives: The aim of this study was to correlate quantitative results of FISH (ratio HER2/CEN17 and number of HER2 signals/nucleus) with the grade of response to neoadjuvant treatment with trastuzumab and chemotherapy. Methods: We analyzed 100 consecutive cases of stage I-III breast carcinomas treated with trastuzumab and chemotherapy in the neoadjuvant setting at A Coruña University Hospital between 2005 and 2016. At Santiago University Hospital, 4 tissue microarrays were prepared and the IQFISH (Dako-Agilent) technique was performed using pretreatment biopsies. Results: HER2 amplification was found in 92 of 100 cases studied. Pathological Complete Response (pCR) (Miller-Payne grading system) was obtained in 58% of the patients whose tumors showed amplification. No pCR was obtained in the 8 patients whose tumors were negative by FISH (not amplified). Analysis of the quantitative results demonstrated a statistical significant direct correlation between pCR and both HER2/CEN17 ratios and HER2 gene copies/nucleus (p = 0.002 and p= 0.004, respectively). We also demonstrated an association between the HER2 amplification level (both ratios and numbers of HER2 signals) and a trend toward improved disease free survival (DFS) (p = 0.451 and p= 0.619, respectively). Conclusions: HER2 amplification level determined by FISH it is a good and available predictive factor of response and must be included in pathologic reports because it can provide valuable information to oncologists on the possibilities of achieving pCR after neoadjuvant treatment in HER2-positive breast cancer. Key words: Breast cancer, FISH, HER2 amplification, trastuzumab, neoadjuvant therapy, pathological complete response.
Translesion synthesis genes POLI and REV1 in breast tumors and response to neoadjuvant chemotherapy.
Authors: Thompson Patricia , Jones Emma V , Preece Christina , Li Jinyu , Bhalla Jigna , Cohen Jules , Baer Lea N. , Pierce Andrew , Stopeck Alison
Published: May 2020

e12642

Background: Translesion synthesis (TLS) of DNA by specialized polymerases (POLs) and REV1, a scaffold protein that recruits other TLS DNA POLs for nascent strand extension, experimentally enable tumor cells to replicate through DNA damage. TLS POLs are hypothesized to contribute to treatment resistance. Methods: We conducted a discovery gene expression study using NanoString technology with a bespoke codeset enriched for DNA damage response genes and RNA from 12 TN, 10 HER2+ and 29 ER+/HER2- breast cancer patients before neoadjuvant chemotherapy (NACT) and when available, in the matching residual tumor. Eleven patients achieved a pathologic complete response (pCR), 12 had < 1 cm residual disease (partial responders) and 28 patients had > 1cm residual disease (non-responders). RNA counts were normalized and log-transformed for differential expression analyses corrected for false discovery. Results: DNA polymerase Iota ( POLI) was the top overexpressed gene in the pretreatment biopsy of non-responders independent of tumor subtype (p corrected = 0.0002). Expression of REV1 was also significantly higher in non-responders and positively correlated with POLI (r = 0.577, p < 0.0001). Despite a small sample size, pretreatment expression levels of POLI and REV1 were significantly higher in ER+ (n = 38) than ER- (n = 13) tumors (p = 0.0006). When restricted to ER+ tumors, POL1 and REV1 expression levels were significantly higher in pretreatment biopsy of non-responders (n = 25) than partial and complete responders (n = 13). For ER+ patients, response by median POL1/REV1 expression levels are shown in Table. Pre/post treatment POL1 and REV1 expression did not change in patients with residual disease. Conclusions: In discovery, two genes involved in TLS of DNA (POLI and REV1) were found overexpressed in pretreatment biopsies from breast cancers poorly responsive to NACT, independent of tumor subtype. Overexpression was more common among ER+ tumors, which exhibit a high inherent resistance to chemotherapy. If confirmed, expressed levels of POLI and REV1 may identify a subgroup of breast cancers resistant to NACT for which targeted inhibition of mutagenic TLS may be beneficial. [Table: see text]
Incidence of brain metastases in patients receiving neoadjuvant chemotherapy (NAC) with trastuzumab and pertuzumab (HP) in HER2-positive early breast cancer (BC).
Authors: Ferraro Emanuela , Barrio Andrea Veronica , Patil Sujata , Robson Mark E. , Dang Chau T.
Published: May 2020

e12653

Background: The addition of pertuzumab in the neoadjuvant setting has become a standard of care in stage II-III HER2-positive BC. In the Katherine study the incidence of brain metastases (BM) at the follow-up of 3-years was 5.9 % in patients (pts) with residual disease who received TDM1. The aim of this study was to assess the incidence of BM in pts who received NAC with HP at a single center who were found to have pathological complete response (pCR) (ypT0/is ypN0) versus non-pCR at the time of surgery. Methods: Chart review on HER2-positive pts treated with NAC and HP between September 1, 2013 to May 1, 2018 was conducted. Only surgical specimens of pts whose pre-NAC specimens were internally reviewed for HER2 status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were included in this analysis. Data on BM as component of distant recurrence along with invasive disease-free (IDFS) and overall survival (OS) were collected. Results: 540 pts were identified. Cases with no internally verified-HER2 status (387), equivocal status (10) and discordant internal assessment (13) were excluded. 130 pts with preoperative HER2 status confirmed by dedicated breast pathologists were included. Clinicopathological features are described in Table. pCR was achieved in 77/130 (60%) of cases, residual disease in 53/130 (40%). The median follow-up was 2.83 (0.35-5.3) years. The rate of BM as first presentation of distant disease was 3.8 % (3/77) and 3.7 % (2/53) in pts with pCR and non-pCR, respectively. Median time to development BM was 35 (13-58) months and 11.7 (9-14) months in the pCR group and non-pCR, respectively. Conclusions: In our cohort, the combination of HP was associated with a high pCR rate. At a median follow-up of 2.8 years, the incidence of BM appeared to be similar in pts who achieved pCR versus non-pCR. The data of IDFS and OS will be reported. Further data are needed to validate our findings before designing clinical trials to test prophylactic strategies to prevent BM. [Table: see text]
Assessment of PD-L1 expression in circulating tumor cells in patients with breast cancer.
Authors: Chen Junqing , Chen Zhanhong , Wang Xiaojia
Published: May 2020

e13001

Background: Evidence is accumulating that the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced breast cancer patients. PD-L1 tumor expression is emerging as a potential biomarker in PD-1/PD-L1 checkpoint blockade therapies. However, PD-L1 expression on tumor tissue is limited by the temporal and spatial heterogeneity as well as insufficient tumor tissue samples. PD-L1 expression in circulating tumor cells (CTCs) might overcome the limitation. We investigated the utility of CTCs as a noninvasive method to evaluate PD-L1 status in breast cancer patients. Methods: 46 breast cancer patients including 42 metastatic breast cancer patients and four early breast cancer patients were enrolled. CTCs were collected from peripheral blood samples using a microfluidic-based CTC separator. A novel staining procedure which included fluorescent glucose analog staining and immunostaining targeting CD45, vimentin and PD-L1 were analyzed. PD-L1 expression level was analyzed as the fraction of PD-L1 positive CTCs among total CTCs. Results: 46 breast cancer patients all had detected CTCs, ranging from 12 to 110. The fraction of PD-L1 positive CTCs varied from 2.08% to 85.69%. PD-L1 expression was obviously higher in triple negative breast cancer (TNBC) patients as compared with non-TNBC patients (47.16% vs 26.23%, P < 0.01). Interestingly, we observed that PD-L1 positive CTCs were also detected in four early TNBC patients. No significant association was found between PD-L1 expression and mesenchymal CTC phenotype. Conclusions: These data suggest that assessment of PD-L1 expression in CTCs from breast cancer patients is feasible. PD-L1 expression in CTCs might serve as a complementary tool for PD-L1 expression analysis in breast cancer patients.
Using novel biomarkers to predict chemotherapy-induced cardiovascular toxicity in patients with breast cancer.
Authors: Krishnarao Krithika , Fairweather DeLisa , Bruno Katelyn , Douglass Erika , Geiger Xochiquetzal , Tan Winston , Cornell Lauren , Yamani Mohamad
Published: May 2020

e13002

Background: Despite improvement in survival in breast cancer patients from advanced therapies, rates of chemotherapy-induced cardiotoxicity manifesting as a decline in left ventricular ejection fraction (LVEF) have offset some of these benefits in patients receiving anthracycline-based chemotherapy followed by trastuzumab. Results suggesting clinical biomarkers predict cardiotoxicity are inconsistent. Recently, expression of angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) has shown to play a role in breast tumor growth. We sought to evaluate whether the presence of ATR1 and ET1 in breast cancer tissue using immunohistochemistry (IHC) and qRT-PCR can predict chemotherapy-induced cardiotoxicity. Methods: We hypothesized that elevated expression of ATR1 and ET1 in tumor tissue is associated with chemotherapy-induced cardiotoxicity (LVEF < 50%) compared to tissue from controls. Preliminarily, 34 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were retrieved for analysis. IHC and qRT-PCR for expression of ATR1 and ET1 was performed on all specimens. Results: We found that ET1 expression was significantly increased in patients with an LVEF < 50%. In addition, we noted the lower the LVEF, the higher the ET1 expression (p = 0.03). We also found patients with a change in LVEF of greater than 10% had more ET1 expression compared to those without a change in LVEF (p = 0.05). We did not find a significant relationship between ATR1 and LVEF. Conclusions: Increased ET1 expression in breast tumor tissue may predict cardiotoxicity. Our findings may aid in future research using novel biomarkers to predict breast cancer patients at risk for developing chemotherapy-induced cardiotoxicity. In addition, targeted therapies to these biomarkers may potentially help prevent the development of cardiotoxicity.
A phase I study of safety and pharmacokinetics of A166, a novel selective inhibitor of human epidermal growth factor receptor-2 in Chinese patients with advanced solid tumors.
Authors: Liu Yongheng , Lian Wei , Zhao Xi , Qi Wei , Xu Jian , Xiao Liang , Qing Yan , Xue Tongtong , Wang Jingyi
Published: May 2020

e13007

Background: Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug (monomethyl auristatin F derivative ) site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker, which has a DAR (Drug Antibody Ratio) of Better efficacy were observed in preclinical CDX and PDX studies including HER2 low expression and T-DM1 resistant models while toxicity studies demonstrated a good safety profile in cynomolgus monkey. Methods: Patients with HER2-expressing or amplified advanced solid tumors refractory to standard therapies were recruited. A modified Fibonacci 3 + 3 dose-escalation design was employed with 7 dose levels (0.1, 0.3, 0.6, 1.2, 2.4, 3.6, and 4.8 mg/kg every 3 weeks). Safety analyses included all patients. PK and antitumor activity were also assessed. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose. Results: As of October 1, 2019 among 19 patients (breast cancer, colorectal cancer and gastric cancer)treated,no one experienced dose-limiting toxicity. No maximum tolerated dose was determined until 4.8mg/kg dose level. Grade≥3 adverse event was reported for 4 patient as neutropenia、anemia、Hyponatremia and Hypophosphatemia. Notably, 36.8% (n = 7) of patients experienced dry eye, as well as corneal epitheliopathy, and 2 patients withdraw from the study due to grade 2 corneal epitheliopathy. In 3.6 and 4.8 mg/kg groups, 6 patients were evaluable for tumor response, including 3 with partial response, 2 with stable disease. A166 exposure increased with the increase of dose, and extremely low exposure of free toxin and toxin-linker conjugates were observed; t1/2 was 8.29 days at the 4.8mg/kg. Conclusions: A166 showed an acceptable safety profile and promising anti-tumor activity in patients with HER2-expressing advanced solid tumors. Clinical trial information: CTR20181301 .
A site-specific approach to improved antibody-drug conjugates.
Authors: Italia James
Published: May 2020

e13009

Background: Antibody based therapeutics have emerged as a highly promising treatment option for various forms of cancer. One such class of emergent antibody therapeutics is antibody-drug conjugates (ADCs), which has experienced remarkable success in the past few decades, including many candidates currently undergoing clinical trials. Despite its promise, developing effective ADCs remains a challenge due to extensive optimization with regard to antibody target identification, conjugate specificity, conjugation chemistry compatibility, heterogeneous side product co-purification, all affecting efficacy, PK/PD characteristics, and toxicity. There is a pressing need to develop alternative strategies for precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates to overcome these limitations and realize the full potential of this highly promising class of therapeutics. Methods: In this study, we demonstrate the feasibility of efficiently incorporating an azide-containing UAA into full-length antibody at different site and facilitate its site-specific functionalization, which provides a facile scale-up compatible route to generate precise antibody-drug conjugates with fine-tuned therapeutic properties. Specifically, we have engineered multiple variants of trastuzumab to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as MMAE/MMAF, via click chemistry to generate ADCs with homogeneous DARs. Results: The resulting BrickBio ADCs exhibit high therapeutic efficacy against HER2+ cell lines in vitro as well as in mouse xenograft models. These homogenous ADCs additionally outperform traditional antibody conjugation technologies which lack site-specificity or site-selectivity. Conclusions: The ability to systematically vary the attachment topology between the drug and the antibody is a major strength of this approach and preliminary data suggest that such variation indeed affect ADC performance. BrickBio ADCs are currently in the preclinical stage with further efforts for safety studies underway.
Barriers to accessibility of targeted therapy for breast cancer: A qualitative study in Yerevan, Armenia.
Authors: Shingala Darshan , Arakelyan Jemma , Bardakhchyan Samvel , Tamamyan Gevorg
Published: May 2020

e13013

Background: The treatment prospects for Human Epidermal Growth Factor Receptor 2 positive (HER2p) breast cancer (BC) patients are continuously evolving, however, BC remains a major public health problem. Multiple therapeutic and biological strategies are already in function, and specifically the anti-HER2 therapy (trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine) remains a mainstream clinically approved treatment method. Implementation of the anti-HER2 therapy has substantially strengthened the prognosis for HER2p patients. This has remarkably improved the 5-year survival rates upto 80% in high-income countries, 60% in middle-income countries and 40% in low-income countries by establishing anti-HER2 therapy. Barriers to anti-HER2p therapies in low- and middle-income countries (LMICs) can be minimized by further instigation and licensing of the bio-similar drugs as a low-cost alternative treatment. Bio-similar drugs will also potentially result in a considerable savings for patients and eventually lessen the burden on the health care systems of LMICs as the usual cancer treatment regimen includes multiple systemic therapies for an extended time period, which are highly expensive. The aim of the study is to identify the barriers to accessibility of targeted therapy for BC, among patients seeking BC treatment in Yerevan, Armenia. Methods: The qualitative study assessed the out-of-pocket (OOP) payment burden among patients and their opinions about the quality of treatment using an interview guide with probe questions, adapted to the Armenian context. The study participants were patients seeking BC treatment at Hematology Center and Mikhaelyan Medical Center. Results: All the study participants were satisfied with the quality of health care and health care providers, however, majority of the study participants paid OOP for the examination, analysis and therapeutic drugs. Most participants were sponsored by family members and stated being financially vulnerable. Conclusions: The study provides evidence for the development and implementation of biosimilar drugs, implementation of mandatory health insurance to increase the access to targeted therapy, enhance collaboration with international funding agencies and strengthen diaspora support.
Clinical outcomes and prognostic factors in HER-2 positive breast cancer with brain metastasis: A single-center experience.
Authors: Karakaya Serdar , Karadağ İbrahim , Duran Ayse Ocak , Oksuzoglu Omur Berna , Demirci Umut
Published: May 2020

e13015

Background: Brain metastasis is common in HER2 positive metastatic breast cancer patients. There is limited data on the prognosis, incidence, treatment, risk factors and complications of brain metastasized breast cancer because most clinical trials excluded these patients. we aimed to determine the characteristics and prognosis of brain metastasized HER2 positive breast cancer in our patient group, retrospectively. Methods: We scanned 3100 patients retrospectively and included 105 patients who met the criteria for inclusion in the study. Patients older 18 years old, had HER2 positive breast cancer and brain metastasis with no secondary malignity participated in the study. Results: In total, 35 (33.3%) patients had de-novo metastasis. Median overall survival (OS) was found to be 50 months in all patients. Median OS was 31 and 66 months for patients with de-novo metastasis (without brain metastasis) and patients with no metastasis at the time of the diagnosis, respectively (p < 0.01). When we compared median OS between 25 patients with one brain metastasis and 80 patients with multiple brain metastasis, it was found to be 90 months in the first-mentioned group whereas it was determined to be 45 in the latter group (p < 0.01). In all patients, the median elapsed time for the occurrence of brain metastasis was 22 months (for de-novo metastasis 15 months, for no metastasis 35 months; p < 0.01). Median OS was determined to be 15 months for all patients with brain metastasis after the occurrence of the metastasis. Patients with ECOG PS score of 0-1 at the time of the brain metastasis had 19 months median OS, while patients with ECOG PS score of 2 at the time of the brain metastasis had 8 months median OS (p < 0.01). Median OS after brain metastasis was 32 and 14 months for patients with one brain metastasis and patients with multiple brain metastasis, respectively (p < 0.01). Multivariate cox regression analyses revealed that elapsed time for the occurrence of brain metastasis was shorter in patients with high-grade tumours compared to patients with low-grade tumours (p = 0.04), and in patients with de-novo metastasis compared to patients without de-novo metastasis (p < 0.01). Conclusions: Our study indicated that tumour grade and de-novo metastasis are independent predictive factors that may cause the earlier occurrence of brain metastasis and affect mortality in breast cancer patients. After the occurrence of brain metastasis, lower ECOG PS score and multiple brain metastasis at the time of the diagnosis affected median overall survival as bad prognostic factors.
Tolerability of neratinib in older adults with HER2 positive or HER2 mutated metastatic breast cancer.
Authors: Lee Jin Sun , Yost Susan Elaine , Stiller Tracey , Blanchard Suzette , Padam Simran , Katheria Vani , Tang Aileen , Martinez Norma , Patel Niki Himat , Sedrak Mina S. , Waisman James Ross , Li Daneng , Sanani Shamel , Presant Cary A. , Mortimer Joanne E. , Yuan Yuan
Published: May 2020

e13018

Background: The tolerability and efficacy of targeted therapy in older adults with cancer have not been adequately studied. Neratinib is an oral pan-HER1, HER2, and HER4 tyrosine kinase inhibitor that has been FDA approved for early stage HER 2+ breast cancer. This phase II trial is designed to evaluate the safety of neratinib in older adults (≥60 years) who have HER2 amplified or HER2 mutated metastatic breast cancer (MBC). Methods: Older adults with HER2+ or HER2 mutated MBC with any number of previous lines of therapy received neratinib at 240 mg daily in 28-day cycles. Loperamide was used for diarrhea prophylaxis: 4mg tid x 14 days followed by 4mg bid for days 15-28, and as needed after first cycle. Participants completed a pre-treatment geriatric assessment (GA) including measures of function, comorbidity, cognition, nutrition, and psychosocial status at cycle 1, cycle 4, and end of the study. Relationships between tolerability (dose reductions and number of completed courses) and log2 risk score were assessed using t-test and linear regression. Response rate (RR), progression free survival (PFS) and overall survival (OS) were evaluated. Results: Twenty-five patients (mean age 68 [60-79]) were enrolled from 12/2016 to 03/2019, and 36% of patients (pts) were >70 years old. Median number of cycles completed was 3 (0-13): 1/25 (4%) pts had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not evaluable for response. PFS was 2.6 months (95% CI [2.56-5.26]). The median OS was 17.4 months (95% CI [10.3, NA]). A total of 9/25 pts (36%) had dose modification. Of these, 3/9 had at least one dose hold, and all 9 had at least one dose reduction (diarrhea, n = 6). 20/25 participants (80%, 95% CI [59%, 93%]) had grade ≥2 toxicities, and 9/25 pts (36%, 95% CI [18%, 57%]) had grade 3 toxicities that were attributable to treatment: diarrhea (n = 5), abdominal pain (n = 2), and vomiting (n = 2). There were no grade 4 or 5 toxicities. Two pts (8%) were hospitalized due to neratinib toxicity, and two pts went off treatment due to toxicity attributed to neratinib (diarrhea and nausea). There was a trend in the difference in toxicity risk scores by whether a participant had a dose reduction (t-test: p-value = 0.054) with participants with higher risk scores being more likely to require a dose reduction; however, toxicity risk score did not predict number of cycles completed based on linear regression (slope = -1.29, se = 1.44, p = .39). Conclusions: Neratinib is safe in older adults with HER2 positive or HER2 mutated MBC. Clinical trial information: NCT02673398 .
Real-world study of the treatments following trastuzumab-emtansine for HER2-positive metastatic breast cancer: A multicentral cohort study (WJOG12519B).
Authors: Kurozumi Sasagu , Yokoe Takamichi , Nozawa Kazuki , Ozaki Yukinori , Maeda Tetsuyo , Yazaki Shu , Onishi Mai , Fujimoto Akihiro , Nakayama Sayuka , Tsuboguchi Yuko , Iwasa Tsutomu , Sakai Hitomi , Ogata Misato , Terada Mitsuo , Nishimura Meiko , Onoe Takuma , Masuda Jun , Kurikawa Michiko , Shimokawa Mototsugu , Takano Toshimi
Published: May 2020

e13019

Background: Since trastuzumab emtansine (T-DM1) was established as a standard treatment option, the treatment strategy of metastatic HER2-positive breast cancer has markedly changed. However, clinical evidence regarding the treatments beyond T-DM1 is insufficient. In this study, we attempted to describe real-world selection and efficacy of treatments following T-DM1 for metastatic HER2-positive breast cancer. Methods: This multi-center retrospective cohort study was conducted in 17 hospitals in Japan. Consecutive patients with metastatic HER2-positive breast cancer who had received T-DM1 and started post-T-DM1 treatments between January 2014 and December 2018 were enrolled. Patients treated with investigational drugs were excluded. The primary endpoint was objective response rate (ORR) of post-T-DM1 treatments. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results: In this study, 325 patients were eligible, of which 182 (56.0%) cases were estrogen receptor-positive and 61 (18.8%) had brain metastases. T-DM1 had been used as the first to 11th (median third) line treatment for metastatic disease. The types of post-T-DM1 treatment were as follows: 1) chemotherapy concomitant with trastuzumab and pertuzumab (n = 102; 31.4%), 2) chemotherapy concomitant with trastuzumab only (n = 78; 24.0%), 3) lapatinib with capecitabine (n = 63; 19.4%), and 4) others (n = 82; 25.2%). ORR of post-T-DM1 treatments was 22.8% (95% confidence interval [CI]: 18.1 to 28.0) and DCR was 66.6% (95% CI: 60.8 to 72.0), calculated with 290 eligible cases with the target lesion. Median PFS was 6.1 months (95%CI: 5.3 to 6.7), median TTF was 5.1 months (95%CI: 4.4 to 5.6), and median OS was 23.7 months (95%CI: 20.7 to 27.4). Conclusions: This real-world study showed that post-T-DM1 treatments had modest anti-tumor activity. Development of more effective treatments beyond T-DM1 is needed for metastatic HER2-positive breast cancer. Clinical trial information: UMIN000037747 .
Patient-reported pain and pain medication impact in patients with HR+ Her2-neg advanced breast cancer: A U.S. FDA pooled analysis.
Authors: King-Kallimanis Bellinda , Gao Jennifer J , Hodgdon Christine , Bandaru Pradeep , Girvin Andrew , Osgood Christy , Ison Gwynn , Amiri-Kordestani Laleh , Pazdur Richard , Bhatnagar Vishal , Kluetz Paul Gustav , Beaver Julia A.
Published: May 2020

e13027

Background: Despite the ubiquitous prescribing of pain medications (PMs) in cancer clinical trials, the impact of such prescribing patterns and reporting on the experience of pain is not often investigated. We examined patient-reported pain before initiation of PM reporting and at the next available pain assessment. Our aim was to understand change in patient-reported pain. Methods: We pooled data from 7 phase 3 randomized, controlled, registration trials of CDKI with endocrine therapy in patients with hormone receptor positive, human epidermal growth factor receptor-2 negative MBC. We restricted our analyses to patients who started therapy with no PM reported and looked at patients who had NSAID or opioid medication documented. We calculated change between 2 assessments in patient-reported pain before and after PM using the pain occurrence item (Q9) on the EORTC Quality of Life questionnaire (QLQ-C30). Results: Of the 4200 patients who received at least 1 dose of CDKI/placebo, 1488 started with no documented PM, with 48% reporting none at all when asked about pain at baseline. Subsequently, 185 patients had documented NSAID and 43 an opioid and had a pain PRO assessment before and after. NSAIDs documentation occurred on average 11 weeks into trial and opioids 5. Before documentation of NSAIDs, 45% of patients reported no pain compared to 23% of patients with an opioid. Patients who had documented NSAIDs, 29% experienced an improvement in their self-reported pain, whereas 32% of patients with documented opioids improved. On average the time between the 2 pain assessments was around 58 days for both PMs. Conclusions: In this analysis in patients who had a pain assessment before and after documentation of a PM, there is a small group whose pain improved. It is important to note that patients’ response to the pain item was not provided to the clinical care team, which may explain why there may have been suboptimal pain control. Further study is needed to examine how pain management can be achieved in patients with advanced breast cancer. Future analysis should be performed with patients whose PRO pain results are communicated with the clinical care team in real-time. [Table: see text]
CDK 4/6 drug target activation mapping of HR+/HER2- metastatic breast cancer for treatment selection and response prediction.
Authors: Abu-Khalaf Maysa M. , Hatzis Christos , Hodge K. Alex , Valdes Frances , Sikov William M. , Mita Monica M. , Denduluri Neelima , Awerkamp Kris , Murphy Rita , Zelterman Daniel , Dunetz Bryant , Petricoin Emanuel , Pierobon Mariaelena
Published: May 2020

e13029

Background: Despite the fact that a number of CDK 4/6 inhibitors have become FDA approved as the main frontline therapy for HR+/HER2- metastatic breast cancer (MBC), there are no validated predictive markers of response to this class of drugs. Additionally, approximately 30-40% of patients (pts) have little to no response to these agents, with disease progression occurring in weeks to a few months after therapy initiation. We have initiated a clinical trial (NCT03195192) to utilize cutting edge proteomic technologies to map the functional activation of the signaling architecture of tumors taken from HR+/HER2- MBC pts at diagnosis. We plan to correlate these functional phosphoprotein-based signaling patterns with PFS intervals to identify candidate markers associated with response to CDK 4/6 inhibitor therapy. Methods: Pre-treatment diagnostic FFPE biopsy material from 26 individuals enrolled on study were analyzed by an LCM- reverse phase protein array workflow. Quantitative measurements of a focused set of 8 qualifying (pre-hypothesized) protein/phosphoprotein CDK 4/6 kinase pathway biomarkers, total Rb, Rb (S780), total Cyclin D1, Cyclin D1 (S286), total pI6INK, total p27, p27 (T187), FoxM1 (T600) were measured. Results: Baseline tumor tissue was successfully analyzed for 26 pts, 17 (65%) White, 8 (31%) African American, and 1 (4%) Asian; average age 62 (range 36-79); 4 pts (15%) had prior endocrine therapy and 4 (15 %) had chemotherapy in the adjuvant setting. Seven pts remain on study treatment. Unsupervised analysis revealed substantial concordance between a number of the total-phosphoprotein paired biomarkers, with 8/26 (31%) patients having relatively low activation/expression pattern (within the bottom quartile of the data range of the 8 markers) and 6/26 (23%) having relatively high activation/expression pattern within the top quartile of the data range of the 8 markers). Conclusions: Functional CDK 4/6 drug target pathway mapping analysis is possible from the pre-treatment diagnostic FFPE material and revealed sub-populations of patients who had systematically low and high levels of CDK 4/6 kinase substrate proteins and phosphoproteins that indicate overall drug target activity. Correlations of those patterns with PFS outcome data is ongoing with final analysis planned for Summer 2020. Clinical trial information: NCT03195192 .