scholarly journals Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Douglas Yee ◽  
Claudine Isaacs ◽  
Denise M. Wolf ◽  
Christina Yau ◽  
Paul Haluska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Complete Response ◽  
Type I ◽  
Drug Induced ◽  
Phase 2 Clinical Trial

AbstractI-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer

2018 ◽  
Vol 36 (10) ◽  
pp. 968-974 ◽  
Author(s):  
Xavier Pivot ◽  
Igor Bondarenko ◽  
Zbigniew Nowecki ◽  
Mikhail Dvorkin ◽  
Ekaterina Trishkina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Adverse Event ◽  
Growth Factor ◽  
Response Rate ◽  
Pathologic Complete Response ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Phase Iii ◽  
Epidermal Growth

Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2–positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.

Association of NBS1 expression with improved pathologic complete response rate in HER2-overexpressing breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11534-e11534
Author(s):  
Fatma Sen ◽  
Ekrem Yavuz ◽  
Gulcin Yegen ◽  
Hasan Karanlik ◽  
Sitki Tuzlali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Response Rate ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Protein Loss ◽  
Paraffin Sections ◽  
Her2 Breast Cancer

e11534 Background: Our aim was to investigate potential correlation between expression levels of Nijmegen breakage syndrome1 (NBS1) protein and phosphatidylinositol-3 kinase (PI3K) and pathologic complete response (pCR) rate to neoadjuvant treatment in locally advanced HER2+ breast cancer. We also assess possible association between NBS1 and PI3K expressions. Methods: Totally 42 patients (median age 49 years), received neoadjuvant treatment due to locally advanced HER2+ breast cancer, were included. Immunohistochemical analyses were performed on paraffin sections, obtained during initial diagnosis. Paraffin sections were stained with anti-NBS1 (P95-NBS1 antibody, Y112, ab32074) and anti-PI3K (PI3-Kinase p85 alpha+gamma antibody, ab741369) antibodies to determine positivity of related proteins. Results: NBS1 protein loss was detected in 19 (%45) patients whereas p85 loss was shown in 25 (%60). There was no initial clinicopathologic variable predicting pCR. Fifteen of 30 patients, received neoadjuvant trastuzumab, had pCR, whereas only 1 of 12 patients, not received trastuzumab, achieved pCR (P = 0.012). p85 loss did not predict treatment response, however NBS1 protein expression positively correlated with increased response rate to neoadjuvant treatment (P = 0.007). Conclusions: NBS1 protein expression associates with increased pCR rate in HER2+ breast cancer. However, P85 positivity did not associate with pCR rate or NBS1 overexpression.

Impact of dual anti-HER2 therapy on pathologic complete response rate in breast cancer in a minority-enriched population.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18111-e18111 ◽  
Author(s):  
Jenny Jing Li ◽  
Hsiao Ching Li ◽  
Ang Gao ◽  
Samira K. Syed ◽  
Nisha Unni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Complete Response Rate ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Safety Net ◽  
Her2 Breast Cancer ◽  
Race Ethnicity ◽  
Pathologic Complete Response Rate ◽  
Racial Ethnic

e18111 Background: The addition of pertuzumab (P) to a neoadjuvant trastuzumab (H) plus chemotherapy combination has been shown to significantly improve the pathologic complete response rate (pCR) in localized HER2+ breast cancer; however, minorities have been under-represented in these trials. Racial/ethnic disparities have also been shown to affect outcomes of cancer treatment. This study is aimed to assess the impact of neoadjuvant dual HER2-blockade in an unselected minority-enriched population. Methods: A retrospective chart review was conducted of women with stage I to III HER2+ breast cancer who received neoadjuvant treatment between 2007 and 2017 at an academic institution and its affiliated safety net health system. Data on stage, chemotherapy, race/ethnicity, site of therapy (academic vs safety net hospital), and hormone receptor status were collected. All patients underwent surgery after completion of neoadjuvant chemotherapy. pCR was defined as ypT0/is, ypN0. Chi-squared test and univariate/multivariate logistic regression were used for statistical analysis. Results: The study population included 261 women with the following race/ethnic distribution: 37.7% Non-Hispanic Whites, 34.6% Hispanics, 20.6% Blacks, and 7% other racial/ethnic origin. Ninety-five patients (36%) received chemotherapy-H vs 166 patients (64%) received chemotherapy-HP. Patients at the safety net health system had higher stage at diagnosis compared to the academic site. Site of care and race/ethnicity did not impact the choice of neoadjuvant treatment. The pCR rate was significantly higher for the chemotherapy-HP group (55.4%) compared to the chemotherapy-H group (34.7%) (p = 0.001). There was no association between race/ethnicity, or site of treatment (academic vs safety net), and the probability of achieving pCR. Multivariate analysis showed only dual anti-HER2 therapy (OR: 2.67, CI: 1.55-4.59, p = 0.0004) and hormone-receptor negative status (OR: 2.18, CI: 1.30-3.67, p = 0.0031) to correlate with pCR. Conclusions: Neoadjuvant dual anti-HER2 therapy was more likely to result in a pCR in our minority enriched population. Our data also suggests the combination of chemotherapy-HP confers similar benefit irrespective of race/ethnicity or site of care.

PrE0807 phase Ib feasibility trial of neoadjuvant nivolumab (N)/lirilumab (L) in cisplatin-ineligible muscle-invasive bladder cancer (BC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4594-TPS4594
Author(s):  
Petros Grivas ◽  
Maneka Puligandla ◽  
Suzanne Cole ◽  
Kevin Dale Courtney ◽  
Robert Dreicer ◽  
...  
Keyword(s):  
Type I Error ◽  
Single Agent ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Upper Urinary Tract ◽  
Feasibility Trial ◽  
Type I ◽  
Phase Ii Trials ◽  
Phase Ib

TPS4594 Background: Neoadjuvant cisplatin-based chemotherapy before radical cystectomy (RC) improves outcomes but ~50% of patients (pts) are cisplatin-unfit. Anti-PD(L)1 agents can prolong overall survival (OS) in platinum-resistant advanced BC and have shown high pathologic complete response rate (pCR) and safety as single agent in phase II trials in the neoadjuvant setting. The combination of anti-PD-1 and anti-KIR agents is feasible and very attractive based on complementary and non-overlapping roles in regulating adaptive and innate immune response as well as impacting the function CD8+ T and NK-cells. Higher CD8+ T cell density (TCD) at RC tissue correlates with longer OS. We hypothesize, that combining anti-PD1 (N) with anti-KIR (L) is safe and feasible as neoadjuvant therapy in cisplatin-unfit pts and results in high CD8+ TCD at RC. Methods: Phase Ib multi-institutional trial evaluating 2 doses (4 weeks apart) of N alone or N+L in 2 cohorts; pts will be assigned sequentially to N (Cohort 1), and if there is no negative safety signal after the first 12 pts, subsequent pts will be assigned to N+L (Cohort 2). Key eligibility: cT2-4aN0-1M0 stage, ≥20% tumor at TURBT, adequate organ function, no autoimmune disease within 2 years, no concurrent invasive upper urinary tract carcinoma or other active cancer. Primary endpoint: safety based on CTCAE v5.0 measured as the rate of ≥G3 treatment related adverse events (AE). Key secondary endpoints: CD8+ TCD absolute and % change between TURBT and RC, % of pts who do not get RC within 6 weeks after neoadjuvant treatment due to treatment-related AE, % pCR, recurrence-free survival, and evaluation of biomarkers in tumor tissue, blood, urine. Rates of ≥Grade 3 AE with neoadjuvant treatment will be reported along with 90% exact binomial CI. In Cohort 1, maximum CI width is 0.51; in Cohort 2, it is 0.36. Our hypothesis is that the change in CD8+ TCD between TURBT and RC will be about 3 CD8+ T cells / 100 tumor cells within HPF. Up to 43 pts will be enrolled for 36 eligible, treated pts (12:N, 24:N+L). Cohort 1 and 2 have 81% and 98% power, respectively, to detect the hypothesized difference with 1-sided type I error rate of 0.05. Trial is open to accrual in US. Clinical trial information: NCT03532451.

Pathologic Complete Response With Six Compared With Three Cycles of Neoadjuvant Epirubicin Plus Docetaxel and Granulocyte Colony-Stimulating Factor in Operable Breast Cancer: Results of ABCSG-14

2007 ◽  
Vol 25 (15) ◽  
pp. 2012-2018 ◽  
Author(s):  
Günther G. Steger ◽  
Arik Galid ◽  
Michael Gnant ◽  
Brigitte Mlineritsch ◽  
Alois Lang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Breast Conserving Surgery ◽  
Operable Breast Cancer ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

Purpose Preoperative (neoadjuvant) chemotherapy for operable breast cancer downstages tumors initially not suitable for breast-conserving surgery. A pathologic complete response (pCR) to neoadjuvant chemotherapy may be a surrogate for longer overall survival, but this beneficial effect remains to be established. This phase III trial evaluated whether doubling the number of cycles of neoadjuvant treatment increased the pCR rate. Patients and Methods Patients with biopsy-proven breast cancer (T1-4a-c, N±, M0; stage I to III) were eligible and randomly assigned to either three or six cycles of epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 and granulocyte colony-stimulating factor on days 3 through 10 (ED+G), every 21 days. The primary end point was the pCR rate of the breast tumor. Secondary end points were pathologic nodal status after surgery and the rate of breast-conserving surgery. Results A total of 292 patients were accrued, and 288 patients were assessable for efficacy and safety. Groups were well balanced for known prognostic factors. Six cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, respectively; P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, respectively; P = .02), and a trend towards more breast-conserving surgery (75.9% v 66.9%, respectively; P = .10). Rates of adverse events were similar, and no patients died on treatment. Conclusion Doubling the number of neoadjuvant ED+G cycles from three to six results in higher rates of pCR and negative axillary nodal status with no excess of adverse effects. Thus, six cycles of ED+G should be the standard neoadjuvant treatment for operable breast cancer if this combination is chosen.

Neoadjuvant and Adjuvant Therapy for HER2 Positive Disease

2015 ◽  
pp. e41-e48 ◽  
Author(s):  
Stephen K. Chia
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Complete Response ◽  
Her2 Positive ◽  
Poor Prognostic Factor ◽  
Her Family ◽  
Clinically Significant ◽  
Initial Description ◽  
American Society

Since the initial description of the HER2 proto-oncogene as a poor prognostic factor in breast cancer in 1987, to the first randomized trial of a monoclonal antibody directed against HER2 in combination with chemotherapy for the treatment of metastatic HER2-positive breast cancer published in 2001, to the American Society of Clinical Oncology (ASCO) 2005 Annual Meeting in which we saw the unprecedented collective presentations demonstrating the dramatic benefit of trastuzumab in the adjuvant setting—the clinical landscape of HER2-overexpressing breast cancer has forever changed. More recently, there has been increasing use of preoperative chemotherapy and anti-HER2 targeted therapies in primary operable HER2 disease in the research domain and in clinical practice. In the next few years, we will see if dual adjuvant anti-HER2 antibody inhibition produces clinically significant improvements in outcome; understand if there is a role of small molecule inhibitors of the HER family of receptors either in combination or sequential to trastuzumab; further refine the relationship between pathologic complete response (pCR) and long-term clinical outcomes; and find predictive biomarkers to identify cohorts of patients that may need differential combinations and/or durations of anti-HER2 therapies.

scholarly journals Neoadjuvant zoledronic acid for HER2-positive breast cancer: the Zo-NAnTax trial

2019 ◽  
Vol 11 ◽  
pp. 175883591985397 ◽  
Author(s):  
Susanne Crocamo ◽  
Renata Binato ◽  
Bruno de Paula ◽  
Giselle Vignal ◽  
Lídia Magalhães ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Zoledronic Acid ◽  
Mevalonate Pathway ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Grade 3 ◽  
Positive Breast Cancer

Background: Preclinical evidence suggests that zoledronic acid (ZOL) works synergistically with chemotherapy by enhancing anti-tumor activity. ZOL blocks the mevalonate pathway and may indirectly interact with human epidermal growth factor receptor 2 (HER2) pathway activation. The clinical efficacy and biological rationale of chemotherapy plus anti-HER2 therapy and ZOL as a part of neoadjuvant therapy has not been previously tested. Patients and methods: We conducted a phase II clinical trial to evaluate the efficacy and safety of ZOL as part of a neoadjuvant treatment in patients with HER2-positive breast cancer (BC). The protocol consisted of four cycles of doxorubicin/cyclophosphamide with ZOL, followed by four cycles of docetaxel with trastuzumab and ZOL prior to surgery. The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints were safety and the identification of clinicopathological characteristics associated with pCR. Results: A total of 71 patients with stage IIA to IIIB BC were included, with 60 eligible for the safety assessment and 58 for the efficacy analysis. Overall, the pCR rate was 42%, with higher rates in hormone receptor (HR)-positive tumors (40%), which contrasts with the results of pivotal trials. The most commonly observed grade 3 and 4 events were febrile neutropenia (grade 3, 20%; grade 4, 3%) and diarrhea (grade 3, 12%). Conclusions: The addition of ZOL as a repositioning drug in neoadjuvant treatment was an effective and well-tolerated therapy. This drug combination might overcome endocrine and anti-HER2 resistance. The higher pCR rates in the HR-positive subgroup deserve further translational investigation.

Circulating Biomarkers for Response Prediction of Rectal Cancer to Neoadjuvant Chemoradiotherapy

2020 ◽  
Vol 27 (25) ◽  
pp. 4274-4294 ◽  
Author(s):  
Chiara Bedin ◽  
Sara Crotti ◽  
Edoardo D’Angelo ◽  
Sara D’Aronco ◽  
Salvatore Pucciarelli ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Clinical Benefit ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Neoadjuvant Chemoradiotherapy ◽  
Treatment Protocol ◽  
Predictive Biomarkers ◽  
Complete Response ◽  
Tumour Regression

: Rectal cancer response to neoadjuvant Chemoradiotherapy (pCRT) is highly variable. In fact, it has been estimated that only about 21 % of patients show pathologic Complete Response (pCR) after therapy, while in most of the patients a partial or incomplete tumour regression is observed. Consequently, patients with a priori chemoradioresistant tumour should not receive the treatment, which is associated with substantial adverse effects and does not guarantee any clinical benefit. For Locally Advanced Rectal Cancer Patients (LARC), a standardized neoadjuvant treatment protocol is applied, the identification and the usefulness of prognostic or predictive biomarkers can improve the antitumoural treatment strategy, modifying the sequence, dose, and combination of radiotherapy, chemotherapy and surgical resection. : For these reasons, a growing number of studies are actually focussed on the discovery and investigation of new predictive biomarkers of response to pCRT. In this review, we have selected the most recent literature (2012-2017) regarding the employment of blood-based biomarkers potentially predicting pCR in LARC patients and we have critically discussed them to highlight their real clinical benefit and the current limitations of the proposed methodological approaches.

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