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Background & Aim: Gene therapies has become recognized for its remarkable clinical benefits in a variety of medical applications, in particular recent approval of an Ad vector-based COVID-19 vaccines have attracted recent global attention. Here, we present key considerations for GMP compliant process development for Coxsackie virus type B3 (CVB3), an oncolytic virus designed for clinical trial in triple-negative breast cancer. Methods, Results & Conclusion(s): CVB3 is a non-enveloped, linear single-strand RNA virus with a size of approximately 27-33 um in diameter. From the initial type using the zonal rotor centrifuge to the advanced type using the tangential flow filtration system and ion chromatograph, we considered the points of the design concept in constructing the manufacturing process. The final design system is constructed as a closed and single-use manufacturing system in which all processes from upstream large-scale cell culture to downstream target purification and concentration steps. In brief, HEK293 cell suspension extended in 3L serum-free medium infected with CVB3, up to 3.6 times 10 to 7 of TCID50 /mL before going to downstream steps, made total 150 mL of final products as 8.43 times 10 to 7 of TCID50/mL concentration. Although further quality control challenges remain that is removal of product-related impurities such as human cellular proteins and residual DNA/RNA to increase virus purity, this concept is effectively applicable even for other types of viruses as GMP manufacturing processes, and would be also important for technology transfer to future commercial production.Copyright © 2023 International Society for Cell & Gene Therapy
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Background Triple-negative breast cancer (TNBC) accounts for ~15% of breast cancer diagnoses but is linked to worse outcomes and comprises a disproportionate number of breast cancer deaths. The TNBC pilot study is a prospective longitudinal study to provide a critical resource for understanding TNBC disease. However, the pandemic impacted the collection of samples. Objective To highlight the impacts of COVID-19 on this longitudinal cancer translational research study including the patient's perspective and to develop recommendations to avoid future disruptions. Methods 389 participants were enrolled in the prospective longitudinal cohort, which collected serial blood samples for up to 5 years. Due to the pandemic, research was curtailed for 6 months due to concerns about patient safety, halting the collection of blood samples. Missed samples and data gaps were documented. To complement this, we initiated a survey capturing the patient perspective on their experience of the study disruption due to COVID. Results 217 enrolled participants missed a blood draw or had a collection outside the study window. 158 patients missed 1 time-point collection, and 59 patients missed >= 2 collections. Of the 217 participants who missed a collection, 6 disease recurrence diagnoses and 3 deaths occurred during research curtailment. The collection of survey responses from participants is ongoing and will be presented at the AACR Annual Meeting. Conclusion Missed samples resulted in irreplaceable data gaps critical to monitoring patient outcomes, and reduced cohort sampling during the pandemic. Our current knowledge of the risks suggests that with proper informed consent, collections could have continued. To mitigate disruption in future clinical studies, clear plans should be part of study design to provide continuity. The participants' experience to be reported will also help researchers understand their issues and help develop policies. (Table Presented).
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Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.
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Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/drug therapy , DNA Damage , Cell Proliferation , Cell Line, Tumor , Oxidative Stress , Apoptosis , Acetylcysteine/pharmacologyABSTRACT
Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2- negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Method(s): PROMETEO (NCT03802604) is a singlearm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 >= 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter >= 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Result(s): Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (>=10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 - 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusion(s): Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the presurgical radiological imaging and the actual surgical pathological report. Pre-operative window-ofopportunity trials in this context might provide important clues regarding the activity of novel treatment strategies.
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Introduction: Triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BC) that is associated with poor prognosis, accounts for 10-15% of all BCs. Chemotherapy remains the standard of care (SOC) for advanced disease, with limited clinical benefit. Oncology clinical trials (CTs) are globally recommended and encouraged as the preferred treatment (tx) option for any cancer patient (pt). 'TrialJectory' (TJ) is an artificial intelligence (AI)-based technology that matches pts to oncology CTs. Here, we identified distinct characteristics of TNBC pts who signed up to the TJ platform compared to non-TNBC pts. Method(s): Using AI and an unsupervised natural language processing approach, the TJ platform clinically matches pts to CTs. Matching is achieved by pt response to an online dynamic questionnaire (www.trialjectory.com) that collects detailed clinical data including clinico-pathologic characteristics, tx history, general health, and comorbidities. Those are compared to the eligibility criteria of available CTs to yield a high-quality actionable matched-trial list. Result(s): Between 1/2020 and 12/2021, out of 9796 BC pts that signed up, 2688 were TNBC pts (27%). There was no significant difference in age at sign-up between TNBC and non-TNBC patients (median age of 57 years vs 58 years, respectively). Consistently with Non-hispanic black (NHB) race prevalence in the different molecular subtypes in the general US population, NHB race had higher signup rate in TNBC compared to non-TNBC (9.95% vs 5.76%, respectively). TNBC pts signed up at a later disease stage compared to non-TNBC pts (19% of TNBC reported having a stage 1 disease compared to 27% of non-TNBC pts, p< 0.001).A significantly higher percentage of pts with advanced/metastatic TNBC signed up to the TJ platform before starting tx compared to non-TNBC patients (34% vs 22%, respectively, p< 0.001). Furthermore, there was a significant difference in the willingness to travel any distance within the US for a matched clinical trial between TNBC and non-TNBC pts (39% vs 34%, respectively, p< 0.001). Conclusion(s): In this study, we found significant differences in the characteristics of TNBC vs non-TNBC pts that have signed up to the TJ platform. There was an up to 2-fold enrichment of TNBC on the TJ platform pts compared to their frequency in the general population. While previous studies do not show a difference in stage distribution between different subtypes, TNBC patients initiated their search for CTs at a higher stage. In addition, advanced TNBC patients started their search earlier in their journey, before starting chemotherapy. This may reflect the lack of effective SOC and possibly, the motivation to avoid the use of chemotherapy. This is also supported by the willingness of TNBC patients to travel farther in order to identify and enroll in a CT compared to non-TNBC pts. Importantly, the motivation of TNBC pts to travel any distance has not been reduced despite the COVID-19 pandemic, reflecting a strong drive of this pt population to enroll in CTs. It also demonstrates that with the right access, diverse patient populations are willing to participate in clinical trials. In sum, TNBC pts are more likely to explore CT options, in the advanced stage setting, earlier in their journey. This study demonstrates the power of TJ platform for clinico-pathologic characterization and diverse pt groups, including their drivers and behavioral choices during their battle with cancer.
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Background In breast cancer, prognosis is marked by histology and stage at diagnosis. Patients presenting with HER-2 positive or triple negative breast (TNBC) often have a worse prognosis. Early detection of breast cancer is mainly based on yearly screening mammograms, which were disrupted during the lockdown stages of the COVID-19 pandemic. In general, underserved populations, especially the Hispanic population often lack access to preventive care due to lack of funding causing delays in access to timely care. The COVID-19 pandemic caused many patients to miss their annual mammogram screening due to lockdown causing subsequent presentation of more advanced cancer. We, therefore, hypothesized that more patients were diagnosed with advanced cancer after lockdown and worse histology in the Hispanic population compared to the non-Hispanic population of San Antonio, Texas. Methods We identified 3 cohorts retrospectively using chart review: Pre-covid-19 era was defined between 2018 to March 2020. Lockdown is defined as a period between April 2020 to December 2020 followed by the post-vaccine era from January 1st 2021 to 2022. Pearson's Chi-squared and logistic regression tests were used to determine the relationship between time, histology at diagnosis and ethnicity. Results More Hispanic patients were found to present with HER2+ disease (OR: 1.65. p-value .047) compared to non-Hispanic women. When looking at presentation of HER2+ disease in the pre-covid-19 era, there was a 15.11% increase in the presentation of HER2+ disease in the post-vaccine era. When looking at the presentation of TNBC disease in women, there was not a significant correlation seen in the lockdown or post-vaccine period in Hispanic compared non-Hispanic women. Other factors such as funding status were associated with TNBC at presentation independently of ethnicity. In the lockdown era, the number of newly diagnosed breast cancer patients reached an all-time low and during the post-vaccine era, the patient numbers are back to the pre-covid era. Conclusion Ethnicity in part played a role in the number of patients presenting with more aggressive histology such as TNBC and Her 2 positive breast cancer in the post-vaccine era. These findings may be secondary to fact that certain ethnic groups are more likely to miss preventive screenings and the covid 19 pandemic lockdown exacerbated this problem. Diagnosis of advance cancer can further deter patients from seeking care due to socioeconomic factors and possibly increase mortality in these populations. These findings suggest that there seems to be a correlation between race and presentation of more aggressive histology caused by the effects of the pandemic in cancer care affecting minorities.
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The proceedings contain 29 papers. The topics discussed include: targeting mutant p53 for the treatment of triple negative breast cancer: a pre-clinical study;senior sign-off in an Irish emergency department: is it feasible?;microfluidic-microwave platforms for real-time, non-invasive and sensitive monitoring of bacteria and antibiotic susceptibility testing;cancer diagnosis using imaging and artificial intelligence applications;enhancing the management of long covid in general practice: a scoping review;feasibility of using a hand-held device to characterize tendon tissue biomechanics;cross sectional study of wristband compliance in St Vincent's University Hospital;man vs machine: do mechanical chest compression devices improve survival outcomes in patients with out-of-hospital cardiac arrest - a systematic review;and investigating the necessity of pediatric emergency medicine in resource limited settings.
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Background: A subgroup of triple negative breast cancer (TNBC) expresses the androgen receptor (AR). In this trial we evaluated the efficacy and tolerability of the AR inhibitor darolutamide (D) or capecitabine (C) in patients (pts) with advanced AR-positive TNBC (NCT03383679). Methods: Pts with centrally reviewed AR-positive (≥ 10% by immunohistochemistry) TNBC treated with up to one line of chemotherapy for advanced disease were eligible. They were randomized in a 2:1 ratio to receive D 600 mg twice daily or C 1000 mg/m2 twice daily 2-weeks on/ 1-week off, until progression or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR) at 16 weeks and was assessed in the eligible population and in the sensitivity analysis population (pts with delayed tumour assessment performed in the context of COVID pandemic). Main secondary endpoints included objective response rate, overall survival, progression-free survival (PFS) and safety. Results: A total of 254 pts from 45 centres were screened;94 pts were randomized (61 in D arm, 33 in C arm) from April 2018 to July 2021. A clinical benefit was observed in D arm in 13 of 53 evaluable pts (CBR at 16 weeks 24.5%;95% CI: 12.9%-36.1%) including 2 PR and 1 CR and in C arm in 11 of 23 evaluable pts (CBR at 16 weeks 47.8%;95% CI: 27.4%-68.2%). In the sensitivity analysis, a clinical benefit was observed in D arm in 17 of 58 evaluable patients (CBR ≥ 16 weeks 29.3%;95% CI: 17.6%-41.0%) and in C arm in 19 of 32 evaluable patients (CBR ≥ 16 weeks 59.4%;95% CI: 42.3%-76.4%). 7 pts presented with drug-related serious adverse events: 3 in D arm and 4 in C arm. In D arm, asthenia (26.7%), nausea (25%) and ASAT increase (21.7%) were the most common adverse events, the majority being grade 1 or 2, similar to previous safety data. Median PFS were 1.8 months (CI 95% 1.7-3.1) and 3.6 months (1.8-9.1) in D arm and C arm respectively. Other secondary endpoints will be presented at the meeting. Conclusions: Despite not reaching the pre-specified CBR, darulotamide demonstrated clinical activity with significant benefit for a group of patients. A research program to identify predictive biomarkers of sensitivity is ongoing. Clinical trial identification: EudraCT: 2017-002284-18 NCT03383679. Legal entity responsible for the study: UNICANCER. Funding: BAYER. Disclosure: All authors have declared no conflicts of interest.
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Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). Anlotinib, a novel multi-target tyrosine kinase inhibitor that effectively inhibits VEGFR, FGFR, c-KIT, c-MET, and RET, monotherapy has been proven effective in HER-2 negative metastatic breast cancer, but its efficacy in early-stage TNBC is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients (pts) with primary TNBC. Methods: Pts with clinical stage II/III TNBC were to be treated with 5 cycles of anlotinib (12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was the total pCR (tpCR;ypT0/is ypN0). A Simon's two-stage optimum design was used, and > 5 of 11 pts were required to achieve tpCR in the first stage, with a pre-specified tpCR rate of 54.5% before proceeding to the second stage. A total of 31 participants was required for the study. Results: Six out of 11 pts achieved tpCR in the first stage, reaching the threshold for the second stage. From Jan 2021 to Jan 2022, a total of 22 pts were enrolled and 12 received surgery after the completion of neoadjuvant therapy, but a total of 2 pts withdrew from the study due to the COVID-19 pandemic or serious adverse events. Of the 22 eligible pts, the median age was 49 years (range, 29-64), 64% were postmenopausal, and 73% were nodal involved. At the time of surgery, 58.3% (7/12) achieved tpCR. Of the 9 pts with the node-positive disease at diagnosis, 88.9% (8/9) became ypN0. The results of FUSCC TNBC classification (IHC-based) revealed the tpCR rates were 57.1% (4/7), 100% (3/3), and 0% (0/2) for BLIS subtype, IM subtype and LAR/unknown subtypes, respectively. Biomarker analysis showed the tpCR rates were 100% (3/3) and 100% (4/4) in patients with gBRCA1 mutation and MYC amplification, respectively. The most common grade 3 or 4 treatment-related adverse events were leucopenia (6/22, 27%), neutropenia (6/22, 27%), anemia (5/22, 23%), decreased appetite (5/22, 23%), hypertension (2/22, 9%), ALT increased (1/22, 5%) and oral mucositis (1/22, 5%). No treatment-related deaths occurred. The trial is ongoing. Conclusions: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and promising antitumor activity for patients with early-stage TNBC.
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Background: As a reaction to the COVID-19 pandemic, a nation-wide lockdown was enforced in Brazil in March 2020, cancer care was impacted, and cancer screening reduced. Therefore, an increase in cancer diagnoses at more advanced stages was expected. In this study, we extracted data from our nationwide real-world database to evaluate the impact of the COVID-19 pandemic on the stage at diagnosis of breast cancer (BC) cases. Methods: We explored curated electronic medical record data of female patients, over 18 years of age, diagnosed with BC and with established disease stage based on the AJCC 8th edition, who started treatment or follow-up in the Oncoclínicas (OC) between Jan 1, 2018, and Dec 31, 2021. The primary objective was to compare stage distribution at first visit during COVID- 19 pandemic (2020-2021) with a historical control cohort from a period prior to the pandemic (2018- 2019). We investigated stage distribution according to age at diagnosis and tumor ER/HER2 subtype in univariate models. Associations were considered significant if they had a minimum significance (P < 0.1 in Chi-square test). The historical numbers of patients with BC at OC make it possible to identify differences in the prevalence of stages in the order of 5% comparing pre and post pandemic periods with a statistical power greater than 80%. Results: We collected data for 11,752 patients with initial diagnosis of BC, with 6,492 patients belonging to the pandemic (2020-2021) and 5,260 patients to the pre-pandemic period (2018-2019). For both ER+/ HER2- and HER2+ tumors, there was a lower percentage of patients with early-stage (defined as stage I-II) in the years 2020-2021 vs 2018-2019 and a considerable increase in advanced-stage disease (defined as stage IV). For triple negative BC (TNBC), there was a significant higher percentage of patients with advanced-stage disease in the pandemic vs pre-pandemic period (table 1). Age over 50 years was associated with a greater risk of advanced stage at diagnosis after the onset of the pandemic, with an absolute increase of 7% (P twosided <0.01). Conclusions: We observed a substantial increase in cases of advanced-stage BC in OC institutions as a result of delays in BC diagnoses due to the COVID-19 pandemic. The impact appeared greater in older adults, potentially because of stricter confinement in this group.
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Background: The COVID-19 pandemic has significantly reduced routinely scheduled in person assessment and examination of early breast cancer patients (EBC). To assess if this is likely to impact the detection of recurrent disease, we reviewed recurrence patterns of EBC patients enrolled in a survivorship program that adheres to ASCO guidelines. Methods: Charts of EBC patients transferred through a single center Wellness Beyond Cancer Program (WBCP) and who subsequently had a breast cancer recurrence between February 1, 2013 and January 1, 2019 were reviewed. Patient, tumor and treatment characteristics were evaluated. Results: Of 206 patients eligible for the current study, 41 patients had ipsilateral breast recurrences (19.9%), 135 had distant recurrences (65.5%) and 30 had contralateral new breast cancers (14.6%). Ipsilateral breast recurrences were detected by the patient in 53.7% (22/41) and by routine imaging in 41.5% (17/21). The majority of distant recurrences (125/135, 92.6%) were detected via patient-reported symptoms. Contralateral breast primaries were detected by patients 16.7% (5/30) or by routine imaging (83.3%, 25/30). Only 2/206 (1.14%) recurrences/new primaries were detected by healthcare providers at routinely scheduled follow-up visits. There was a statistical difference in recurrence detection between image detected vs. self-detected in the following factors: grade 3 (26.5% vs 51%, p < 0.007), triple negative breast cancer (3.9% vs. 15.1%, p = 0.03), HER2 disease (18.4% vs. 9.8%, p = 0.04). Conclusions: Despite following ASCO follow-up guidelines for routinely scheduled follow-up appointments with physical examination, healthcare providers rarely detect recurrence disease. While reduced in person visits may affect other aspects of follow- up (e.g., toxicity management), it appears unlikely, provided patients attend regular screening tests, that reduced in-person follow-up is associated with worse breast cancer-related outcomes during the COVID-19 pandemic.
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The proceedings contain 5148 papers. The topics discussed include: baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer;fertility preservation decisions and outcomes of young women with breast cancer;adjuvant trastuzumab and vinorelbine (TV) for early-stage HER2+ breast cancer;Outcomes of neoadjuvant (NA) and adjuvant (A) chemotherapy in geriatric patients with stage I-III triple-negative breast cancer (TNBC): a single institution experience;Telehealth delivered Tai Chi intervention for managing aromatase inhibitor-induced arthralgia in breast cancer patients: TaiChi4Joint during the COVID-19 pandemic a pilot study;a prospective real-world study to assess the effectiveness and safety of trastuzumab biosimilar in the adjuvant treatment of HER2-positive breast cancer: preliminary safety results;effectiveness of chemotherapy on prognosis of elderly breast cancer: a retrospective cohort study based on SEER database;and prognostic role of the stromal tumor-infiltrating lymphocytes (TILs) in women with early ER+/HER2+ breast cancer (BC) in whom adjuvant chemotherapy (ChT) was omitted.
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Purpose: To explore the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with breast cancer based on type of anticancer treatment. Methods: Patients with breast cancer had anti-spike antibody concentrations measured ⩾14 days after receiving a full SARS-CoV-2 vaccination series. The primary endpoint was IgA/G/M anti-spike antibody concentration. Multiple regression analysis was used to analyze log10-transformed antibody titer concentrations. Results: Between 29 April and 20 July 2021, 233 patients with breast cancer were enrolled, of whom 212 were eligible for the current analysis. Patients who received mRNA-1273 (Moderna) had the highest antibody concentrations [geometric mean concentration (GMC) in log10: 3.0 U/mL], compared to patients who received BNT162b2 (Pfizer) (GMC: 2.6 U/mL) (multiple regression adjusted p = 0.013) and Ad26.COV2.S (Johnson & Johnson/Janssen) (GMC: 2.6 U/mL) (p = 0.071). Patients receiving cytotoxic therapy had a significantly lower antibody titer GMC (2.5 U/mL) compared to patients on no therapy or endocrine therapy alone (3.0 U/mL) (p = 0.005). Patients on targeted therapies (GMC: 2.7 U/mL) also had a numerically lower GMC compared to patients not receiving therapy/on endocrine therapy alone, although this result was not significant (p = 0.364). Among patients who received an additional dose of vaccine (n = 31), 28 demonstrated an increased antibody response that ranged from 0.2 to >4.4 U/ mL. Conclusion: Most patients with breast cancer generate detectable anti-spike antibodies following SARS-CoV-2 vaccination, though systemic treatments and vaccine type impact level of response. Further studies are needed to better understand the clinical implications of different antibody levels, the effectiveness of additional SARS-CoV-2 vaccine doses, and the risk of breakthrough infections among patients with breast cancer.
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Triple-negative breast cancer (TNBC) constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. The development of new TNBC treatment strategies has become an urgent clinical need. Diagnosis and subtyping of TNBC are essential to establish alternative treatments and targeted therapies for every TNBC patient. Chemotherapy, particularly with anthracycline and taxanes, remains the backbone for medical management for both early and metastatic TNBC. More recently, immune checkpoint inhibitors and targeted therapy have revolutionized cancer treatment. Included in the different strategies studied for TNBC treatment is drug repurposing. Despite the numerous medications available, numerous studies in medicinal chemistry are still aimed at the synthesis of new compounds in order to find new antiproliferative agents capable of treating TNBC. Additionally, some supplemental micronutrients, nutraceuticals and functional foods can potentially reduce the risk of developing cancer or can retard the rate of growth and metastases of established malignant diseases. Finally, nanotechnology in medicine, termed nanomedicines, introduces nanoparticles of variable chemistry and architecture for cancer treatment. This review highlights the most recent studies in search of new therapies for the treatment of TNBC, along with nutraceuticals and repositioning of drugs.
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INTRODUCTION An increasing body of evidence demonstrates that the COVID-19 pandemic of 2020 saw large reductions in the number of US patients being diagnosed with a variety of conditions, including cancer. A previous real world evidence study based upon analysis of CMS claims data showed a large drop in cancer diagnoses across multiple solid tumor diseases and evidence suggesting changes in testing behaviors for these patients over the period of maximal lockdown measures to mitigate spread of infection. Further, the drop in patient numbers had not returned to normal once these measures were relaxed by the end of June. Therefore, we decided to examine CMS data for the entire year of 2020 and focus on a single sub-group in breast cancer, TNBC. These patients have poor prognosis and are relatively intensively managed;it was reasoned that changes in management, especially testing behavior, might be more apparent in this group than in breast cancer patients as a whole. METHODS CMS data for 2019-20 were queried using a proprietary business rule for identifying TNBC cases and then subdivided into 2 groups: those who received a treatment under a "J" HCPCS code and those who had not. Office visits, Level IV surgical pathology (SP) and immunohistochemistry (IHC) were defined by appropriate HCPCS codes. Since all PD-L1 testing is covered by HCPCS code 88360, a claim for 88360 was considered indicative of a PD-L1 test. A decrease in the number of patients during the COVID-19 pandemic Swas defined as a ≥ 10% drop for the value in a given month in 2020 compared to the same month in 2019, as a percentage of the 2019 median value. This is termed the "COVID-Dip". RESULTS Data were gathered from a total of 68, 018 patients, 8, 131 with a J code treatment and 59, 887 without. Results of COVID dip analysis are presented in Table 1. Trastuzumab administration showed an overall decline across the entire study period. While IHC for 88360 showed a COVID dip, administration of atezolizumab and pembrolizumab increased across the study period with administration of nivolumab (collectively immuno-oncology, IO, drugs) remaining relatively constant. 47% of patients receiving IO therapy received a presumed PD-L1 test. There was longitudinal variation in the use of chemotherapy agents but no apparent COVID dip in their use. DISCUSSION There were declines both in patient presentation to doctors' offices, as well as diagnostic testing among TNBC patients during the COVID-19 pandemic of 2020 with differences between those receiving chemotherapy under J codes and those not. There was no evidence of decline in use of chemotherapy under J codes. Increased IO use but declines in IHC testing suggest a greater use of off-label prescribing of these drugs during the pandemic. The decline in presentation to doctors' offices and in testing of patients not receiving J code drugs suggests that these patients may experience significant delays in management of their condition with concomitant increases in morbidity and mortality.
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Background: Platinum agents induce DNA crosslinking and cause accumulation of genotoxic stress, which leads to immune activation via IFN-γ signaling, making the combination with nivolumab (PD-1 antibody) an attractive strategy to enhance the benefit of either agent alone in metastatic triple-negative breast cancer (mTNBC). Methods: In this phase II open-label, investigator-initiated, multicenter trial, patients with unresectable locally advanced or mTNBC treated with 0-1 prior lines of chemotherapy in the metastatic setting were randomized 1:1 to carboplatin (AUC 6) with or without nivolumab (360 mg) IV every 3 weeks. Stratification factors included: germline BRCA (gBRCA) status, prior neo/adjuvant platinum, and number of prior lines of metastatic therapy. After approval of PD-L1 inhibition for mTNBC, the study was amended to include first-line mTNBC only and PD-L1 status was added as a stratification factor. Patients randomized to carboplatin alone were allowed to crossover at progression to receive nivolumab (+ nab-paclitaxel post-amendment). The primary objective was to compare progression-free survival (PFS) per RECIST 1.1 criteria of carboplatin with or without nivolumab in first-line mTNBC in the S intent-to-treat (ITT) population. Key secondary objectives were objective response rate (ORR), overall survival (OS), clinical benefit rate, and duration and time to objective response. PD-L1 status was confirmed centrally using the SP142 Ventana assay (positive, ≥1% IC). Paired researchbiopsies at baseline, on-treatment and at progression were performed, if safely accessible. The trial closed to accrual prior to reaching target accrual due to approval of PD-1 inhibition in combination with platinum-based chemotherapy for PD-L1+ mTNBC. Results: Between 1/30/2018 and 12/9/2020, 78 patients enrolled. Three patients did not receive protocol treatment, and the safety analysis was conducted among the 75 that received any treatment;37 received carboplatin + nivolumab (Arm A), 38 received carboplatin alone (Arm B). Median age was 59.1 yrs (range: 25.4-75.8). Four patients (5.3%) had a known gBRCA1/2 mutation. Sixty-two (82.7%) patients received 0 prior lines (ITT population) and 13 (17.3%) 1 prior line of metastatic therapy. Sixty-seven patients (89.3%) experienced any grade ≥2 treatment-related adverse event (AE). The most frequent AE were platelet count decrease (n=40;53.3%), anemia (n=36;48.0%), neutrophil count decrease (n=33;44.0%) and fatigue (n=24;32.0%). Grade 3/4 AE were observed in 46 (61.3%) patients, and there was one grade 5 AE (COVID19 pneumonia). Any grade ≥2 immune-related AE (irAE) were observed in 25 of the 37 (67.6%) patients treated with carboplatin + nivolumab. Grade 3/4 irAE were observed in 11 (29.7%) patients. In the ITT population (32 on Arm A;30 on Arm B), median PFS was 4.2 months with carboplatin + nivolumab, and 5.5 months with carboplatin (stratified HR 0.98, 95% CI [0.51-1.88];p=0.95). ORR was 25% vs. 23.3%, respectively. At a median follow-up of 23.5 months, median OS was 17.5 months vs. 10.7 months (stratified HR 0.63, 95% CI [0.32-1.24];p=0.18). In patients with PD-L1+ mTNBC (13 on Arm A;11 on Arm B), median PFS was 8.3 months and 4.7 months, respectively (stratified HR 0.63, 95% CI [0.21-1.89];p=0.41). ORR was 23.1% vs. 27.3%, respectively. Median OS was 17.5 months vs. 9.6 months (stratified HR 0.59, 95% CI [0.20-1.75];p=0.34). Conclusions: Addition of nivolumab to carboplatin in patients with previously untreated mTNBC, unselected by PD-L1 status, did not significantly improve PFS. A trend toward improved PFS and OS was observed in patients with PD-L1+ mTNBC. Tissue, blood and intestinal microbiome biomarker analyses are planned;bulk tumor and single-cell sequencing, and TCR sequencing in peripheral blood are ongoing.
ABSTRACT
The value of genetic counseling and testing to cancer prevention, early detection, and treatment options to ensure optimal outcomes is widely acknowledged by providers, payers and patients. However, many individuals who should receive genetic counseling are never offered this service. All patients with early onset (<=age 45), triple negative (<=60) and metastatic HER2 negative breast cancer should be offered genetic counseling and testing (GC/GT) per National Comprehensive Cancer Network guidelines. A quality improvement project to actively identify and offer genetic counseling to all women with early onset, triple negative and metastatic breast cancer was implemented. Baseline information on the number of early onset (<=45), triple negative and metastatic HER2 negative breast cancers diagnosed January 2018-June 2019 was collected and cross-referenced with the Cancer Genetics Risk Assessment patient database and the electronic health record (EHR) to see how many had GC/GT in our department or the breast surgeons' office. We developed questions for an electronic screening tool used by the navigation team when meeting with patients for the first time, screening for personal or family history criteria that would flag patients at increased risk for hereditary cancer. If any questions were flagged, the patient was asked by the navigator if they would be interested in a genetic counseling appointment to consider genetic Stesting. Training was provided to the navigation team so that they could answer basic questions, biweekly meetings were set up to discuss patients, and a flier and informational videos were made available to patients who wanted more information about GC/GT. If a patient was agreeable to genetic counseling, an automated email was triggered to the genetics team, who contacted the patient for an appointment. A standing order was obtained from willing breast surgeons and oncologists within our network to streamline the referral process. In the 18-month baseline period, there were 126 patients diagnosed with early onset, 36 with triple negative <=60 and 30 with metastatic HER2 negative breast cancer. Of these, 57.1% of early onset, 66.7% triple negative and 3.3% of those with metastatic breast cancer had documentation of GC/GT. A paper screening tool was implemented in July 2019 with implementation of an electronic version in November 2019. In the 18-month intervention period, there were 100 patients diagnosed with early onset, 39 with triple negative and 22 patients with metastatic breast cancer. Of these, 86% of early onset, 87.2% of triple negative and 31.8% of metastatic breast cancer patients had documented GC/GT.A limitation of this project is that some patients leave the system to be treated elsewhere after diagnosis and some may have been tested in their private practitioner's office that does not connect with our EHR. Additionally, some may have been offered GC/GT but declined or were unwilling/unable to complete an appointment. Finally, the pandemic likely had an impact on this project, since fewer women were undergoing mammography screening due to COVID-19 restrictions, resulting in fewer diagnoses of breast cancer. By leveraging the navigation team's interaction with breast cancer patients, we were able to improve identification and referral of more patients with early onset, triple negative <=60 and metastatic HER2 negative breast cancer for GC/GT. One barrier to genetic counseling that has been previously identified is a lack of physician referral. Active engagement with a breast navigator can circumvent this barrier. De-identified aggregate data from this quality improvement project was shared with the Association for Community Cancer Centers as part of a larger project, supported by a grant from Pfizer.
ABSTRACT
Background Detection of circulating tumour DNA (ctDNA) in patients (pts) who have completed treatment for early-stage triple negative breast cancer (TNBC) is associated with a very high risk of future relapse. Identifiying those at high risk of subsequent relapse may allow tailoring of further therapy to delay or prevent recurrence. The c-TRAK TN trial assessed the utility of prospective ctDNA surveillance in pts treated for TNBC and the activity of pembrolizumab (P) in pts with ctDNA detected. Methods c-TRAK TN, a multi-centre phase II trial with integrated prospective screening component, enrolled pts with early-stage TNBC and either residual disease following neoadjuvant chemotherapy, or tumour size >20mm and/or axillary lymph node involvement if adjuvant chemotherapy was given. Tumour tissue was sequenced to identify somatic mutations suitable for tracking using personalised digital PCR ctDNA assays (BioRad QX200). Pts had "active" ctDNA surveillance via blood sample testing every 3 months to 12 months (potential up to 18 months if S samples missed due to COVID) during which time if ctDNA was detected (ctDNA+) pts could be randomised 2:1 to P (200mg i.v. q 3 weeks for 1 year) or observation (Obs). Pts and clinicians were blinded to ctDNA+ results unless they were allocated P, when staging scans were done and those free of clinical recurrence started treatment. Following advice from the Independent Data Monitoring Committee, the Obs arm closed on 16/06/2020 with all subsequent ctDNA+ pts allocated P. Following the completion of active ctDNA surveillance, 3-monthly visits continued to 24 months to be analysed retrospectively. The aim was to recruit 150 pts to ctDNA surveillance, assuming 30% would be ctDNA+ within 12 months, allowing ctDNA+ rate to be estimated with a 2-sided 95%CI of +/-7.3%. Co-primary endpoints are i) rates of ctDNA detection by 12 and 24 months from start of ctDNA surveillance;ii) rates of sustained ctDNA clearance on P defined as absence of detectable ctDNA, or disease recurrence 6 months after starting P. Results 208 pts were registered between 30/01/18 and 06/12/19, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. The rate of ctDNA detection by 12 months after start of surveillance was 27.3% (44/161, 95% CI 20.6-34.9). ctDNA+ rates from baseline, 3, 6, 9 and 12 month ctDNA samples were 23/161 (14.3%), 6/115 (5.2%), 6/99 (5.1%), 7/84 (8.3%), and 2/84 (2.4%) respectively. An additional 2 pts were ctDNA+ on COVID extended active surveillance at 15 (1/51, 2%) or 18 months (1/11, 9%). 7 pts relapsed without prior ctDNA detection. 45 pts entered the therapeutic component of the trial (initially 31 to P and 14 to Obs). 1 Obs pt was re-allocated to P. Of pts allocated to P, 72% (23/32) had metastatic disease at time of ctDNA detection on staging scans (75% (12/16) who were ctDNA+ at baseline and 69% (11/16) at other timepoints). 4 pts declined to start P, largely due to COVID concerns. Of the 5 pts who commenced P, at the time of analysis none achieved sustained ctDNA clearance and 4 had recurred. In pts allocated to Obs, median time to recurrence was 4.1 months (95% CI: 3.2-not-defined). Conclusion The c-TRAK TN trial is to our knowledge the first study to assess the proof-of-principle of whether ctDNA assays have clinical utility in guiding further therapy in TNBC. Relatively few pts commenced P treatment precluding assessment of potential activity. At enrollment, patients had a relatively high of rate of undiagnosed metastatic disease when imaged. Our findings have implications for future trial design, emphasizing the importance of early start of ctDNA testing, and more sensitive and/or more frequent ctDNA testing regimes.
ABSTRACT
Neoadjuvant treatment (NAT) has become a standard treatment in locally advanced breast cancer and an option in early stage (stage I–II) breast cancer (EBC). It is known that patients who achieve a pathologic complete response (pCR) have better long-term out comes, especially Her2 positive and triple negative (TN) breast cancer. Selection of patients for NAT in early stage breast cancer rely in several factors, as patient characteristics (i.e., age and comorbid ities), tumor histology, stage at diagnosis and the potential changes in surgical or adjuvant treatments when NAT is administered. Early stage breast cancer patients that are not candidates for breast conservative surgery (BCS) at front, may benefit from NAT to reduce tumor size and facilitate surgery. In other cases, as young patients with TN tumors between 1–2 cm may benefit from NAT, even if BCS can be performed up front, as chemotherapy will be given anyway along the treatment and there is a high likelihood of pCR. Patients with a positive axilla at diagnosis, regardless of tumor size, may also benefit from less axillary surgery if axillary pCR is achieved. Rates of axillary pCR are especially high in TN and Her2 positive tumors. A distinct approach is suggested in luminal tumors subtypes. In these patients, besides the factors already mentioned, intensity of hormone receptor expression would help to decide on neoadjuvant hormone or chemotherapy treatment. Immunohistochemistry differentiation between luminal A and B by Ki67 assessment and in some cases, the use of genomic platforms may help defining type of NAT. Assessing breast cancer patients for NAT include incorporating all factors into the decision making process. In the COVID era, we have witnessed the use of NAT in patients who may be directed to surgery, unable to have it performed, as surgery has been reserved for emergency cases only. In this situation, it has been a great challenge managing breast cancer patients and tailoring individualized treatment decisions. Besides physical examination, breast imaging is performed to assess extent of disease and to determine BCS eligibility before NAT. Breast imaging should include mammogram with tomosynthesis, breast and axillary US and in most of cases MRI. MRI may be omitted in S12 Speakers’ s / The Breast 56S1 (2021) S1–S16 selected cases (i.e. fatty breasts, neoadjuvant hormone therapy). Contrast enhanced mammogram is an emerging technique, whether it will add accuracy to the MRI findings or replace it in selected cases is still to be defined. Shear wave elastography is under investigation for assessment of response to neoadjuvant therapy as well as for predicting response. Generally, in EBC no further body imaging (CT or bone scan) is needed unless metastatic disease is suspected. PET scan is reserved for patients with inconclusive metastatic dissemination or with more advanced disease. Pathology confirmation by core biopsy and evaluation of estrogen and progesterone receptor, Her2, and Ki67 must be obtained before treatment. Axillary US will characterize axillary lymph nodes and will guide biopsy of axillary nodes. If planning NAT, markers need to be placed in breast tumor/s and in biopsy proven positive axillary node. Same breast imaging should be repeated after NAT to assess response and to determine type of breast and axillary surgery. Sentinel lymph node biopsy after NAT is the preferred method. After NAT, surgical plan is delineated taking into account baseline characteristics, tumor response and patient desire. Conflict of Interest: Honoraria: Agendia. Advisory Board: Sirius medical.