Breaking Research News from sources other than Breastcancer.org
Comments
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Burden of Pre-, Postmenopausal Breast Cancer Up Worldwide
Countries with very high HDI have highest pre- and postmenopausal breast cancer incidence
- HealthDay TUESDAY, July 28, 2020 (HealthDay News) -- There is evidence of an increasing burden of premenopausal and postmenopausal breast cancer worldwide, according to a study published in the August issue of The Lancet Global Health.Emily Heer, from Alberta Health Services in Calgary, Canada, and colleagues conducted a population-based analysis of global breast cancer incidence and mortality among premenopausal and postmenopausal women.The researchers found that in 2018, about 645,000 premenopausal and 1.4 million postmenopausal breast cancer cases were diagnosed worldwide; in each menopausal group, there were more than 130,000 and 490,000 deaths, respectively. Compared with higher-income countries, countries with a low United Nations Development Programme human development index (HDI) faced a greater burden of premenopausal breast cancer for both new cases and deaths. The highest premenopausal and postmenopausal breast cancer incidence was seen for countries with a very high HDI (30.6 and 253.6 cases per 100,000, respectively), while the highest premenopausal and postmenopausal mortality was seen for countries with low and medium HDI (8.5 and 53.3 deaths per 100,000, respectively). Significantly increasing age-standardized incidence rates were seen for premenopausal and postmenopausal breast cancer in 20 and 24 of 44 populations, respectively. Growth exclusively at premenopausal ages mainly occurred in high-income countries, while in countries under transition, the increasing premenopausal breast cancer burden was most notable."Our study provides evidence of a rising burden of both premenopausal and postmenopausal breast cancer worldwide and wide inequities in breast cancer care," the authors write.https://www.practiceupdate.com/C/104327/56?elsca1=emc_enews_topic-alerthttps://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30215-1/fulltextDOI:https://doi.org/10.1016/S2214-109X(20)30215-1Related editorial: https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30307-7/fulltextDOI:https://doi.org/10.1016/S2214-109X(20)30307-7
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Metastatic Breast Cancer and Pseudocirrhosis
- ESMO open In this retrospective study of 48 women with metastatic breast cancer to the liver, the authors analyzed patient characteristics and assessed the prevalence of complications associated with decompensated cirrhosis. There was a trend toward more patients with luminal cancer in this sample compared with the hospital cancer registry. Of these patients, 47 had widespread liver invasion and 28 had ascites, including 18 with ascites classified as transudate. Esophageal varices were observed in 11 patients, with 3 experiencing rupture. Cisplatin and 5-fluorouracil were most frequently used at the time of liver contour abnormality appearance. Approximately half of the patients achieved a partial response.These findings suggest that pseudocirrhosis develops at the expense of a substantial burden of liver disease and commonly with 5-fluorouracil, with or without cisplatin, and may follow treatment response.
Commentary by Lillie D Shockney RN, BS, MAS, ONN-CGA subset of metastatic breast cancer patients may manifest pseudocirrhosis; however, we would need to know if all radiologists report this finding. Radiologists commonly measure the increase in the size of known lesions in the liver or report new lesions; however, they might not be noting this additional anatomic finding.0 -
JoynerL: Thanks for sharing that about checking your Foundation One test info from 2019. That is also really interesting that "this drug works most specifically to fusions rather than other modifications." I would not have realized that from what I read in the prior article.
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Independent Prognostic Factors and Treatment Modality Associated With Survival and Recurrence in Breast Cancer
JAMA Network Open
- The authors of this study of 956 women with invasive breast cancer evaluated the independent prognostic performance of various clinical and molecular variables (age, tumor size, nodal status, high tumor grade, p53 status, estrogen receptor status, ERBB status) by specific treatment.
- The performance of these factors was weighted by the specific treatment and outcome category.
Published: July 9, 2020. doi:10.1001/jamanetworkopen.2020.7213{Kind of technical. If you like parsing this minutia, this may be of interest. Open access to article.}0 -
BevJen - thank you for explanation.
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Bev-Jen, thanks for that article. I guess that would be a one-shot treatment, wow, if effective, that is a game changer for HER-2. No more being tied to every-three-weeks-at-the-cancer-center.
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Olma.
Yes, it sounds very interesting. Hopefully they will get good results from the trial.
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Moth, thanks for the heads up on the Research Gate link. Your grateful neighbor to the south salutes you.
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Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer
Purpose
To determine the significant genomic alterations in patients with metastatic breast cancer (MBC) and survival outcomes in common genotypes.
Patients and MethodsHigh-depth next-generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 with estrogen receptor/progesterone receptor–positive and human epidermal growth factor receptor 2 (HER2 [hormone receptor positive (HR+)])–positive, 32 with HER2-positive, and 60 with triple-negative (estrogen receptor/progesterone receptor–negative and HER2-negative) disease. Kaplan-Meier survival analysis was performed in the discovery set, in patients with breast cancer analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing.
ResultsSignificantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was an SMG in all three subtypes. The most SMGs in patients with HR+ cancer were PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P = .004), progression-free survival (P < .001), and overall survival (P = .003). Furthermore, TP53 status was prognostic among patients with HR+ cancer with PIK3CA mutations. TP53 mutations were associated with poorer overall survival in the 442 patients with HR+ breast cancer analyzed in The Cancer Genome Atlas (P = .042) and in an independent set of 96 patients with HR+ MBC who underwent clinical sequencing (P < .001).
ConclusionSignificantly mutated genes (SMGs) differ by tumor subtype, but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer and should be considered in the design and interpretation of precision oncology trials.
Other points of interest:
GATA3 alterations were mutually exclusive with TP53 alterations.
The authors concluded that HR+ tumors with TP53 mutations are mostly aromatase inhibitor resistant and would be more appropriately treated with other modalities. However, we do not know whether other regimens would be more effective for these tumors or whether TP53 mutations would equally confer resistance to other agents.
https://ascopubs.org/doi/10.1200/PO.17.00245
DOI: 10.1200/PO.17.00245 JCO Precision Oncology - published online April 25, 2018
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Four-stranded DNA structures found to play role in breast cancer
...These structures form in regions of DNA that are rich in one of its building blocks, guanine (G), when a single strand of the double-stranded DNA loops out and doubles back on itself, forming a four-stranded 'handle' in the genome. As a result, these structures are called G-quadruplexes...
During the process of DNA replication and cell division that occurs in cancer, large regions of the genome can be erroneously duplicated several times leading to so-called copy number aberrations (CNAs). The researchers found that G-quadruplexes are prevalent within these CNAs, particularly within genes and genetic regions that play an active role in transcription and hence in driving the tumour's growth.
..."The abundance and location of G-quadruplexes in these biopsies gives us a clue to their importance in cancer biology and to the heterogeneity of these breast cancers," added Dr Robert Hänsel-Hertsch who is now at the Center for Molecular Medicine Cologne, University of Cologne, and is first author on the publication.
"Importantly, it highlights another potential weak spot that we might use against the breast tumour to develop better treatments for our patients."
...By targeting the G-quadruplexes with synthetic molecules, it may be possible to prevent cells from replicating their DNA and so block cell division, halting the runaway cell proliferation at the root of cancer. The team identified two such molecules - one known as pyridostatin and a second compound, CX-5461, which has previously been tested in a phase I trial against BRCA2-deficient breast cancer.
https://www.eurekalert.org/pub_releases/2020-08/uoc-fds073120.php
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The 'Dynamic Space' of HER2 Breast Cancer Treatment Strategies
More evident than ever that one-size-fits-all approach is less likely to work
A review by Danielle File, MD, and colleagues in the ASCO Educational Book highlights the recent advances in treatment and discusses how the clinical landscape is shifting toward tailored therapies based on disease characteristics and biomarkers.
Early stage HER2 breast cancer treatment strategies have proven to be a dynamic space and it's more evident that a "one size fits all" approach is less likely to work and should be tailored to the patient by considering anatomic and biological risk.
Read the paper here and an interview about it here.
Primary Source: ASCO Educational Book
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Stage IV Stampede!
Reminder to anyone interested who has not yet registered.... there is still time! The Stampeded is going virtual! **August** is Stampede month. The Stage IV Stampede is part of a grassroots advocacy effort designed to advocate for MBC priorities with members of Congress. Join us, bring friends and family - anyone who might advocate with us. Help educate members of Congress about priorities for the MBC community. No experience necessary! {cross posting}
Thanks for your indulgence of the PSA....
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Aug 1, 2020
Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer
Abstract
Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination. We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
https://pubmed.ncbi.nlm.nih.gov/32732224/
{Exciting that this is in clinical trial phase.}0 -
Sequencing Endocrine Therapy for Metastatic Breast Cancer: What Do We Do After Disease Progression on a CDK4/6 Inhibitor?
I recently asked my MO to download this article for me so I didn't have to pay for it. Just got it today.
(maybe others can get your MO to download these articles that charge fees. )It has great info for what could be next if you fail a cdk4/6 and what could be driving resistance. It listed several trials by number and offered some hope for triplet therapy (3 drugs together)Dee0 -
Thanks, AlabamaDee. Another hint regarding accessing journals: if you have a kid in college who has access to an academic library, they may have access, too. Friend who has gone back to school? Same. At our community college, it is not easy, but members of the public could get limited access to the health sciences library. And ask at your public library, too. With all the COVID stuff, sometimes remote access to databases has been liberalize. Even your local hospital. It has a medial library. How open it is to the public varies. And right now it is probably restricted. College alumna? Call your alma mater and ask their librarian if there is any access for alumni... sometimes you gotta pull out all the stops.
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Low-Dose Metronomic Chemotherapy as an Efficient Treatment Option in Metastatic Breast Cancer
- In this retrospective study of patients with metastatic breast cancer (MBC), the efficacy of low-dose metronomic chemotherapy (LDMC) was compared with that of conventional chemotherapy (CCT). Disease control rate longer than 24 weeks was the primary endpoint, and it was reached by 30.0% of patients receiving LDMC and 22.5% of those receiving CCT. Median progression-free survival was 12 weeks in both treatment arms. Disease control rates were 40.0% (LDMC) versus 25.0% (CCT) in younger patients, 33.3% (LDMC) versus 25.0% (CCT) in non–heavily pretreated patients, and 36.0% (LDMC) versus 18.0% (CCT) in patients without multiple metastases. Similar efficacy was also observed among patients with HR-positive and triple-negative disease.
- These results demonstrate comparable efficacy of LDMC and CCT in patients with MBC, suggesting that LDMC may be a valuable treatment option in a select patient population.
Note: LDMC is defned as a continuous administration of cytotoxic drugs at low doses, distinctly lower than the maximum tolerable dose (MTD) of conventional chemotherapy (CCT)Breast Cancer Research and Treatment (2020) 182:389–399 https://doi.org/10.1007/s10549-020-05711-50 -
Shallow Whole-Genome Sequencing From Plasma Identifies FGFR1-Amplified Breast Cancers and Predicts OS
- In this study of formalin-fixed paraffin-embedded tissue samples from 100 patients with metastatic breast cancer, the authors sought to investigate the utility of cell-free DNA for the evaluation of FGFR1 copy number. FGFR1 amplifications were identified via tissue-based analyses in 20 tumors. Of these, 12 tumors with a ctDNA allele fraction above 3% demonstrated concordance for FGFR1 status between cell-free DNA and tissue. High ctDNA levels were associated with poor prognosis.
- These findings suggest that ctDNA may be used to identify patients who will respond to FGFR inhibition, and ctDNA analysis may indicate prognosis in clinical trials.
- Background: Focal amplification of fibroblast growth factor receptor 1 (FGFR1) defines a subgroup of breast cancers with poor prognosis and high risk of recurrence. We sought to demonstrate the potential of circulating cell-free DNA (cfDNA) analysis to evaluate FGFR1 copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients.
- Conclusions: Screening for FGFR1 amplification in ctDNA might represent a viable strategy to identify patients eligible for treatment by FGFR inhibition, and mBC ctDNA levels might be used for the evaluation of prognosis in clinical drug trials.
Cancers 2020, 12(6), 1481; https://doi.org/10.3390/cancers120614810 -
Quantifying the Impact of Axillary Surgery and Nodal Irradiation on Breast Cancer–Related Lymphedema and Local Tumor Control
- Journal of Clinical Oncology The authors of this prospective study of 1815 patients with invasive breast cancer evaluated the impact of axillary surgical extent and lymph node radiation on breast cancer–related lymphedema rates. Breast cancer–related lymphedema rates were lower at 5 years among patients with sentinel lymph node biopsy with or without regional lymph node radiation compared with those with axillary lymph node dissection with or without regional lymph node radiation. Tumor control rates were similar in the two groups.The type of axillary surgery appears to be the major determinant of breast cancer–related lymphedema.
Although RLNR adds to the risk of lymphedema, the main risk factor is the type of axillary surgery used.DOI: 10.1200/JCO.20.00459 Journal of Clinical OncologyPublished online July 30, 2020.PMID: 327301840 -
Cancer-Related Fatigue in {Early Stage} Breast Cancer Survivors
- The authors reviewed cancer-related fatigue (CRF) among breast cancer survivors. CRF was highest among young women, obese women, and women with diabetes. Women with CRF were more likely than women without to report pain, depression, insomnia, and cognitive dysfunction. Coping strategies appeared to impact the risk of CRF. CRF was not associated with tumor characteristics, previous treatments, and physical activity. CRF predicted quality of life.
- More awareness and education are needed to allow clinicians to effectively address the frequent problem of CRF among breast cancer survivors.
Fatigue is the most distressing and frequent symptom in Breast Cancer (BC) survivors after treatment. Although fatigue can be found in other cancer survivors, women with a history of breast cancer may share some distinctive features. This study aims to recapitulate the knowledge about risk factors and correlates of cancer-related fatigue (CRF) in BC survivors after oncological therapy. An electronic literature search was conducted in PubMed using the terms "fatigue", "breast", "cancer", and "survivors". Records were included if they were original articles, available in English, used a quantitative scale, had more than 100 participants, and excluded women who had relapsed. BC survivors should have finished their treatments at least 2 months before, except for hormonal therapy. Physiopathology or interventions were considered beyond the scope of this review. Correlates were subsequently classified into seven main categories: 1) sociodemographic, 2) physical variables, 3) tumour- and treatment-related, 4) comorbidities, 5) other symptoms, 6) psychological and 7) lifestyle. Notably, fatigue was consistently higher in younger, obese and diabetic women. Women reporting fatigue often communicated symptoms such as pain, depression, insomnia and cognitive dysfunction. Coping strategies such as catastrophising could play an important role in the persistence of fatigue. However, tumour characteristics, previous treatments and physical activity were not consistently related. CRF was a strong predictor of quality of life in BC survivors after treatment. To conclude, CRF is a frequent and serious symptom that severely affects the quality of life of BC survivors after treatment. More awareness and information among health practitioners is needed.0 -
Aromatase Inhibitor Symptom Management Practices
- This retrospective study was designed to compare aromatase inhibitor (AI) symptom management practices among 179 women with hormone receptor–positive breast cancer. AI-related symptoms were documented in 82% of patients, but just over half of these received guideline-based management.
- Only around half of patients with AI-related symptoms received guideline-based treatment.
PURPOSE
Aromatase inhibitor (AI) associated symptoms are large contributors to early discontinuation. Though guidelines exist for management of these symptoms, little is known about the degree to which physicians address symptoms and adhere to the guidelines for treatment.
PATIENTS
In this retrospective chart review, 179 women with hormone receptor positive breast cancer who were prescribed an AI between October 15, 2012 and September 14, 2017 were randomly selected from the institution's National Association of Central Cancer Registry.
RESULTS
Among 179 women prescribed an AI, 82% had at least one symptom and 46% had multiple symptoms. Of the 147 women with any documented symptom, 97 (66%) received some form of symptom-palliating treatment. Seventy-seven patients (52%) received guideline-based treatments or guideline-based treatments in combination with non-guideline based treatments. There were no differences in receipt of treatment overall (i.e. guideline or non-guideline-based for either vasomotor musculoskeletal by age, race, or stage.
CONCLUSIONS
Although 82% of patients had symptoms documented in their medical records, just over half of those patients received guideline-based treatment.
https://www.practiceupdate.com/C/104124/56?elsca1=emc_enews_topic-alert
https://www.clinical-breast-cancer.com/article/S1526-8209(20)30174-9/pdf
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Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial
PURPOSE The oligometastatic paradigm hypothesizes that patients with a limited number of metastases may achieve long-term disease control, or even cure, if all sites of disease can be ablated. However, long-term randomized data that test this paradigm are lacking.
METHODS We enrolled patients with a controlled primary malignancy and 1-5 metastatic lesions, with all metastases amenable to stereotactic ablative radiotherapy (SABR). We stratified by the number of metastases (1-3 v 4-5) and randomized in a 1:2 ratio between palliative standard-of-care (SOC) treatments (arm 1) and SOC plus SABR (arm 2). We used a randomized phase II screening design with a primary end point of overall survival (OS), using an a of .20 (wherein P , .20 indicates a positive trial). Secondary end points included progressionfree survival (PFS), toxicity, and quality of life (QOL). Herein, we present long-term outcomes from the trial.
RESULTS Between 2012 and 2016, 99 patients were randomly assigned at 10 centers internationally. The most common primary tumor types were breast (n 5 18), lung (n 5 18), colorectal (n 5 18), and prostate (n 5 16). Median follow-up was 51 months. The 5-year OS rate was 17.7% in arm 1 (95% CI, 6% to 34%) versus 42.3% in arm 2 (95% CI, 28% to 56%; stratified log-rank P 5 .006). The 5-year PFS rate was not reached in arm 1 (3.2%; 95% CI, 0% to 14% at 4 years with last patient censored) and 17.3% in arm 2 (95% CI, 8% to 30%; P 5 .001). There were no new grade 2-5 adverse events and no differences in QOL between arms.
CONCLUSION With extended follow-up, the impact of SABR on OS was larger in magnitude than in the initial analysis and durable over time. There were no new safety signals, and SABR had no detrimental impact on QOL.
CONTEXT
Key Objective: To determine the impact of stereotactic ablative radiotherapy (SABR) on overall survival (OS) in patients with a controlled primary tumor and 1-5 oligometastases.
Knowledge Generated: In this long-term report from an international randomized phase II trial, patients who received SABR demonstrated a 22- month improvement in median OS compared with patients who received a standard-of-care approach alone, corresponding to an absolute survival benefit of 25% at 5 years. There were no new safety signals detected.
Relevance: These data add to the growing evidence base that suggests that SABR can improve long-term outcomes in patients with a limited burden of metastatic disease. These results may influence treatment decisions while awaiting the results of phase III trials.
CLINICAL TRIAL INFORMATION NCT01446744
https://ascopubs.org/doi/pdf/10.1200/JCO.20.00818
DOI: 10.1200/JCO.20.00818 Journal of Clinical Oncology Published online June 02, 2020.
{Wow. These are HUGE improvements. It is a small study, so that has to be taken into account. If you are oligometastatic, be sure your doctor is up to date on this research. Free access to full article on ASCO website.}
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Cumberlege review exposes stubborn and dangerous flaws in healthcare {re NHS}
Editorial
On 8 July the Conservative peer Julia Cumberlege published her much anticipated Independent Medicines and Medical Devices Safety Review, looking into the response of England's healthcare system to patients' reports of harm from drugs and medical devices.
The Cumberlege review was inspired by longstanding patient campaigns alleging harm from these three interventions, and the panel's explicitly declared approach was that patients' and families' voices, experiences, and views should be "at the heart of the review."
The Cumberlege review made nine recommendations {including} a dedicated patient safety commissioner to help patients navigate the bureaucratic tangle and to troubleshoot problems throughout the system, has generated interest both inside and outside England. It is clearly the panel's centrepiece, characterised as a "golden thread" tying the disjointed system together in the interest of patients. Other recommendations include a Redress Agency to provide remediation to victims of medical harm without forcing them to litigation; schemes and specialist centres to provide care, support, and treatment; reform of the approval and tracking process for drugs and devices; and a public list of doctors' conflicts of interests, to be run by the General Medical Council.
the report .... has the potential to extend its influence far beyond the UK.
https://www.bmj.com/content/370/bmj.m3099
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3099 (Published 06 August 2020)Cite this as: BMJ 2020;370:m3099
{Matters related to patient safety often do not get the attention they deserves. I would be interested to hear whether this report has gotten much attention on the "other side of the pond."}
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Lumpie as always thanks for what you do!
Re the Cumberlege report, there was significant recent media coverage of the case surrounding the use of pelvic mesh and the fact that patients who suffer extensive harm from it’s use had basically been ignored as ‘ women’s problems’. NHS issued an unprecedented public apology and the report was cited as a catalyst for change in how patients are advocated for and listened to.0 -
Lumpie and Karen,
This is fascinating stuff. Thanks, Lumpie, for posting.
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Lumpie - thank you for your posts on lymphedema and AIs. AIs definitely have SEs, and I don't think DRs know much about managing them. I have BC for the third time, twice left breast, and now R-axilla. Even though Ibrance is shrinking the tumor, oncologist suggested I look at surgery, which terrifies me. I think the risks and SEs will be much worse than bi-lateral was. Tendons, nerves, muscles - and I already have lymphedema from the tumor. Just had a CT Thursday, really hoping for more shrinking. Radiation might be out since I had that in 2009 on Left side, whole breast.
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BlueGirl,
If you were not radiated on the R side, radiation might still be a possibility. And they are getting much better at targeting radiation. So don't give up on that thought!
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consider proton rads - very targeted
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Novel Therapies in the Management of HER2-Positive Breast Cancer
- Interview with Reshma L. Mahtani DO
- 9 minute video offers overview of treatment options for both early stage and MBC HER2+ disease. There is discussion of new therapies and Dr. Mahtani briefly mentions HR+, HER2+ disease. Transcript provided, too.
- https://www.practiceupdate.com/C/101965/56?elsca1=emc_enews_topic-alert
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Karenfizedbo15: Thanks for sharing insight on NHS situation. I hope that all of our health systems will pay more attention to patient concerns!
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On the use of DNA as a linker in antibody-drug conjugates: synthesis, stability and in vitro potency
Here we present the synthesis and evaluation of antibody-drug conjugates (ADCs), for which antibody and drug are non-covalently connected using complementary DNA linkers. These ADCs are composed of trastuzumab, an antibody targeting HER2 receptors overexpressed on breast cancer cells, and monomethyl auristatin E (MMAE) as a drug payload. In this new ADC format, trastuzumab conjugated to a 37-mer oligonucleotide (ON) was prepared and hybridized with its complementary ON modifed at 5-end with MMAE (cON-MMAE) in order to obtain trastuzumab-DNA-MMAE. As an advantage, the cON-MMAE was completely soluble in water, which decreases overall hydrophobicity of toxic payload, an important characteristic of ADCs. The stability in the human plasma of these non-engineered ONbased linkers was investigated and showed a satisfactory half-life of 5.8 days for the trastuzumabDNA format. Finally, we investigated the in vitro cytotoxicity profle of both the DNA-linked ADC and the ON-drug conjugates and compared them with classical covalently linked ADC. Interestingly, we found increased cytotoxicity for MMAE compared to cON-MMAE and an EC50 in the nanomolar range for trastuzumab-DNA-MMAE on HER2-positive cells. Although this proved to be less potent than classically linked ADC with picomolar range EC50, the diference in cytotoxicity between naked payload and conjugated payload was signifcant when an ON linker was used. We also observed an interesting increase in cytotoxicity of trastuzumab-DNA-MMAE on HER2-negative cells. This was attributed to enhanced non-specifc interaction triggered by the DNA strand as it could be confrmed using ligand tracer assay.
https://www.nature.com/articles/s41598-020-64518-y.pdf
https://doi.org/10.1038/s41598-020-64518-y
Nature Scientific Reports | (2020) 10:7691 {open access}
{This article is pretty technical. I think that there is press reporting on it, too, which may be more reader friendly. I will post that if I can find it. In short... many of us are familiar with antibody drug conjugates, like Kadcyla aka T-DM1. It combines two drugs: Traztuzamab and DM1. They are "linked." Making the link stable is challenging. This article discussed a different method of linking drugs which may be more stable and may allow the linkage of more than two drugs.}
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