Tag: triple-negative breast cancer

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Triple-negative Breast Cancer Survival Nearly Doubled with New Treatment

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Results of a global, multicentre, phase III clinical trial indicate that datopotamab deruxtecan (Dato-DXd) is effective in improving survival for untreated, advanced triple negative breast cancer (TNBC) 

Photo by National Cancer Institute on Unsplash

A global, multicentre phase III trial, TROPION-Breast02, led by a senior medical oncologist and researcher from the National Cancer Centre Singapore, has demonstrated a significant breakthrough in improving the survival of patients with untreated, advanced triple negative breast cancer (TNBC) using the novel antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd). Published in the Annals of Oncology, the findings demonstrate the potential of Dato-DXd as an effective new treatment option for this aggressive disease.

“In the TROPION-Breast02 trial, first-line Dato-DXd demonstrated clinically meaningful and significant improvements in progression-free survival and overall survival for these TNBC patients, and a higher overall response rate compared with chemotherapy. As a medical oncologist treating triple-negative breast cancer patients for the past 20 years, I am deeply encouraged that this data shows we now have a much-needed new tool to help women affected by this devastating disease,” said lead investigator Prof Rebecca Dent, Deputy CEO (Clinical) and Senior Consultant in the Division of Medical Oncology at the National Cancer Centre Singapore.

The burden of triple negative breast cancer (TNBC)

Breast cancer is the leading cause of cancer death in women globally. Approximately 10 to 20% of breast cancers are TNBC, an aggressive subtype that disproportionately affects young women under the age of 40. TNBC is associated with early recurrence, high likelihood of metastasis and shorter survival. In recent years, TNBC patients with PD-L1-positive tumours or germline BRCA mutations have been eligible for immunotherapy. However, 70% of TNBC patients are ineligible for immunotherapy and receive first-line chemotherapy treatment, which has modest and limited efficacy. Approximately half of patients with metastatic TNBC do not receive treatment beyond first-line chemotherapy, making it an urgent need to find new treatment options to improve clinical outcomes.

A new treatment for TNBC

To address this need, clinician-investigators from multiple centres around the world conducted the TROPION-Breast02 open-label, phase III clinical trial using Dato-DXd to treat TNBC. Dato-DXd is an ADC that delivers a potent cancer-killing drug directly to tumour cells by targeting the TROP2 protein. Currently, Dato-DXd is approved for the treatment of patients with unresectable or metastatic, hormone receptor-positive, HER2-negative breast cancer, but not TNBC.

In total, 644 TNBC patients were enrolled in TROPION-Breast02 across multiple sites across the globe including the United States, Canada, Europe, China, Korea, Japan and Singapore. Patients were randomly assigned to two treatment arms: intravenous Dato-DXd 6 mg/kg once every three weeks (323 patients) or the investigator’s choice of chemotherapy (321 patients). Patients had to be 18 and above to enrol, have locally recurrent inoperable or metastatic TNBC that was untreated, and be ineligible for treatment with immunotherapy.

Trial results showed that:

  • Progression-free survival (PFS) was significantly longer with Dato-DXd compared with chemotherapy: median PFS 10.8 months versus 5.6 months (nearly double) 
  • Overall survival (OS) was improved with Dato-DXd compared with chemotherapy: median OS 23.7 months versus 18.7 months 
  • Patients treated with Dato-DXd had an overall positive response rate to treatment of 63% compared to patients treated with chemotherapy who had an overall response rate of 29%. Median duration of response, or how long patients responded to treatment, was 12.3 months in the Dato-DXd arm and 7.1 months in the chemotherapy arm.

Dato-DXd’s most common drug-related adverse events were stomatitis (inflammation of tissue lining the mouth or lips), nausea, alopecia and neutropenia (lower levels of a type of white blood cell), whilst the most common for chemotherapy were alopecia, neutropenia and fatigue. Only 4% of patients on Dato-DXd stopped treatment due to drug-related adverse events compared to 7% of patients on chemotherapy.

What this means for TNBC patients

Not only did the trial find Dato-DXd to be an effective treatment for untreated, inoperable metastatic TNBC, but ASCENT-03, a separate, earlier phase III clinical trial of TROP2-directed ADC sacituzumab govitecan, also demonstrated improved PFS compared to chemotherapy. Combined, the results from TROPION-Breast02 and ASCENT-03 indicate that TROP2-directed ADCs are a promising class of drugs to treat TNBC.

The team is further evaluating Dato-DXd in phase III clinical trials to treat patients with Stage I-III TNBC with residual invasive disease after neoadjuvant systemic therapy, Stage II-III triple-negative or hormone receptor (HR)-low, HER2-low or -negative breast cancer and metastatic TNBC PD-L1 expressed tumours.

Dato-DXd is currently under review as first-line treatment for unresectable, metastatic TNBC by the US Food and Drug Administration and the Singapore Health Sciences Authority.

Source: National Cancer Centre Singapore

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Scientists Develop One-product-fits-all Immunotherapy for Breast Cancer

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Breast cancer cells. Image by National Cancer Institute

Triple-negative breast cancer is one of the most aggressive cancers. The name tells the story: It lacks the three main targets that make other types of breast cancers more treatable with powerful therapies.

UCLA researchers have developed a novel therapy that could fundamentally change the treatment plan for this deadly disease. In a study published in the Journal of Hematology & Oncology, the team details how this new type of immunotherapy, called CAR-NKT cell therapy, could attack tumors from multiple fronts while dismantling their protective shields.

“Patients with triple-negative breast cancer have been waiting far too long for better treatment options,” said senior author Lili Yang, a professor of microbiology, immunology and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “To finally have a therapy that shows superior cancer-fighting ability – and to be just one step away from clinical testing – is incredibly exciting.”

The therapy uses engineered immune cells called CAR-NKT cells, which can be mass-produced from donated blood stem cells and stored ready-to-use. This off-the-shelf approach offers an immediately available treatment option at a fraction of the cost of current personalized cell therapies, which can soar into the hundreds of thousands of dollars.

A triple threat against a triple-negative cancer

CAR-T cell therapies have transformed treatment for certain blood cancers by turning patients’ own immune cells into precision weapons. However, these therapies have struggled against solid tumours like breast cancer, which employ sophisticated defence mechanisms and constantly evolve to evade treatment.

To tackle these hurdles, the UCLA team’s cell therapy harnesses a rare but powerful type of immune cell called invariant natural killer T cell, or NKT cell. When equipped with a chimeric antigen receptor, or CAR, targeting mesothelin (a protein found on triple-negative breast cancer cells) these potent tumour-fighting cells gain the ability to recognise and destroy cancer through three distinct mechanisms.

The first mechanism uses the engineered CAR to target mesothelin, which is associated with more aggressive, metastatic disease. The second leverages the cells’ natural killer receptors that recognize more than 20 molecular markers, making it nearly impossible for tumours to evade all of them. The third employs the cells’ unique T cell receptor to reshape the tumour microenvironment by eliminating immunosuppressive cells.

“We’re not just targeting one molecular marker on cancer cells — we’re identifying dozens of them simultaneously,” said first author Yanruide (Charlie) Li, a postdoctoral scholar in the UCLA Broad Stem Cell Research Center Training Program. “It’s like attacking a fortress from every direction at once. The cancer simply can’t adapt fast enough to escape.”

When the research team tested the novel therapy on tumour samples from patients with late-stage metastatic breast cancer, the CAR-NKT cells successfully killed cancer cells in every single sample tested, while also eliminating the immunosuppressive cells that tumours recruit as protective escorts.

Engineering universal accessibility

Beyond its multipronged cancer-fighting capabilities, the CAR-NKT platform addresses critical barriers that have limited cell therapy access: manufacturing complexity and cost.

Current cellular immunotherapies require collecting each patient’s immune cells, shipping them to specialised laboratories for genetic modification, then returning the customized product into the patient weeks later — a process that can cost six figures and create dangerous delays for patients with aggressive cancers.

Yang’s team takes a fundamentally different approach. Because NKT cells naturally work with any immune system, they can be mass-produced from donated blood stem cells using a scalable system. A single donation could generate enough cells for thousands of treatments, reducing costs to approximately $5,000 per dose.

One product to tackle multiple cancers

The therapy’s promise extends beyond triple-negative breast cancer. Since mesothelin is also highly expressed in ovarian, pancreatic and lung cancers, the same cell product could potentially treat multiple cancer types that remain difficult to address with current immunotherapies.

“This is really a platform technology,” said Yang, who’s also a member of the UCLA Health Jonsson Comprehensive Cancer Center.

With all preclinical studies complete for both triple-negative breast cancer and ovarian cancer, the team is preparing to submit applications to the Food and Drug Administration to begin clinical trials.

“We’ve walked 99 steps to get here,” Yang said. “We’re missing just one final step to begin clinical testing and demonstrate what this promising therapy can really do for patients.”

Source: University of California – Los Angeles

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Is it Time for the International Definition of Triple-negative Breast Cancer to be Revised?

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Photo by National Cancer Institute on Unsplash

An analysis of Swedish data, where the definition of triple negative breast cancer (TNBC) differs from that used internationally, brings additional insights to on ongoing discussion in the scientific community. The study was presented at the 2023 European Society for Medical Oncology (ESMO) meeting and is now published in Lancet Regional Health – Europe.

The Swedish definition of TNBC differs from the international version in that it also includes tumours with low expression of the Oestrogen Receptor (ER) biomarker, ie in 1–9% of tumour cells. Internationally, ER-low breast cancer is classified as hormone-sensitive and treated differently from TNBC patients. This is despite previous studies demonstrating that the majority of ER-low tumours are molecularly similar to ER-zero, the latter completely without expression of ER, and meta-analyses that show no survival benefit from endocrine therapy in ER-low tumours.

The Swedish population-based study included all women diagnosed with TNBC in Sweden during 2008–2020 using the National Quality Register for Breast Cancer. Patient and tumour characteristics, treatment and survival in patients with low ER expression was compared to patients with no ER tumour expression.

The study identified and included 5655, and 560 patients (10%) were defined as ER-low and 5095 (90%) as ER-zero. The data demonstrated there are only small differences in tumour characteristics, no differences in response to neoadjuvant chemotherapy and no significant differences in prognosis.

“The international cut-off for ER-positivity and thus the definition of TNBC as only completely ER-negative is now increasingly questioned. ER-low tumours behave like ER-zero tumours and should be treated as such. On the basis of real-world data, the Swedish cutoff for hormone receptor positivity appears to be more clinically relevant. A changed international definition would give patients with ER-low expressing breast cancer the same treatment options as in TNBC, within studies and in clinical routine,” says study leader Dr Irma Fredriksson.

The study was carried out in collaboration with the pharmaceutical company MSD.

Source: Karolinska Institutet

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Breast Cancer Stage and Receptor Type Predict Recurrence

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Photo by National Cancer Institute on Unsplash

New research indicates that for patients with breast cancer, the cancer’s stage and receptor status can help clinicians predict whether and when cancer might recur after initial treatment. The findings are published in the journal cancer CANCER.

For the study, Heather Neuman, MD, MS, of the University of Wisconsin, and her colleagues analysed data on 8007 patients with stage I–III breast cancer who participated in nine clinical trials from 1997–2013 and received standard of care therapy.

Time to first cancer recurrence varied significantly between cancers with different receptors – including oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Within each receptor type, cancer stage influenced time to recurrence.

Risk of recurrence was highest and occurred earliest for ER−/PR−/HER2− (triple negative) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 45.5%. Risk of recurrence was lowest for ER+/PR+/HER2+ (triple positive) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 15.3%.

Based on their findings, the investigators developed follow-up recommendations by cancer stage and receptor type. For example, patients with the lowest risk should be seen by their oncology team once annually over five years, whereas those with the highest risk should be seen once every three months over five years.

“Our developed follow-up guidelines present an opportunity to personalize how we deliver breast cancer follow-up care,” said Dr Neuman. “By tailoring follow-up based on risk, we have the potential to have a strong, positive impact on both survivors and their oncology providers by improving the quality and efficiency of care.”

Source: Wiley

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Transforming the Way Cancer Vaccines are Designed and Made

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Photo by Louise Reed on Unsplash

A new way to significantly increase the potency of almost any vaccine has been developed by researchers from the International Institute for Nanotechnology (IIN) at Northwestern University, which they describe in Nature.

The scientists used chemistry and nanotechnology to change the structural location of adjuvants and antigens on and within a nanoscale vaccine, greatly increasing vaccine performance. The antigen targets the immune system, and the adjuvant is a stimulator that increases the effectiveness of the antigen. 

“The work shows that vaccine structure and not just the components is a critical factor in determining vaccine efficacy,” said lead investigator Chad A. Mirkin, director of the IIN. “Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognises and processes it.”

This new heightened emphasis on structure has the potential to improve the effectiveness of conventional cancer vaccines, which historically have not worked well, Mirkin said. 

Mirkin’s team has studied the effect of vaccine structure in the context of seven different types of cancer to date, including triple-negative breast cancer, papillomavirus-induced cervical cancer, melanoma, colon cancer and prostate cancer to determine the most effective architecture to treat each disease.   

Conventional vaccines take a blender approach   

With most conventional vaccines, the antigen and the adjuvant are simply blended and injected into a patient, giving no control over the vaccine structure, and, consequently, limited control over trafficking and processing of the vaccine components. Thus, there is no control over how well the vaccine works.  

“A challenge with conventional vaccines is that out of that blended mish mosh, an immune cell might pick up 50 antigens and one adjuvant or one antigen and 50 adjuvants,” said study author and former Northwestern postdoctoral associate Michelle Teplensky, who is now an assistant professor at Boston University. “But there must be an optimum ratio of each that would maximise the vaccine’s effectiveness.” 

Enter SNAs (spherical nucleic acids), which are the structural platform, invented and developed by Mirkin, used in this new class of modular vaccines. SNAs allow scientists to pinpoint exactly how many antigens and adjuvants are being delivered to cells. SNAs also enable scientists to tailor how these vaccine components are presented, and the rate at which they are processed. Such structural considerations, which greatly impact vaccine effectiveness, are largely ignored in conventional approaches.  

Vaccines developed through ‘rational vaccinology’ offer precise dosing for maximum effectiveness

Mirkin came up with this approach to systematically control antigen and adjuvant locations within modular vaccine architectures, and called it ‘rational vaccinology’. It is based on the concept that the structural presentation of vaccine components matters as much as the components themselves in driving efficacy.   

“Vaccines developed through rational vaccinology deliver the precise dose of antigen and adjuvant to every immune cell, so they are all equally primed to attack cancer cells,” said Mirkin. “If your immune cells are soldiers, a traditional vaccine leaves some unarmed; our vaccine arms them all with a powerful weapon with which to kill cancer. Which immune cell ‘soldiers’ do you want to attack your cancer cells?”

Building an (even) better vaccine  

The team developed a cancer vaccine that reduced tumour growth by more than four times compared to checkpoint inhibitor monotherapy, and led to a 40% extension in median survival.  

By reconfiguring the architecture of a vaccine containing multiple targets, the SNA enables the immune system to find tumour cells. The team investigated differences in how well two antigens were recognised by the immune system depending on their placement, on the core or perimeter, of the SNA structure. For an SNA with optimum placement, they could increase the immune response and how quickly the nanovaccine triggered cytokine (an immune cell protein) production to boost T cells attacking the cancer cells. The scientists also studied how the different placements affected the immune system’s ability to remember the invader, and whether the memory was long-term.  

“Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognises and processes it,” Mirkin said. 

The most powerful structure throws two punches to outsmart the tumour  

The study data show that attaching two different antigens to an SNA comprising a shell of adjuvant was the most potent approach for a cancer vaccine structure. These engineered SNA nanostructures stalled tumour growth in multiple animal models.   

“It is remarkable,” Mirkin said. “When altering the placement of antigens in two vaccines that are nearly identical from a compositional standpoint, the treatment benefit against tumours is dramatically changed. One vaccine is potent and useful, while the other is much less effective.”  

Many current cancer vaccines are designed to primarily activate cytotoxic T cells, only one defence against a cancer cell. Because tumour cells are always mutating, they can easily escape this immune cell surveillance, quickly rendering the vaccine ineffective. The odds are higher that the T cell will recognise a mutating cancer cell if it has more antigens to recognise it.   

“You need more than one type of T cell activated, so you can more easily attack a tumour cell,” Teplensky said. “The more types of cells the immune system has to go after tumours, the better. Vaccines consisting of multiple antigens targeting multiple immune cell types are necessary to induce enhanced and long-lasting tumour remission.”  

Another advantage of the rational vaccinology approach, especially when used with a nanostructure like an SNA, is that it’s easy to alter the structure of a vaccine to go after a different type of disease. Mirkin said they simply switch out a peptide, a snippet of a cancer protein with a chemical handle that “clips” onto the structure, not unlike adding a new charm to a bracelet.   

Towards the most effective vaccine for any cancer type 

“The collective importance of this work is that it lays the foundation for developing the most effective forms of vaccine for almost any type of cancer,” Teplensky said. “It is about redefining how we develop vaccines across the board, including ones for infectious diseases.” 

In a previously published paper, Mirkin, Teplensky and colleagues demonstrated the importance of vaccine structure for SARS-CoV-2 by creating vaccines that exhibited protective immunity in 100% of animals against a lethal viral infection.  

“Small changes in antigen placement on a vaccine significantly elevate cell-to-cell communication, cross-talk and cell synergy,” Mirkin said. “The developments made in this work provide a path forward to rethinking the design of vaccines for cancer and other diseases as a whole.”   

Source: Northwestern University