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.
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.”
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.”
