Tagged: Breast Cancer

Oncotarget

A Remote Weight Loss Strategy for Breast Cancer Survivors

March 9, 2022

Researchers Jennifer Y. Sheng and Vered Stearns discussed the results of a study that compared weight loss interventions among overweight or obese survivors of breast cancer.

Weight loss for survivors of breast cancer
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After being diagnosed with breast cancer, up to 96% of women have reported gaining weight. Medications, inactivity, food choice, and food quantity can all lead to weight gain. Studies have shown that weight gain can increase the risk of breast cancer recurrence by 40–50% and breast cancer-related mortality by 53–60%. Thus, for women with breast cancer and those who have survived breast cancer, weight management is a potentially life-saving intervention.

In an editorial paper published by Oncotarget in 2021, researchers Jennifer Y. Sheng and Vered Stearns from Johns Hopkins School of Medicine and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discussed the results of the 2020 POWER-Remote Trial—a study among breast cancer survivors on the results of a remote-based weight loss program compared with a self-directed approach. Their editorial paper is entitled, “Innovating and expanding weight loss strategies for breast cancer survivors.”

The POWER Intervention

The Practice-based Opportunities for Weight Reduction (POWER) intervention is a 12-week behavioral weight loss program designed for overweight and obese participants. The POWER program strategy focuses on physical activity and behavioral changes, nutrition education and setting individual goals. Researchers developed the POWER-remote intervention to enable participants to engage in this weight loss program remotely through weekly video conferences and phone calls. In the current editorial paper, the researchers discussed the results from a study that adapted the POWER-remote intervention for breast cancer survivors: the POWER-Remote Trial.

“The original Practice-based Opportunities for Weight Reduction (POWER) study in obese individuals with a risk for cardiovascular disease demonstrated equivalent weight loss outcomes between in-person coaching and a remote intervention [24].”

The POWER-Remote Trial

The POWER-Remote Trial was a randomized, controlled comparative effectiveness trial that evaluated the POWER-remote intervention compared to a self-directed weight loss approach among overweight or obese breast cancer survivors. Between 2013 and 2015, 87 overweight or obese women with stage 0-III breast cancer (who completed local therapy and chemotherapy) were evaluable for analysis in this study. Forty-five women were enrolled in the POWER-remote arm of the study and 42 women were enrolled in the self-directed arm.

“Our group compared the remote-based POWER intervention (telephone calls by a coach, access to online learning materials, online self-directed dietary/activity monitoring) to self-directed weight loss in overweight or obese survivors of early-stage breast cancer [25].”

Over the course of the study, the researchers found high adherence in the POWER-remote arm, with only one participant lost in follow-up. At the 12-month mark, 51% of the POWER-remote participants lost greater than or equal to 5% of their baseline body weight. Among the self-directed participants, 17% lost 5% or more of their baseline body weight. The results of this study suggest that the POWER-remote intervention is an effective weight loss strategy. It is a cost-effective, scalable and conscientious solution to assist with weight loss among many breast cancer survivors.

Conclusion

Despite the significant improvements in weight, body composition, fitness, and quality of life seen by over half of the participants in the POWER-remote arm, the researchers also pointed out a problem. The POWER-remote intervention still did not yield significant results in almost half of the other participants. Trouble sleeping was shown as a potential culprit that hindered weight loss, while many other factors inhibiting weight loss in this population are not yet fully understood.

The authors wrote that it may be necessary to further individualize or enhance the POWER intervention to achieve greater success in breast cancer survivors. They also suggested that, in some people, the POWER program may need to be augmented with pharmacological agents to aid in weight loss. In addition, the authors believe that the payer system should be reevaluated to expand coverage for obesity treatments.

“At present, I’m conducting a phase two study to determine whether an adaptor approach with pharmacotherapy can augment obesity treatment in breast cancer survivors. This study is called the A-NEW study, which stands for an Adaptive Nutrition and Exercise Weight Loss Study,” Dr. Jennifer Sheng said in a recent Behind the Study interview with Oncotarget. “We’re also looking forward to analyzing results from the COOIN study, the Cancer, Obesity, Overweight, and Insomnia study, which was led by Dr. Janelle Coughlin.”

Click here to read the full editorial paper published by Oncotarget.

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Trending With Impact: Are NOTCH1 Variants Prognostic in Breast Cancer?

February 24, 2022

Researchers determined the prognostic ability of three NOTCH1 gene variants by incorporating them into two non-tumorigenic breast cell lines.

Breast cancer illustration
Breast cancer illustration

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The genetic changes that occur within the protein-coding gene NOTCH1 have not yet been fully studied or classified. Despite a lack in research, previous studies have suggested that NOTCH1 may be a potential target for novel cancer therapies, particularly against triple-negative breast cancer (TNBC). NOTCH1 variants in TNBC tend to cluster in the PEST region and have previously been linked to gamma secretase inhibitor (GSI) sensitivity and chemotherapy resistance.

“Furthermore, TNBC patients with increased Notch1 expression have demonstrated increased aggressive phenotypes and lower median overall survival [25].”

Since TNBC is well-known for a lack of actionable therapeutic targets, aggressive phenotypes and poor prognoses, there is an important need to develop new targeted therapies—as well as predictive markers for those therapies. Researchers from The Johns Hopkins University School of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center experimented in vitro with NOTCH1 variants and their ability to predict TNBC responsiveness to GSIs and standard of care chemotherapies. Their trending research paper was published by Oncotarget on February 16, 2022, and entitled, “NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model.”

The Study

The researchers used three publicly available tumor-associated variant databases to identify three NOTCH1 variants that are commonly mutated in breast cancers; two variants were located in the A2441 site on NOTCH1 and the third variant was located in the PEST region of NOTCH1. To investigate the role of these NOTCH1 variants in TNBC in vitro, the team cultured two non-tumorigenic breast epithelial cell lines. Uniquely, they used an adeno-associated virus (AAV) vector to isogenically incorporate the NOTCH1 variants into the two cell lines. The researchers also developed a wildtype vector for the control arm of the study.

“In addition to the NOTCH1 variants, a targeted wildtype (TWT), which underwent the same gene targeting mechanism with a wildtype vector, was generated for both parental cell lines to act as a control.”

A standard growth factor supplemented media was used to determine if the NOTCH1 variants caused increased proliferation in the non-tumorigenic cell lines. Compared to the controls, no significant change in proliferation was observed. They also removed the epidermal growth factor (EGF) from the cells to determine if these NOTCH1 variants impart a ligand-independent proliferative advantage. In both cell lines, their results demonstrated that the A2441 variants exhibited EGF-independent growth, while the PEST NOTCH1 variant did not. Immunoblot analyses suggested that, in the absence of EGF, the A2441 NOTCH1 variants activated the MAPK pathway. These EGF-independent NOTCH1 variants (not the PEST NOTCH1 variant) conferred an invasive growth phenotype, increased migratory potential, had dysregulated 3D morphology, and significantly altered gene expression in cancer pathway genes.

Next, to measure the responsiveness and susceptibility of these variants to therapeutic agents, the cells were treated with six chemotherapeutic agents and nirogacestat—a GSI drug. Interestingly, none of the three variants demonstrated significantly different responses to the treatments when compared to one another. Furthermore, all of the variants showed sensitivity to these standard therapies used against TNBC. This suggests that these specific genetic changes within NOTCH do not have a large impact on tumor behavior and may not be useful as predictive markers for therapy response.

Conclusion

“Taken together, these data suggest that the oncogenic potential of NOTCH1 PEST domain variants depends on both variant type and amino acid location.”

Contrary to previous studies, the researchers found that the three NOTCH variants did not demonstrate significantly different responses to the GSI or the chemotherapies despite demonstrating distinct phenotypes. The lack of differential responses demonstrated by the variants in this study suggests that there is high variability among NOTCH1 variants. The prognostic potential of NOTCH1 may be dependent on the type of variant and its location, but more expansive research is necessary.

“Future studies involving meticulous characterization of an expansive panel of NOTCH1 variants in a similar model may provide mechanistic insight and predictive and/or prognostic value that is both variant type and site dependent.”

Click here to read the full research paper published by Oncotarget.

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Chemical in Sunscreen Promotes Breast Cancer in Diet-Dependent Manner

November 18, 2021

The bioactivity of oxybenzone—a harmful chemical often found in sunscreens—was examined within mouse models of breast cancer in high- and low-fat dietary contexts.

sunscreen
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Oxybenzone (benzophenone-3; BP-3) is a toxic endocrine-disrupting chemical (EDC). Alarmingly, this chemical has been identified as a common ingredient in some brands of sunscreen. Oxybenzone can often be found in humans, household dust, fish and, due to its widespread human use, the water environment—causing harm to coral reefs and other murine life. Previous studies have shown that environmental toxins and estrogenic chemicals have emerged as potential culprits in the promotion of breast cancer. Furthermore, oxybenzone has been known to have estrogenic and anti-estrogenic properties.

“Although BP-3 has a very short half-life, its presence is widespread in human urine [9], in as much as 98% of the general U.S. population [13].”

Researchers from the Breast Cancer and the Environment Research Program at Michigan State University studied the diet-dependent effects of oxybenzone in mouse models of mammary tumorigenesis during puberty and adulthood. Their paper was published by Oncotarget in 2020, and entitled, “Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent.” 

“We [previously] demonstrated enhancement of mammary tumorigenesis by a diet high in saturated animal fat (HFD) [5–8]. Thus, examination of the activity of EDCs in a dietary context may provide additional insight into the potential role of EDCs in promoting breast cancer.”

The Study

In the current study, the team employed the Trp53–null transplantation of a basal-like breast cancer mouse model. The researchers previously demonstrated that proliferative, inflammatory and angiogenic activity in the mammary gland can be modulated by estrogen and a high-fat diet (HFD). Therefore, both pubertal and adult mice were placed on either low- or high-fat diets. After one week, study mice were ovariectomized, given time for recovery and the natural dissipation of endogenous hormones, and then treated for five days with either saline (control) or 17β-estradiol (E2). 

Next, the estrogenic or anti-estrogenic effects of oxybenzone were examined in these mice under three dietary conditions: mice fed a life-long low-fat diet (LFD), mice fed a LFD during puberty and then a HFD in adulthood (LFD-HFD) and finally, mice fed a HFD during puberty and then a LFD in adulthood (HFD-LFD). Mice in LFD-HFD and HFD-LFD groups were fed their initial diet from three to 10 weeks of age, and were then switched to the alternative diet. Half of these mice were injected with oxybenzone and the other half (control) were injected with saline.

“We found that BP-3 had complex effects that were dependent upon dietary regimen and tumor histopathology.”

Results

Consistent with their previous studies, the researchers found that most of the tumors developed were epithelial in histological composition, and few were spindle cell carcinomas. They found that oxybenzone reduced the tumorigenesis of epithelial tumors in LFD mice. The LFD-HFD combination resulted in more spindle cell tumors compared to the life-long LFD mice. Oxybenzone treatment increased the tumorigenesis of epithelial tumors in mice fed the LFD-HFD. 

“Kaplan-Meier analysis revealed that BP-3 reduced tumorigenesis of epithelial tumors in mice fed LFD (Figure 3A). On the other hand, consistent with the increased proportion of epithelial tumors, BP-3 was promotional for epithelial tumorigenesis in mice fed LFD-HFD (Figure 3C), while reducing spindle cell tumorigenesis (Figure 3D).” 

Researchers saw that proliferation was increased by oxybenzone treatment most significantly in the mammary glands of 26-week-old HFD mice. Curiously, oxybenzone treatment increased the number of lesions only in mice fed the HFD-LFD. The researchers note that, in this study and others, a “pubertal window of susceptibility” was observed, reinforcing the important notion that puberty is a highly sensitive window of time for poor diets and adverse exposures to environmental toxins. Ultimately, the team found that oxybenzone enhances estrogen-stimulated breast cancer cell proliferation in pubertal mice fed a HFD.

“Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology.”

Conclusion

Collectively, the researchers’ findings suggest that exposure to oxybenzone has adverse consequences in mammary tumorigenesis. The degree of severity appeared to be modulated differently among the three dietary regimens studied. Mice fed a HFD in adulthood experienced a decrease in tumor cell apoptosis and an increase in tumor vascularity and tumor cell proliferation. They note that there is future value in exploring the differences between pubertal and adult exposure to oxybenzone on a constant diet regimen.

“This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.”

Click here to read the full scientific study, published by Oncotarget.

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New Study: Vaccine Enhances Breast Cancer Treatment

October 27, 2021

Researchers conducted a study to examine the efficacy of adding the P10s-PADRE vaccine to chemotherapy treatments for patients with HR+/HER2− breast cancer.

Cancer vaccine
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The most common type of breast cancer in the United States is HR+/HER2− breast cancer. Patients with HR+/HER2− breast cancer often face the threat of distant recurrence—long after the completion of their treatment. Previous studies have found that high levels of tumor infiltrating lymphocytes (TILs) were associated with improved outcomes and recurrence-free survival in patients with HR+/HER2− breast cancer. These studies and many others have prompted researchers to further develop and test cancer vaccines in an effort to elicit anti-tumor immune responses in these patients.

“Therefore, a rational combination therapy that enhances the immune-stimulatory properties of NAC [neoadjuvant chemotherapy], can provide long-term survival benefits for this patient population.”

Researchers from University of Arkansas for Medical Sciences, University of Texas Southwestern, Highlands Oncology Group, and Université Claude Bernard Lyon 1 conducted a new single-arm Phase Ib clinical trial. Early-stage HR+/HER2− breast cancer patients were treated with carbohydrate-mimetic peptides, the P10s-PADRE vaccine, in combination with chemotherapy treatments. Their paper was chosen as the cover of Oncotarget’s Volume 12, Issue 22, and entitled, “P10s-PADRE vaccine combined with neoadjuvant chemotherapy in ER-positive breast cancer patients induces humoral and cellular immune responses.”

“The main objective of our study was to determine an appropriate schedule to be used for adding the P10s-PADRE vaccine to cancer chemotherapy in the neoadjuvant setting considering the ability of the vaccine to elicit adequate antibody response.”

The Study

After meeting the study’s detailed inclusion/exclusion criteria, a total of 25 patients with HR+/HER2− breast cancer were selected to partake in this single-arm Phase Ib clinical trial. Patients were divided into five cohorts (five patients per cohort): A, B, C, D, and E. Each patient was treated with a combination of four therapies over the course of 22-25 weeks, including three doses of the peptide-based P10s-PADRE cancer vaccine, four doses of Cyclophosphamide (chemotherapy), four doses of Doxorubicin (chemotherapy) and four doses of Docetaxel (chemotherapy). Using a cohort-specific treatment schedule for the previously stated combination of therapies, the researchers assessed the feasibility, safety and immunogenicity achieved in each cohort and each patient.

Additionally, patients underwent surgery between weeks 26 and 33 (four to eight weeks after their last chemotherapy treatment). Each cohort also had a cohort-specific blood draw schedule—blood was drawn at eight different times in the 73-week time frame. Blood draws were used to conduct flow cytometry, measure the concentration of cytokines, natural killer (NK) cells and antibodies, and to determine the presence of anti-peptide antibody response and the percentage of TILs. The researchers observed that all five cohorts saw a significant reduction in tumor size.

“The data suggest that subjects enrolled in schedule C generated a more consistent and robust antibody response, therefore schedule C appears as the schedule of choice for future combination therapy.”

Their findings concluded that, in combination with chemotherapy, P10s-PADRE immunization in HR+/HER2− breast cancer patients induced “acceptable” antibody responses in study cohorts C and E. The treatment schedule in cohort C demonstrated the strongest antibody response by affecting the expression levels of NK-cell markers, stimulating the production of cytokines, T-cells and TILs. However, the researchers note that continued analysis of the blood samples collected could show serum antibodies may begin to appear later on in patients enrolled in the other treatment schedules.

Conclusion

“This Phase Ib clinical trial of the P10s-PADRE vaccine shows that immunization in combination with a standard-of-care NAC is feasible and well-tolerated. Combination therapy induces antibody response, stimulates activation of NK cells, and is associated with infiltration of T cells in tumor microenvironment. Randomized phase II trials focusing on treatment schedule C are needed to validate current findings and evaluate clinical efficacy.”

Click here to read the full research paper, published by Oncotarget.

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Trending With Impact: Analysis of Breast Cancer in Nigerian Women

August 16, 2021

In this trending paper published by Oncotarget in 2021, a cohort of Nigerian women were assessed for a useful biomarker in aggressive molecular subtypes of breast cancer.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Forms of cancer can vary in prevalence and aggression in different populations of people around the world. For instance, incidence rates of breast cancer (BC) have been rising in Africa over the past few decades. Research finds that Nigerian women have the highest age-standardized mortality rate of breast cancer on the African continent. This population in particular also faces disproportionately aggressive molecular subtypes of breast cancer.

“BC in Nigeria is characterized by disproportionately aggressive molecular subtypes, with exceptionally high rates of triple-negative (TN) BC [4], similar to BC in other countries in West Africa [5] and among African American women in the United States [6].”

In order to develop better treatment strategies, there is a distinct need to identify biomarkers that indicate, and even predict, these aggressive subtypes of breast cancer in Nigerian women. In 2021, a new study was conducted by researchers from Duke University, University of Lagos, Obafemi Awolowo University Teaching Hospital, University of Ibadan, Federal Medical Center Abeokuta, UNC Gillings School of Global Public Health, Our Lady of Apostle Catholic Hospital in Ibadan, University of Alabama at Birmingham, University of Kentucky, and University of Kansas Medical Center. Their trending research paper was published by Oncotarget and entitled, “Association of high-sensitivity C-reactive protein and odds of breast cancer by molecular subtype: analysis of the MEND study.”

C-Reactive Protein

“C-reactive protein (CRP) is associated with risk and aggressiveness for several types of cancer.”

When there is inflammation in the body, levels of the C-reactive protein (CRP) increase. This easily measurable protein can be a useful biomarker of systemic inflammation, infection, or tissue damage. Previous studies show that circulating CRP has been elevated in various types of cancers; it has also been associated with tumor prognosis. Past studies about CRP’s association in breast cancer subtypes have been notably few, and none have focused on isolating subpopulations in Africa.

“Additionally, it is worth noting that most of these past studies have been conducted in populations from the United States and Europe, among mostly White study populations, and to our knowledge, none have been conducted in populations from Africa.”

The Study

In this study, 555 Nigerian participants were assembled—of which 296 were confirmed breast cancer cases, and 259 were controls. The researchers collected clinical and reproductive characteristics of each participant, including the controls. In their first analysis, the researchers observed that newly diagnosed cases of Nigerian breast cancer were significantly more likely to have high levels of highly-sensitive CRP (hsCRP) compared to the controls. After adjusting for socio-demographic, clinical, and reproductive variables, the team still observed significant statistical significance for high levels of hsCRP associated with Nigerian BC. The findings from this cohort study also showed that high hsCRP was associated with a four-fold increased odds of BC.

“We also provide novel evidence of associations between hsCRP and BC molecular subtypes, with significant associations observed for luminal A, TN, and HER-enriched subtypes.”

Conclusion

“In conclusion, our analysis revealed a positive association between hsCRP and odds of BC, overall and for all molecular subtypes. Because CRP is an easily measured biomarker in the blood, it may represent a useful predictor of BC in the Nigerian context. We urge larger studies, preferably prospective cohort studies, among women of African descent to further characterize this association.”

Click here to read the full research paper, published by Oncotarget.

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Oncotarget

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer

July 1, 2021

A novel therapeutic combination converts anti-proliferative effects in breast cancer cells to pro-apoptotic.

Trending With Impact: ONC201 Induces Apoptosis in Breast Cancer
3D illustration of the stages of cell apoptosis.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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In the 1990s, Dr. Wafik El-Deiry’s cancer research laboratory discovered a gene that encodes a protein, called death receptor 5, or TRAIL receptor 2. TRAIL is a protein that induces the process of cell death, or apoptosis. This pathway activates the body’s innate immune system and is capable of suppressing cancer cells by inducing apoptosis. 

After this discovery, researchers from the same lab considered the notion that increasing the production of TRAIL to enhance the body’s own immune response may have a safe therapeutic benefit in the treatment of cancer. The team searched for small molecules capable of upregulating the TRAIL gene and discovered the therapeutic compound TIC10, also known as ONC201. ONC201 is a well-tolerated drug currently being evaluated in advanced clinical trials for the treatment of various malignant solid tumors, including refractory metastatic breast cancer.

Researchers in Dr. El-Deiry’s laboratory have continued to investigate this drug in order to learn more about how it works, and what tactics or combinations may be used to produce better results for cancer patients. In a 2016 study, the researchers learned that ONC201 produces heterogeneous results in different tumor types.

“The question is, with this specific drug, what is the pattern of response, what determines that, and how can we get it to work a little bit better,” Dr. El-Deiry said in a recent Oncotarget interview.

Based out of Temple University, Fox Chase Cancer Center, Brown University, and the El-Deiry Cancer Research Laboratory, researchers wrote a paper detailing their latest study on ONC201. The paper was published by Oncotarget in 2020 and entitled, “TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.”

THE STUDY

Led by first-author Dr. Marie Ralff, the researchers in this study found that ONC201 induces differential responses across various breast cancer tumor subtypes. Few breast cancers are responsive to TRAIL, and one subtype that is responsive to TRAIL is triple-negative breast cancer.

“We saw that in some of these tumor types (the triple-negative breast cancer type in particular) the compound was having a pro-apoptotic effect, and in other [breast cancer] tumor types, it was having an anti-proliferative effect,” said Dr. Ralff.

When comparing in vivo and in vitro results of the drug, the team found that the pro-apoptotic effects translated to efficacy, while the anti-proliferative effects did not. The researchers then decided to investigate strategies to convert breast cancer cell response to ONC201 from anti-proliferative to apoptotic. ONC201 affects two known mechanisms of TRAIL resistance in breast cancer: death receptor 5 and anti-apoptotic proteins. This fact led the researchers to introduce a TRAIL receptor agonist antibody in combination with ONC201.

“If we pretreat TRAIL resistant breast cancer cells with ONC201, the level of surface death receptor 5 goes up and the intracellular levels of anti-apoptotic proteins go down, thereby priming the cells to undergo death through the TRAIL pathway. So, if we then add in a TRAIL receptor agonist, it induces apoptosis in a very potent way,” Dr. Ralff said.

CONCLUSION

“The concept is when cells are treated with the small molecule compound, not a whole lot happens. When cells are treated with TRAIL, not a whole lot happens. When you put them together, it’s like flipping a switch. The cells now undergo potent cell death,” Dr. El-Deiry said.

The potential efficacy of this therapeutic combination was strengthened by results in the study showing that ONC201 paired with the TRAIL receptor agonist antibodies is non-toxic to fibroblasts. The researchers also showed that the natural killer cells are only active against the breast cancer cells that have been exposed to ONC201. In vivo studies reaffirmed the safety of this combination in mouse models.

Click here to read the full research  study, published by Oncotarget.

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Trending With Impact: Low-Dose Chemo Inhibits Resistant Breast Cancer

June 18, 2021

In this trending in vitro study, researchers assessed the efficacy of low-dose 6-mercaptopurine and 5-azacitidine to inhibit high resistance triple-negative breast cancer cells.

Photomicrograph of a breast cancer (grade 3 invasive ductal carcinoma) with frequent mitoses (mitotic figures), including a large central atypical mitoses.
Photomicrograph of a breast cancer (grade 3 invasive ductal carcinoma) with frequent mitoses (mitotic figures), including a large central atypical mitoses.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Triple-negative breast cancer (TNBC) accounts for 10-15% of all breast cancers. “Triple-negative” in this subtype of breast cancer cell refers to the lack of HER2 protein and estrogen and progesterone receptors. This means that TNBC cannot be treated with hormone inhibition and must be treated with conventional chemotherapy. In addition, many of these breast cancer cells can opportunistically switch between proliferation and quiescence—a difficult phenotype to treat. Patients diagnosed with this highly adaptable cancer frequently relapse and develop resistance to treatments.

In 2021, researchers from The University of Texas MD Anderson Cancer Center conducted a research study in hopes of developing a safe and effective therapeutic combination to treat resistant triple-negative breast cancer. Their paper, published in Oncotarget’s Volume 12, Issue 7, was entitled: “Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine.” 

The Study

“Evidence suggests that SUM149-metabolic adaptable (MA) cells are a suitable model of resistant human triple-negative breast cancer (TNBC) cells that can survive bottlenecks in the body, including therapeutic interventions, by opportunistically switching between quiescence and cell proliferation [5, 7, 8].”

In this in vitro study, researchers cultured three highly drug-resistant and metastatic progenitor-like TNBC cell lines with opportunistic switching between quiescence and proliferation. Researchers focused on designing a safe treatment that is effective in both low- and high-risk patients. The researchers note that it was critical to their study that the regimen is proven safe to administer to patients for early use in the minimal residual disease (MRD) stage after surgery, and before clinical metastasis is detected.

“For a potential therapy to be suitable at the MRD stage, it must be safe (an important criterion prior to clinical relapse) and disrupt heterogeneous progenitor-like cancer cells that evolve into clinical metastases.”

Two chemotherapy and immunosuppressive drugs (ribonucleoside analogues) were tested on the cell lines at low doses for the sake of viability in the MRD stage: 6-mercaptopurine (6-MP) and 5-azacitidine (5-AzaC). Both of these drugs have been clinically proven to be well-tolerated and to have drug-sensitizing, quiescence-stabilizing, and apoptosis-inducing effects in cancer cells.

“We chose 5-AzaC because it could complement 6-MP’s effects on the transcriptome and epigenome, and—as indicated by many Phase 1 clinical trials—5-AzaC is well tolerated [11].”

Results & Conclusion

“Our studies suggest that low-dose 6-MP, which is a purine analogue and very effective in maintaining remission in IBD [9], inhibits highly adaptable TNBC cells in our model, presumably by disrupting their transcriptome and epigenome.”

Researchers found that these low-dose therapeutics take several weeks to become effective. Despite the low dose, 6-MP (complimented by 5-AzaC) was capable of inhibiting highly adaptable TNBC cells. The researchers also point out that, based on decades of 6-MP’s use in patients with inflammatory bowel disease (IBD), this drug may be used regularly to modulate the immune system and prevent disease recurrence through its ability to inhibit chronic inflammation associated with advanced cancers.

“We suggest that low dose 6-MP and other drugs that would complement 6-MP’s action, such as 5-AzaC, could be suitable for preventing recurrence and metastasis in high-risk breast cancers. 6-MP could be taken lifelong if it is necessary for maintaining a long-term remission.”

Click here to read the full scientific study, published by Oncotarget.

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Oncotarget

Trending with Impact: Benign, Borderline, and Malignant Breast Tumors

March 19, 2021


Researchers conducted a 2021 study to better characterize phyllodes tumors and other breast fibroepithelial lesions in order to improve diagnosis and treatment for patients.

Photomicrograph showing histology of a benign phyllodes tumor of the breast, from sections of an excision specimen (lumpectomy).
Photomicrograph showing histology of a benign phyllodes tumor of the breast, from sections of an excision specimen (lumpectomy).

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Thankfully, around 80% of lumps found in human breasts turn out to be benign, or indolent, fibroadenoma (FAD). FADs fall into a category of breast fibroepithelial lesions (FELs), which include many heterogeneous pathological tumors, ranging from benign FADs to rare and potentially aggressive phyllodes tumors (PTs). After examination by a physician, these FELs may be diagnosed as either benign, borderline, or malignant. 

However, there is a need to improve accurate diagnosis and distinction between FELs using a marker-based diagnostic approach. In an effort to better characterize FELs, researchers from India’s CSIR-Centre for Cellular and Molecular Biology, Institute of Bioinformatics, Gandhi Hospital, Government Medical College, and Manipal Academy of Higher Education conducted a trending 2021 study, titled: “Quantitative proteome profiling stratifies fibroepithelial lesions of the breast.”

“The current grading system remains unreliable in differentiating these tumors due to histological heterogeneity and lack of appropriate markers to monitor the sudden and unpredictable malignant transformation of PTs.”

The Study

To begin identifying the differentially expressed genes and proteins among FADs and PTs in benign, borderline, and malignant states, the researchers conducted quantitative global proteomics on Formalin-Fixed Paraffin-Embedded (FFPE) tissue sections. They conducted a principal component analysis of the protein expression matrix to identify the overlapping proteomic profiles among FELs.

“Interestingly, we observed FADs and benign PTs clustered together compared to borderline and malignant ones, albeit with overlapping protein expression profiles.”

When FADs were compared with benign PTs, the researchers identified 32 proteins in FAD that were differentially regulated. The researchers elucidated many important distinctions between benign, borderline, and malignant FADs and PTs, and identified at least three potential prognostic markers that may aid in patient diagnosis and treatment. The progression of PTs from borderline to malignant and their mechanistic framework was clearly explained by the researchers in this study.

“The presence of extensive ECM proteins and EMT markers led us to hypothesize a model of deposition and degradation of these proteins thus triggering ECM remodeling and EMT acquisition in borderline PTs leading to its malignant state. Enrichment of platelet degranulation factors in malignant PT indicates active angiogenesis during this transformation.” 

The Study

“Herein, our initial findings suggest that MUCL1, HTRA1, and VEGFD can be used as potential proteomic markers that could augment existing diagnosis, and help in monitoring the progression of the disease.” 

Additional characterization of FELs using different omics platforms was recommended by the researchers to help better understand and manage the dynamics of PTs and malignant breast tumors.

“The present work shed light on a brief mechanistic framework of PTs aggressive nature and present potential biomarkers to differentiate overlapping FELs that would be of practical utility in augmenting existing diagnosis and disease management for this rare tumor.”

Click here to read the full scientific study, published in Oncotarget.

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Oncotarget

Trending with Impact: New Prognostic Parameters for Breast Cancer

February 16, 2021

Different imaging and assessment tools across multiple clinics can result in varied prognostic values. Researchers from Japan conducted a retrospective study of harmonized pretreatment volume-based quantitative FDG-PET/CT parameters for prognostic values in breast cancer patients.

PET Scan image of whole body Comparision Axial, Coronal plane in patient breast cancer recurrence treatment.

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Breast cancer consists of a wide variety of tumor types, symptoms, disease progression courses, and responses to treatments. In the clinic, researchers decide which disease interventions to use by evaluating the patients’ stage of tumor-node-metastasis (TNM), histologic tumor grade, and the levels of hormone receptors and molecular markers that are present.

Standardized uptake value (SUV), metabolic tumor volume (MTV), and tumor lesion glycolysis (TLG) are derived from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). These variables have also been reported to correlate with clinicopathological prognostic factors and are considered predictive factors of prognosis.

Breast Cancer Prognostic Parameters

“Recently, noninvasive diagnostic tools have been gaining popularity for prediction of tumor behavior, with magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) with magnetic resonance imaging (MRI) reported to provide surrogate imaging biomarkers showing correlations with clinicopathological prognostic factors [2, 3].”

In a multi-institutional retrospective study in Japan, researchers—from the Hyogo College of Medicine, Nippon Medical School Hospital, National Cancer Center Hospital, Kinki University Faculty of Medicine, and Gunma Prefectural College of Health Sciences—explain that the factors and algorithms used by different assessment tools across multiple clinics can result in varied standardized uptake values. These inconsistencies have provided an opportunity for the researchers to standardize parameters of prognostic values when imaging breast cancer patients to improve patient outcomes.

“Thus, a harmonization strategy is necessary for comparing semi-quantitative PET parameters among available imaging methods, which is a notably relevant issue for multicenter trials employing different PET systems.”

The Study

Researchers gathered records of 546 patients treated from 2010 to 2016 with stage I–III invasive breast cancer. Of those patients, 344 were estrogen receptor (ER)-positive/human epidermal growth factor receptor two (HER2)-negative, 110 were HER2-positive, and 92 were triple-negative. The patients were treated at four separate institutions using different PET/CT scanner systems. In addition to surgeries, chemotherapy, and radiotherapy, patients were assessed during their follow-up appointments.

“Mammography, ultrasound, CT, bone scanning, and FDG-PET/CT were used for determining disease recurrence, metastasis, and progression during follow-up.”

Researchers in this study retrospectively performed histological and statistical analyses of overall survival and recurrence-free survival in patients of each breast cancer subtype group.

“An experienced reader (12 years of experience with oncologic FDG-PET/CT) who had no knowledge of other imaging results or clinical and histopathologic data retrospectively reviewed all of the FDG-PET/CT images.”

They found that the average maximum standardized uptake values (SUVmax) for HER2-positive and triple-negative tumor patients were higher than in patients with ER-positive/HER2-negative tumors.

“Harmonized primary tumor and nodal maximum SUVmax, metabolic tumor volume (MTV), and TLG indicated in pretreatment FDG-PET/CT results were analyzed.”

Conclusion

Results from this study suggest that harmonized PET classifications with final clinical response assessments demonstrate a better ability to predict disease-free survival compared to non-harmonized PET classification.

“We concluded that harmonized quantitative volume-based values, especially those for the primary tumor and nodal SUVmax and TLG, obtained with FDG-PET/CT can provide useful information regarding prognosis for both recurrence and death in patients with operable invasive breast cancer, including all three main subtypes. The findings presented here are considered useful for improving care of individual patients.”

Click here to read the full retrospective study, published in Oncotarget.

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Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Trending with Impact: Review of HER2 Variants in Breast Cancer Tumors

December 31, 2020

This review compiles splice variations in HER2 breast cancer, specifically in the context of the tumor environment, and co-expression of variants. The study also provides an up-to-date (as of Nov. 2020) account of HER2 and HER2 variant patterns of resistance to anti-HER2 therapies and other interventions.

Photomicrograph of immunohistochemistry for HER2, showing positive cell membrane staining in this infiltrating ductal carcinoma
Photomicrograph of immunohistochemistry for HER2, showing positive cell membrane staining in this infiltrating ductal carcinoma

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news and articles about the latest trending publications here, and at Oncotarget.com.

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According to Cancer Research UK, breast cancer occurs in one in every eight women within their lifetime and is the second highest cause of cancer related deaths in the UK. Breast cancer is a blanketed term for a wide variety of tumors that occur in the mammary glands. In over 20% of breast cancers, the human epidermal growth factor receptor two gene, officially named ErbB2 but otherwise known as HER2, is overexpressed. HER2 is a member of the epidermal growth factor receptor family of EGFR, HER2, HER3, and HER4. Overexpression of the HER2 protein was discovered in 1987 as a biomarker associated with poor prognosis and aggressive tumor types in breast cancer. This finding has accelerated research studies and progress in HER2 diagnostic testing and targeted therapeutics. However, the issue of HER2 resistance in these targeted therapies remains problematic.

“At the present time, we have an incomplete understanding of why patients with HER2+ breast cancer exhibit variable responses or resistance to targeted therapies [73, 74].”

Researchers from the Translational and Clinical Research Institute at Newcastle University in the United Kingdom have compiled a review of variations in HER2 breast cancer, specifically in the context of the tumor environment and when multiple variants are co-expressed at altered ratios. Their study also provides an up-to-date (as of Nov. 2020) account of the current landscape of HER2 variants and links this to patterns of resistance against HER2 therapies and other interventions.

“It is clear HER2 expression is not as simple as a single oncogenic overexpressed protein. It is likely many variants, arising from splicing and other mechanisms, are present in tandem. The relative ratios of these are likely to fluctuate depending on cellular conditions, during tumorigenesis and breast cancer progression.”

HER2 Variants & Co-expression

This paper provides an exquisitely detailed description and explanation of the HER2 protein structure, signaling pathways, sub-typing, and in-depth treatment functionality of a number of different HER2 targeted therapeutics. 

“Different forms of the HER2 protein exist within tumours in tandem and can display altered biological activities.” 

The unique interest in researching variations in HER2 breast cancer has increased since the identification of Δ16-HER2: a particular splice variant and link to resistance of anti-HER2 therapies. The “Δ16” in Δ16-HER2 refers to the lack of exon-16, which encodes a small extracellular portion of the DNA. Δ16-HER2 represents approximately 9% of the normal HER2 transcripts and its expression is considered common in breast cancer. Previous studies have identified Δ16-HER2 and HER2 normal transcripts can be co-expressed at varying levels in breast carcinomas. 

In the variant P100, less is known about this truncated HER2 protein. It has been hypothesized that P100 reduces the efficacy of monoclonal antibody HER2 treatments.

The splice variant Herstatin is produced by the retention of intron-8 in the HER2 protein. Herstatin acts as a tumor suppressor by blocking HER2 activity and cell proliferation, while promoting apoptosis. The researchers mention that it is important to note that cells expressing high levels of Herstatin are more sensitive to Tamoxifen.

“It’s noteworthy that one study proposed that the presence of Herstatin transcript does not segregate by tumour grade or size, patient age, lymph node involvement or ER status and that mRNA transcripts were present in matched non-cancerous breast tissue and breast carcinomas [96].”

Researchers in this review note that identifying and assessing the expression ratios of these different variants and classifying them as prognostic and predictive biomarkers may aid in further personalized treatment of breast cancer in HER2 positive patients.

Testing and Research Landscape

“Studying splicing regulation and how this is altered in breast cancer could explain patterns of expression and how these link to treatment resistance [111].”

The researchers write that tests assessing for both HER2 status and HER2 variant expression could potentially refine their predictions of a patients’ response to treatment. One common way that researchers gauge levels of HER2 proteins, and only some HER2 variants, is through immunohistochemistry tests. mRNA assessments are also used to identify gene expression patterns. Another biomarker test the researchers noted that may be best used for prognostic predictions is the Enzyme-Immunoassay—to assess levels of plasma or serum HER2 (sHER2) in the blood produced by cleavage or splicing.

“Cohort studies have identified sHER2 testing as a useful complementary test to IHC owing to the correlations between high sHER2 and aggressive tumour phenotypes such as invasion and metastases.”

Targeted HER2 Treatments

The review elaborates in detail about targeted treatments for HER2 breast cancer, which include: trastuzumab, pertuzumab, lapatinib, and T-DM1. They note that endocrine therapy is utilized for ER positive patients and chemotherapy, radiotherapy, and surgery are all still utilized.

Conclusion

“Work in vitro and in vivo as well as analysis from clinical trials has identified patterns of resistance to the standard of care treatment options in HER2+ patients which are correlated to variant expression.” 

This goal of their review was to summarise the current landscape of HER2 variant research and to explain why researchers should consider HER2 variant levels and ratios when offering the best treatment plan for breast cancer patients.

Click here to read the full review, published in Oncotarget.

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Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.


For media inquiries, please contact media@impactjournals.com.