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Monday, January 8, 2018

A new genetic-based model may explain how ductal carcinoma in situ (DCIS) progresses to a more invasive form of cancer, according to researchers at The University of Texas MD Anderson Cancer Center, Houston.

The study provides new insight into how DCIS leads to invasive ductal carcinoma (IDC), and provides a clearer understanding of why some of these cancers go undetected (Cell 2018; The discovery was made possible by the researchers’ development of a new analytical tool called topographic single cell sequencing (TSCS).

“While DCIS is the most common form of early-stage breast cancer and is often detected during mammography, 10-30 percent of this type of cancer progresses to IDC,” said Nicholas Navin, PhD, Associate Professor of Genetics. “Exactly how DCIS invasion occurs genomically remains poorly understood due to several technical challenges in tissue analysis.”

The problem lies within the tumor itself, with cells that often have individual genetic characteristics, known as intratumor heterogeneity. Their unique cellular makeup makes treatment more difficult, while a low number of tumor cells in the breast milk ducts make the cells harder to spot due to their scarcity.

Navin’s team found that genome evolution occurs in the ducts before cancer clones can be disseminated by breaking through the thin layer of tissue known as the basement membrane. They found that multiple cancer cell clones co-migrate from the ducts into adjacent regions to form invasive tumors.

Previous single cell DNA sequencing methods have emerged as powerful tools for understanding intratumor heterogeneity, but they delete information about individual tumor cells’ precise location within the tissue. Cellular spatial data is critical for knowing whether tumor cells are DCIS or IDC. TSCS more accurately measures and describes specific characteristics of single tumor cells.

“Because TSCS provides spatial information on cell location, it represents a milestone over previous methods that can only use suspension of cells, therefore losing all spatial information,” said Navin. “We hypothesized that invasive cells share a direct genomic lineage with one or more single cells in the ducts. Our data revealed a direct genomic lineage between both DCIS and IDC, and further showed that most mutations and DNA copy number aberrations evolved within the ducts, prior to invasion.”

To arrive at these findings, Navin’s team used exome sequencing and applied TSCS to 1,293 single cells from 10 patients with both DCIS and IDC. “TSCS and other similar single cell sequencing methods hold great potential for opening new avenues of investigation in early stage cancers,” he noted. “It is our hope that this type of study will shed light on the enigmatic question of why some pre-malignant cancers do not progress while others become invasive.”

Monday, January 8, 2018

The presence in advanced breast cancer of mutational signatures characteristic of homologous recombination deficiency (HRD) was associated with improved clinical outcomes when treated with platinum-based chemotherapy, according to results published in Clinical Cancer Research (2017; doi:10.1158/1078-0432.CCR-17-194).

“Many patients with breast cancer, especially those with the difficult-to-treat triple-negative subtype, are treated with platinum-based chemotherapies like cisplatin, but not all have responses to this treatment,” said Steven J.M. Jones, PhD, Head of Bioinformatics and Co-Director of Canada’s Michael Smith Genome Sciences Centre at BC Cancer in Vancouver, British Columbia. “If we could better identify those who are likely to respond to platinum-based chemotherapy, we could optimize patient treatment.

“We found that whole-genome sequencing of breast cancers can reveal mutational patterns characteristic of HRD that identify patients who are likely to respond well to platinum-based chemotherapies,” added Jones. “As whole-genome sequencing becomes more affordable, this presents an opportunity to improve breast cancer treatment.”

Homologous recombination is one of several cellular mechanisms by which normal cells repair damaged DNA. Deficiencies in this pathway occur in many cancers, including the 5-10 percent of breast cancers with hereditary BRCA1 and BRCA2 mutations. In cells that are deficient in homologous recombination, the DNA develops signature mutational patterns, said Jones.

Because it is known that platinum-based chemotherapy is particularly effective for patients with BRCA1 or BRCA2 mutations, Eric Y. Zhao, a graduate student in Jones’ laboratory, and colleagues set out to determine whether genomic mutational patterns characteristic of HRD, which are found in as many as 20-40 percent of breast cancers, may also be associated with good responses to platinum-based chemotherapy.

The researchers performed whole-genome sequencing on tumor tissue and matched normal tissue from 93 patients with breast cancer, 33 of whom had been treated with a platinum-based chemotherapy. After analyzing the data for the presence of six HRD-associated mutational signatures, they used a mathematical model called HRDetect, previously shown to predict BRCA1 and BRCA2 deficiency, to calculate a HRDetect score for each breast cancer. Nineteen breast cancers had high HRDetect scores (greater than 0.7), 37 had moderate scores (0.005-0.7), and 37 had low scores (less than 0.005).

“Importantly, all seven cancers with pathogenic BRCA1 or BRCA2 mutations had high HRDetect scores,” said Jones. “Thus, our study validated HRDetect using an independent cohort, which is important because whole-genome sequencing protocols can be variable across institutions.”

Further analysis showed that after adjusting for BRCA1/2 mutation status, high HRDetect scores were significantly associated with clinical improvement, as assessed by radiographic tumor shrinkage, following platinum-based chemotherapy. Among the 26 patients who had been treated with a platinum-based chemotherapy and for whom imaging data were available, clinical improvement was observed for eight of the 11 patients whose breast cancers had high HRDetect scores but only two of the 15 patients whose breast cancers had moderate or low HRDetect scores. Three of the eight patients with high HRDetect scores who had clinical improvement had known or likely pathogenic BRCA1 or BRCA2 mutations.

The median total duration on platinum-based chemotherapy and median overall survival was 3 months and 1.3 years longer, respectively, for those with high HRDetect scores compared with those with low HRDetect scores. However, the authors cautioned that these results should be interpreted carefully as they were calculated based on data from a small number of patients.

According to Jones, the main limitation of the study is that it was observational and therefore, does not establish causation. He explained that establishing causation would require a randomized controlled trial but that the findings of their study will likely be helpful in the design of such a trial.

Monday, January 8, 2018

Nearly 10 percent of eligible women in a recent study did not receive radiation therapy after breast conservation surgery, although it is proven to reduce the risk of recurrence. The researchers, from Fox Chase Cancer Center and the Lewis Katz School of Medicine at Temple University, Philadelphia, also sought factors that led to omission of radiation in these women (J Surg Res 2018; doi:10.1016/j.jss.2017.08.008​). 

The researchers analyzed data from the National Cancer Database to examine the course of treatment for more than 10,000 women with unilateral breast cancer that was stage II or III at diagnosis. All women in the study received a combination of neoadjuvant chemotherapy and breast conservation surgery between 2008 and 2012. They found that 9.53 percent of the women who were eligible for radiation after the surgery did not receive it.

“Although neoadjuvant chemotherapy can be used to shrink tumors prior to surgery, radiation after breast conservation surgery remains standard of care and preoperative chemotherapy doesn’t eliminate the need for it. Radiation is still critical in reducing the rate of recurrence in women who undergo breast conservation therapy,” said Richard Bleicher, MD, a surgical oncologist at Fox Chase and senior author of the study. “We found that 3 percent of these women refused the radiotherapy, but we need to understand why the other 6 percent did not even have it recommended. Since all of these women had chemotherapy, an inability to tolerate the radiation may not be the primary reason.”

The study found that older age, insurance status, the facility type where the patient received treatment, geographic region, and more recent year of diagnosis were factors that led to omission of radiation as part of breast conservation therapy. The researchers were able to determine that race, education, income, comorbidities, rural versus urban setting, and tumor histology were not among the reasons women did not receive radiation.

Thursday, December 21, 2017

Molecular classification of the four distinct subtypes of gastric cancer could potentially shape tailored treatment options by helping to predict survival outcomes and patients’ response to chemotherapy (Clin Cancer Res 2017; doi: 10.1158/1078-0432.CCR-16-2211​).

In 2014, The Cancer Genome Atlas (TCGA) project discovered there are four molecular subtypes of gastric cancer, said the study’s lead author, Ju-Seog Lee, PhD, Associate Professor in the Department of Systems Biology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. The four subtypes are Epstein-Barr virus subtype (EBV), microsatellite instability subtype (MSI), genomically stable subtype (GS), and chromosomal instability subtype (CIN). 

Lee said most patients with early-stage gastric cancer are treated with a surgical resection, followed by chemotherapy. “However, outcomes vary significantly, and that difference in clinical outcomes is likely due to biological and molecular differences in tumors. These differences have not been fully understood,” he said.

To identify the clinical significance of the four subtypes, Lee and colleagues re-analyzed gene expression data for these subtypes using data from the gastric cancer cohort of the TCGA project. They used that data to develop prediction models and tested the models in two independent cohorts of 267 and 432 gastric cancer patients, respectively, in South Korea and at MD Anderson.

The researchers used the model to examine the prognosis of each subtype. Overall, they found that the EBV subtype was associated with the best prognosis for both recurrence-free survival (RFS) and overall survival, and the GS subtype was associated with the worst prognosis.

The MSI subtype was associated with a moderate prognosis. The CIN subtype was also associated with moderate prognosis, but poorer in the South Korean cohort than in the MD Anderson cohort. Lee said this suggests that the CIN subtype may be less homogeneous and therefore harder to characterize.

The study also sought to examine whether specific subtypes of gastric cancer were associated with a clinical benefit from adjuvant chemotherapy. The researchers based this part of the study solely on the MD Anderson cohort, because more than half of them had received adjuvant chemotherapy, compared with a smaller segment of the South Korean population.

This portion of the study indicated that patients with the CIN subtype received the greatest benefit from chemotherapy; the three-year RFS rate was 58.7 percent for those who had received chemotherapy, compared with 33.5 percent for those who had not. Patients with the GS subtype showed no benefit, while those with the MSI subtype showed a moderate benefit. The effects of chemotherapy on patients with the EBV subtype could not be assessed, because all the patients had received it, leaving no basis for comparison.

Lee said the failure of the GS subtype to respond to chemotherapy was one of the study’s most intriguing findings.

“This means that we need to find novel targets and drugs for this subtype,” Lee said, adding that patients with the GS subtype could now potentially be spared the damaging side effects of chemotherapy that will most likely not work.

Lee said the study’s results indicate that classifying gastric cancer cases according to subtype could provide guidance to physicians as they try to determine the best treatment option for a particular patient.

“These findings, if confirmed, could provide some information for personalized medicine,” Lee said. “As we learn more about the biological characteristics associated with each subtype, it will help determine which patients will benefit from immunotherapy, chemotherapy, or other treatment options.”

Lee said the primary limitation of the study is that data were collected retrospectively. Further research would be necessary to confirm the findings in a prospective study setting.

Wednesday, December 20, 2017

Pembrolizumab, a drug that has effectively extended the lives of countless people with many types of cancer, was recently approved by the FDA to treat people with metastatic gastric adenocarcinoma. The research that led to the approval was conducted at UCLA and 67 other sites in the U.S., Europe, South America, and Asia. 

“Stomach cancer is particularly challenging to treat, and when the disease progresses to the advanced stages, a cure is no longer possible,” said Zev Wainberg, MD, one of the leading investigators on this study and a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “Traditional treatments may control the disease for a short period of time, but eventually the tumor will regrow. The approval of pembrolizumab shows that immunotherapy is now a viable option for some of these patients, delivering responses that are long-lasting, and with little to no side effects.”

In the clinical trial, the drug was tested on 257 patients with the disease. Because so many of the patients in the study showed significant long-lasting responses, the FDA granted the drug accelerated approval in stomach cancer.

In the early and intermediate stages of gastric cancer, doctors can treat patients only in the affected area of the stomach with surgery, or traditional approaches such as chemotherapy and radiation. However, as the cancer progresses and localized treatments do not work, some people may be candidates for systemic therapies, said Wainberg, who also is an Associate Professor of Medicine at the David Geffen School of Medicine and Co-Director of the UCLA Gastrointestinal Oncology Program.

As the expected survival of patients with metastatic gastric cancer is less than 1 year, the approval of pembrolizumab now provides encouraging new hope for people whose stomach cancer has progressed on prior traditional and systemic treatments. In this study, the emphasis was on patients who express PD-L1, and the FDA approval is only in these patients. This is an example of a biomarker selected subgroup, which will help allow physicians to better identify patients who can potentially benefit from treatment based on features of their tumors, said Wainberg.

Results of the 2-year study showed that overall response rate was 12 percent. Among people in the trial that had PD-L1 expression, the overall response rate was nearly 16 percent. In people who responded to treatment, the average duration of response exceeded 12 months, a remarkable advance in this difficult disease. Some people receiving the drug did experience side effects such as fatigue and loss of appetite, but they were generally manageable.

Michael Teitell, MD, PhD, Director of UCLA’s Jonsson Comprehensive Cancer Center, said that “this approval marks another milestone as the tenth new indication for pembrolizumab in just 3 years. This new approval for stomach cancer is a testament to the work of our researchers and the progress we have made in using immunotherapy to treat this disease and other cancers.”

Further research is ongoing to explore combinations of pembrolizumab with other therapies, and help develop new treatment approaches for people with advanced stomach cancer. The goal is that the drug will become the standard of care for these patients in the near future, Wainberg concluded.