US Pharm. 2022;47(10):40-41.

Discovery Sheds Light on Cancer Chemotherapy Resistance

Researchers have uncovered a novel pathway that explains how cancer cells become resistant to chemotherapies, which offers a potential solution for preventing chemotherapy resistance. The research describes for the first time how a type of enzyme, previously known for its roles in DNA repair, prevents DNA damage in cancer cells and makes them tolerant to chemotherapy drugs.

“It provides us tools to manipulate and then break chemo-resistance in cancer cells,” said Marcus Smolka, interim director of the Weill Institute for Cell and Molecular Biology and professor of molecular biology and genetics in the College of Agriculture and Life Sciences. Diego Dibitetto, a former postdoctoral researcher in Dr. Smolka’s laboratory who is currently at the University of Bern in Switzerland, is the paper’s first author.

Many anticancer drugs work by creating blocks on the DNA of cancer cells as they replicate. During replication, DNA strands entwined in a double helix separate into two individual strands so each strand can be copied, eventually leading to two new double helixes. The junction where this separation and copying occurs is called a replication fork, which unzips down the double helix.

If these replication forks were cars on a road, chemotherapy drugs can be imagined as obstacles that interfere with the flow of the cars, thus stopping replication and breaking DNA. Cancer cells, however, slow down these forks, which allows them to avoid such collisions and protect their DNA, leading to drug tolerance.

This study reports, for the first time, how a kinase (enzyme) called DNA-PKcs acts as a sensor when a fork is stressed due to blocks and promotes slowing of the fork and chemo-resistance. DNA-PKcs has been known for its role in DNA repair related to immune system antibody generation and resistance to radiation. This is the first time the kinase has been associated with slowing a replication fork, a process called fork reversal. “It’s a completely new way of thinking about the action of this kinase,” Dr. Smolka said. “It’s not repairing DNA in this case; it’s slowing down forks to prevent breaks from happening in the first place.”

The results open the door to new cancer treatments, as DNA-PKcs inhibitors already exist and are being used for clinical trials in tandem with radiation therapies. In those treatments, radiation damages cancer cell DNA, and the thought was that inhibiting DNA-PKcs would limit cell repair. However, DNA-PKcs inhibitors do not work well in that context, as cancer cells have other ways to repair themselves.

This study provides early proof that a DNA-PKcs inhibitor could be effective in combination with chemotherapies, where chemotherapy drugs would create blocks to DNA replication, and the inhibitor would prevent the slowing of the replication forks that leads to chemo-resistance.

Fertility Preservation Measures Do Not Appear to Increase Breast Cancer Recurrence Risk

Women with a breast cancer diagnosis undergoing procedures for fertility preservation are not at increased risk of recurrence of the disease or disease-specific mortality, according to a study by Karolinska Institutet in Sweden that followed the participants for an average of 5 years. The results, published in JAMA Oncology, could provide safety and new hope to women who want to preserve their fertility after cancer treatment with chemotherapy.

Almost one in 10 women affected by breast cancer are of childbearing age and are at risk of infertility from chemotherapy treatment. With the hope of being able to have children after completing cancer treatment, many women choose to undergo procedures for fertility preservation with or without hormonal stimulation. These methods include cryopreservation, the freezing of embryos, female gametes (oocytes), and ovarian tissue.

“It is not unusual that women with hormone-positive breast cancer or their treating doctors opt out of the procedures for fertility preservation because of the fear that these procedures will increase the risk of cancer recurrence or death. In some cases, women are also advised to wait 5 to 10 years before trying to conceive, and with increasing age, fecundity in all women decreases. More knowledge is therefore needed about the safety of procedures for fertility preservation at the time of a breast cancer diagnosis,” said Anna Marklund, researcher in the Department of Oncology-Pathology, Karolinska Institutet.

In this study, researchers at Karolinska Institutet and Karolinska University Hospital investigated whether procedures for fertility preservation in connection with a breast cancer diagnosis lead to an increased risk of disease recurrence or death.

The registry study tracked 1,275 women of childbearing age who were treated for breast cancer between 1994 and 2017 in Sweden. Of these, 425 underwent procedures for fertility preservation with or without hormonal stimulation. The control group of 850 women was treated for breast cancer but did not undergo procedures for fertility preservation.

The women who underwent procedures for fertility preservation and the women in the control group were matched on age at diagnosis, calendar period at diagnosis, and healthcare region. The statistical data were taken from both nationwide healthcare registers and population registers with data on outcomes, disease- and treatment-related variables, and socioeconomic characteristics.

The proportion of women without relapse over the 5 years was 89% among those who underwent hormonal stimulation of the ovaries, 83% among women with ovarian tissue freezing, and 82% among women who did not undergo procedures for fertility preservation.

After treatment for breast cancer for 5 years, the survival rate was 96% in the group that underwent hormonal stimulation to freeze eggs or embryos, 93% in the group that underwent procedures for fertility preservation who did not undergo hormone stimulation, and 90% in the group that did not undergo procedures for fertility preservation.

Annual Screening Before Age 50  Years Cuts Down on Advanced Breast Cancer

A new study led by University of Ottawa (uOttawa) professors has found Canadian provinces that annually screen women aged 40 to 49 years had lower proportions of advanced breast cancer compared with women aged 50 to 59 years from provinces that did not provide annual mammograms.

The study, published in Current Oncology, found lower proportions of stage 2, 3, and 4 breast cancer in women aged 40 to 49 years and lower proportions of stage 2 and 3 breast cancer in women aged 50 to 59 years from provinces that screened the age 40- to-49-year subset annually.

“This is the first Canadian study to show that screening policies for women 40-49 impact women 50-59,” said colead author Dr. Anna Wilkinson, an associate professor in the Faculty of Medicine at uOttawa. “Women who are not screened in their 40s are presenting with later stage breast cancer in their 50s. This means more intensive treatment and a worse prognosis for these women.”

Dr. Wilkinson and fellow lead author Jean Seely reviewed the data of 55,490 women aged 40 to 49 years  and 50 to 59 years from the Canadian Cancer Registry who were diagnosed with breast cancer between 2010 and 2017. They evaluated the impact of the 2011 Canadian breast cancer screening guidelines by looking at changes in the incidence of breast cancer by stage from 2011 to 2017.

The authors found that since Canadian guidelines changed in 2011 to recommend against screening women aged 40 to 49 years, there has been a 13.6% decrease in incidence of stage 1 and a 12.6% increase in stage 2 for women in their 40s. For women in their 50s, the incidence of stage 2 increased by 3.1% over the same period. In provinces that did not continue to have organized screening programs for women aged 40 to 49 years, there was a 10.3% increase in stage 4 breast cancer in women aged 50 to 59 years over the 6 years.

Survival rates decrease in relation to the more advanced stage of breast cancer. The 5-year survival rate for stage 1 breast cancer is 99.8% compared with 23.2% for cancers diagnosed by stage 4. Such outcomes potentially lead to more advanced cancer and intensive treatments and surgeries and increased mortality.

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