New Biological Approaches Shed Light on the Genomics of Cervical Cancer

In May 2018, Becky Wallace received a call from her gynecologist. Abnormal cells had shown up on Wallace’s recent Pap test, so she needed additional testing.

“I’d been seeing my gynecologist for 10 years at that point. She delivered my two daughters,” says Wallace, now 36, who lives in San Jose, California. “Since I’d never tested positive for HPV or had an abnormal Pap smear, she told me she was not too worried about it.”

Wallace went in for a biopsy of her cervix, the narrow passageway of tissue between

the vagina and the uterus. She expected the results in three or four days, but it took several doctors two weeks to come to a conclusion about the nature of the abnormal cells. Finally, a nurse called and asked her to come in before the doctor left for lunch. Wallace knew it was serious.

“My doctor said, ‘I’m sorry, but you have cervical cancer.’ It was a rare type, adenosquamous carcinoma, that only makes up about 5% of cases,” Wallace recalls.

Wallace had a cone biopsy, an office-based procedure that removes a layer of cervical tissue to be examined under a microscope. In stage 1 disease, in which cancer cells have not spread beyond the cervix, this procedure can be enough to remove all the cancer.

Stage 1 is curable for most women, although some need a complete hysterectomy (removal of the uterus, including the cervix), with or without radiation, plus chemotherapy. Stage 2, in which the cancer has not reached the walls of the pelvis, also has high cure rates. Wallace had stage 1b2, the tumor didn’t extend beyond her cervix but was larger than 2 centimeters. She had a radical hysterectomy, which involves removing the uterus, cervix and part of the vagina.

“After my radical hysterectomy, I was told that there was less than a 4% chance that my cancer would come back, because there was nothing in my lymph nodes or any of the surrounding tissue,” she says.

Wallace was cancer-free for a little over a year. Then, in October 2019, she called her oncologist about abdominal and vaginal pain. The doctor brought her in for a scan, which revealed tumors on her pelvis and liver.

When cervical cancer spreads past the pelvis and doctors cannot surgically remove it or radiate it, there are fewer treatment options. So far, Wallace is responding well to chemotherapy with carboplatin, Taxol (paclitaxel) and Avastin (bevacizumab).

“I knew going in, though, with this recurrence, this cancer may just keep popping back up,” she says. “But I beat it once before, and I’m going to beat it again.”

New research aims to provide more and better options for women like Wallace. Researchers are working to harness the promise that genomic medicine has brought to other cancers and bring it to bear on cervical cancer.

“In the last few years, we’ve learned a lot about the genomics of cervix cancer,” says Dr. Janet S. Rader, chair of the department of obstetrics and gynecology at the Froedtert & Medical College of Wisconsin in Milwaukee. “The hope is that new drugs that get approved to target

gene mutations in other cancers will also be approved in cervical cancer.”

Studies already underway are exploring whether drugs approved by the Food and Drug Administration (FDA) to treat other cancers, including breast and ovarian, may also shrink cervical tumors.

CLASSIFYING CERVICAL CANCER

Two main types of cervical cancer exist: squamous cell carcinoma and adenocarcinoma. In squamous cell carcinoma, cancerous cells develop near the base of the cervix, closer to the vagina. Gynecologists collect cells from this part of the cervix during a Pap test. In adenocarcinoma, cancer cells develop higher in the cervix, closer to the uterus, and are harder to reach.

“The way cervical cells are collected requires scraping around the outer edge of the cervix and then inserting the brush inside, but unless you get a really good brushing, you might miss the glandular cells that cause adenocarcinoma altogether,” says Dr. Alexi Wright, director of gynecologic oncology outcomes research at Dana-Farber Cancer Institute in Boston, who has a master’s in public health.

Less common cervical cancers include Wallace’s type, adenosquamous carcinoma, and mixed carcinomas, which have characteristics of both major types. Most but not all cervical cancers develop from chronic, recurrent infections with HPV, a sexually transmitted infection. Researchers only recently learned that some adenocarcinomas, which may be more common in older women, seem to be unrelated to HPV.

As uptake of the HPV vaccine, which the FDA approved in 2006, has become more widespread, HPV and cervical cancer rates have steadily fallen. But unvaccinated women and those exposed to HPV before the vaccine existed remain susceptible.

“I was clueless. I didn’t even know what HPV was,” says LaTasha Bostick, a 40-year-old floral designer and cervical cancer survivor in Jacksonville, Florida. Routine Pap tests and HPV screenings help doctors catch cervical lesions at early, sometimes even precancerous, stages, known as cervical intraepithelial neoplasia. In part because of these screenings, cervical cancer rates dropped by more than 50% between 1975 and 2015.

Bostick received a stage 1 diagnosis in 2011. About six months after going to the emergency room for a ruptured ovarian cyst, she still had irregular bleeding and vaginal pain. She saw a gynecologist at Mayo Clinic in Jacksonville, who diagnosed the cervical cancer.

“With all the pain and bleeding that I went through, it feels like a blessing that it was only stage 1,” Bostick says.

After a cone biopsy, Bostick had no remaining cancer cells. She went in for Pap tests every three months for about a year to make sure she remained cancer-free. Today, she is an advocate for the HPV vaccine. “I’ve got a daughter and son coming up behind me. I’ve got to protect them,” she says. “It’s time to vaccinate.”

BLOCKING CANCER CELLS’ PATH

Decoding a person’s inherited DNA or the DNA of a tumor can help patients and their doctors make more informed decisions about health care from prevention to diagnosis and treatment. Genes can influence risk of disease, severity of a disease, and which treatments work and how well.

Sometimes specific gene variants in a tumor drive its growth and survival, and medications that disable or other- wise interfere with that gene may be available. This approach, a type of genomic or precision medicine, has helped many people with cancer. “But,” Wright says, “cervical cancer treatment is behind other cancers — ovarian, breast, lung — in using these rational targets.”

Doctors and patients are enthusiastic about precision medicine: It targets a specific feature of an individual’s cancer cells, based on gene sequencing or protein analysis of the tumor, rather than targeting all cells, as conventional one-size-fits-all chemotherapy does.

In 2017, researchers with the Cancer Genome Atlas published the results of the first comprehensive genomic study of cervical cancer. They sequenced the genome, the complete genetic makeup, of 178 primary cervical tumors.

The findings revealed that 70% of cervical cancers had gene changes in one or both of two important cell-signaling pathways, PI3K/MAPK and TGF-beta. These channels of communication between cells and often allow cancer to grow and thrive. Current research examines drugs that might cut off signaling in these and other crucial pathways in other cancers, halting the disease’s progress.

“PIK3CA is one of the most common gene changes,” says Rader. “It’s in over 40% of cervical cancers, so that makes a nice drug target.”

Alpelisib (Piqray) was approved (late last year) to target this gene alteration in breast cancer, and I’m sure there will be studies looking at it for the cervix.”

The Cancer Genome Atlas study also showed that some HPV-negative cancers look more like uterine cancers than other HPV-positive cervical cancers. The researchers don’t know whether HPV-negative cancers respond to treatment in the same way that HPV-positive ones do.

In several of the cervical cancer cases, the researchers found gene fusions, part of the DNA from one chromosome moves into another, involving the gene BCAR4. Several types of cancer sometimes involve gene fusions. In breast cancer, the BCAR4 fusion may make tumors responsive to a drug called Tykerb (lapatinib); perhaps this medication could benefit some women with cervical cancer, too.

Cervical tumors can also have mutations in EGFR, a gene variant involved in some lung, breast, skin, colorectal and nervous system cancers. Numerous EGFR inhibitors have FDA approval to treat other cancers.

KRAS gene mutations are also found in cervical cancer. Already known to be involved in colorectal, lung, pancreatic, uterine and ovarian cancers, KRAS mutations are the driving force behind about one in three cancers. The first drug designed to block KRAS, AMG 510, previously considered an “undruggable” target, recently showed promising results in the first human trial.

INVESTIGATING OTHER OPTIONS

Among the many gene variants found to have a role in cervical cancer is the gene FANCD2. Notably, it belongs to the same group of genes as BRCA, which is often mutated in breast and ovarian cancer tumors. Women whose cancer has this mutation might benefit from a class of drugs called PARP inhibitors.

PARP is a substance in cells that helps damaged DNA repair itself. Critical for survival of healthy cells, PARP can also help cancer cells survive treatment. By blocking this enzyme, PARP inhibitors prevent some cancer cells from repairing their own DNA so that they die. Essentially, the drugs lower cancer cells’ defenses against chemotherapy and might have a role in cervical cancer, too.

In a small phase 1 trial, women with cervical cancer received a PARP inhibitor combined with two chemotherapy drugs. “Most of the patients in the study had a good response, comparable to the standard of care and maybe with (fewer toxic side effects),” says lead study author Dr. Ritu Salani, a gynecologic oncologist at The Ohio State University College of Medicine in Columbus.

Contrary to the researchers’ expectations, mutations in FANCD2 may not be the reason the drug works. “It overlaps with the BRCA gene, so it made sense that PARP inhibitors might work, but when we looked, we found no correlation between patients who had the (mutation) and those who responded to the drug,” Salani says.

The researchers are now investigating another possible genetic biomarker of cervical cancer response to these drugs: homologous recombination deficiency, a different type of impairment in DNA repair. This deficiency is present in ovarian cancers that respond to treatment with PARP inhibitors.

“With the right combination of drugs, I think we could really make an impact on cervical cancer with PARP inhibitors,” Salani says.

Nerlynx (neratinib), a dual inhibitor of EGFR and HER2, is FDA approved for breast cancers that have a HER2 mutation and might also help women with certain cervical cancers that have this type of mutation. In the phase 2 SUMMIT trial, which enrolled patients with HER2-mutated tumors of many origins, a little over half the women with cervical cancer who received the drug benefited. The trial is ongoing.

“HER2 mutations are found in about 5% of patients with metastatic cervical cancer, and they might be a sign of a negative prognosis,” says Dr. Anishka D’Souza, a gynecologic oncologist at Keck School of Medicine of University of Southern California in Los Angeles. “HER2 is a potential drug target in these patients, and they tolerated neratinib relatively well.”

Widespread screening and HPV vaccination mean that cervical cancer is becoming less common in the United States. That’s great news for women, but the lower numbers may slow the progress of desperately needed research that depends on volunteers.

“It’s key for us to have larger groups of women that we can follow over time,” Wright says, “both to better understand which genomic characteristics we can target and which will predict a better prognosis.”