HPV-Negative Cervical Cancer: Myth or An Area to Therapeutically Tackle?


The idea that HPV-negative cervical cancer is possible, especially in a disease that is mainly driven by HPV positivity, is not a unanimous opinion.

Maurie Markman, MD


That is the estimated number of cases of cervical cancer that were expected to be diagnosed in the United States in 2020.1 Of those, 4290 deaths would have likely occurred.

However, some numbers have turned a corner. Cervical cancer incidence and mortality rates have dropped significantly, in part due to screening via the Pap test, which has allowed for early cancer detection. 

Nearly all cervical cancers are driven by the human papillomavirus (HPV), and HPV vaccination is recommended in all boys and girls by the age of 13 years, according to the Centers for Disease Control and Prevention.1 According to the American Cancer Society, HPV vaccines do not protect against all HPV types—emphasizing the importance of adherence to cervical cancer screening guidelines.1 

The 5-year relative overall survival (OS) rate in the United States for cervical cancer is 66%; however, these rates differ for African American women who are aged 50 years and older (46%) and white women younger who are than 50 years (78%).1 For patients who have localized disease (44%), the 5-year OS rate is 92%.

HPV-Negative Cervical Cancer  

Conversely, another area of cervical cancer that is less discussed but has been documented, is HPV-negative disease. 

In a study of Belgium women with cervical cancer prior to 2000, 13% were found to have HPV-negative disease,2 while an additional trial reported 7.1% of women with HPV-negative cervical cancer between 2001 and 2008.3 Globally, the percentage of HPV-negative cervical cancer cases ranges from 7% to 11%.4-9

Potential explanations for HPV-negative results include cervical cancers that are independent of high-risk HPV, cervical cancers that lose HPV expression, cervical cancers due to low-risk and intermediate-risk HPV, misclassified cancers, and HPV testing methods, including false-negative results.10 One explanation for why the global rates of HPV-negative disease are so low is because of an increase in HPV testing overall, and improved testing methods over time.10

For example, in an observational study out of Spain, investigators reanalyzed a cohort of 136 women with cervical cancer who previously underwent HPV testing, 14 (10.2%) of which were found to be HPV negative through Hybrid Capture 2 testing. However, when investigators retested these samples with highly sensitive polymerase chain reaction techniques, 8 of the total cancers (5.8%) were actually found to be HPV negative.11 The confirmed HPV-negative cases were observed in 5 patients with adenocarcinoma and 3 with squamous cell carcinoma (P = .017). Additionally, HPV negativity showed a significantly worse disease-free survival than those with HPV‐positive tumors at 51.9 months versus 109.9 months, respectively (P = .010]. 

Furthermore, results of another study showed that next-generation sequencing, which was used to characterize primary cervical cancers, demonstrated 5% of 178 analyzed cervical cancers were HPV-negative and harbored relatively high frequencies of KRAS, ARID1A and PTEN mutations.12

However, the idea that HPV-negative cervical cancer is possible, especially in a disease that is mainly driven by HPV positivity, is not a unanimous opinion. Maurie Markman, MD, editor-in-chief, OncologyLive®, and physician and president of Medicine and Science at Cancer Treatment Centers of America, said that the issue surrounding HPV-negative disease is that the HPV may simply not be found through testing, but is present.

“If you're talking about the cervical cancer that we speak about, you can have the HPV found after very carefully searching, [even] if it's 1% [of HPV positivity] or less,” Markman said. “Some of this is definitional. The fact that you don't find it doesn't mean it isn't there.”

Furthermore, the possibility of not having HPV detected in a disease should not deter individuals from undergoing HPV vaccination nor regular cervical cancer screening, he emphasized.

“We can certainly show that 70% to 80% of HPV-positive cervical cancers are due to the 2 major types: HPV 16 and 18. There are another 20% to 30% of cervical cancers that are due to other [HPV] types, and there are dozens of HPV types. Therefore, it's not at all clear that the issue with lack of preventing cervical cancer has anything to do with being HPV negative. It's just there are types of HPV that we may not be including in the vaccine.” 

Cervical Cancer: Treatment Advances 

HPV status is not a factor of a treatment considerations for a patient with cervical cancer, Markman said. Overall, cervical cancer continues to be an active area of exploration beyond chemoradiation and surgery. Bevacizumab (Avastin) is also available in combination with paclitaxel plus cisplatin or topotecan as a treatment for patients with persistent, recurrent, or metastatic cervical cancer.

Immunotherapy has been an area of research in the space in recent years, following the FDAs’s 2018 accelerated approval of pembrolizumab (Keytruda) in patients with advanced, PD-L1–positive cervical cancer with disease progression on or after chemotherapy.

Clinical trials focusing on immunotherapeutic strategies, including combinations and targeting the up-front setting, continue to enroll patients with cervical cancer. For example, a single-arm, phase 2 trial is evaluating pembrolizumab, bevacizumab, and chemotherapy in patients with recurrent, persistent, or metastatic disease (NCT03367871), while the phase 1/2 SKYSCRAPER-04 trial (NCT04300647) is looking at atezolizumab (Tecentriq) with or without tiragolumab in patients with recurrent/metastatic PD-L1–positive cervical cancer. 

Moreover, the phase 3 FERMATA trial (NCT03912415) is looking at the PD-1 inhibitor BCD-100 combined with platinum-based chemotherapy with and without bevacizumab in the frontline setting of advanced cervical cancer. 

The investigational PD-L1 inhibitor balstilimab, alone and in combination with the CTLA-4 inhibitor zalifrelimab, is actively being explored in metastatic disease. The rolling submission was from an ongoing phase 2 trial (NCT03894215), which demonstrated that the monotherapy elicited encouraging responses in patients with advanced cervical cancer. However, the completion of a biologics license application for the drug in this setting has been delayed to the first half of 2021, in order to have data reviewed on 2 patients who went from having durable disease stabilization to confirmed responses on long-term treatment.13 The agent was also granted fast track status by the FDA in April 2020. 

An additional agent, tisotumab vedotin, has also shown antitumor activity. In data that were virtually presented during the 2020 ESMO Congress, the antibody-drug conjugate showed a 24% objective response rate (ORR) in patients with recurrent and/or metastatic cervical cancer who were previously treated with doublet chemotherapy and bevacizumab, if eligible, in the single-arm, phase 2 innovaTV 204 trial.14

Robert L. Coleman, MD, chief scientific officer of The US Oncology Research, explained that the year 2021 is expected to be a banner year for cervical cancer treatment. 

Robert L. Coleman, MD

“Other really important things that are happening in cervical cancer this year would be the continuous move of immunotherapies into earlier lines of treatment, all the way up to not only in the adjuvant setting, but also with chemoradiation or radiation plus [immunotherapy], followed by maintenance therapy. [There is] the concept of moving maintenance therapy into cervical cancer, and into earlier lines of therapy, which is going to be an important addition. We'll hear data starting to emerge from those kinds of strategies. That's going to be really exciting for cervical cancer; we just haven't had anything for quite a while for that space.”

Getting More Precise With Biomarkers

The issue lies in patient selection for some of these therapies, Markman explained, especially as ORRs with checkpoint inhibitors in cervical cancer range from 10% to 15%.

“As exciting as these drugs are, it is a minority of patients who benefit from them. It is actually even a smaller minority of patients, but a very relevant minority, in whom those benefits not only occur, but they're long lasting,” said Markman.

The overall arena of biomarker development is one that experts are still trying to grapple with in cervical cancer, Markman said.

“The future of cancer medicine is precision cancer medicine, which means trying to be more precise in determining the relevant targets and direct our therapy towards those targets to both improve effectiveness and decrease toxicity,” he concluded. “That is the future: to try to figure this out so that we direct our therapies where they're more likely to work. And, where they're not likely to work doesn't mean we give up. It means we look for other therapeutic strategies.”

Editor’s Note: This article on HPV-negative cervical cancer is part of OncLive®’s recently launched Rare Cancer Series.


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