Reply to why follow‐back studies should be interpreted cautiously: The case of an HPV‐negative cervical lesion

We thank Rossi et al for their interest in our article. We believe that they have erroneously suggested that 2 potential biases in our study design may have led to an overestimation of cytology sensitivity and/or an underestimation of human papillomavirus (HPV) sensitivity for cervical intraepithelial neoplasia (CIN). Our study is a large, retrospective, cross-sectional analysis of cervical cancer screening and biopsy drawn from more than 8.6 million women who had testing performed at Quest Diagnostics. It represents a snapshot of women throughout different stages of screening and represents true clinical practice. All women with valid cytology and HPV test results and biopsy results within 1 year (average time to biopsy, 56 days) were included in the analysis, regardless of the reason for the screening and colposcopy/biopsy visit. The size and diversity of the study cohort aided in minimizing any biases suggested by Rossi et al. We also believe that a number of points concerning the study design and resulting data were potentially misunderstood by Rossi et al, and we would like to take the opportunity to provide additional details and clarification. The approximately 75% of samples with valid cytology and HPV results that lacked biopsy findings may be explained by a combination of factors such as 1) colposcopy/biopsy referral outside Quest Diagnostics, 2) patient deferment or failure to follow up, and 3) incorrect coding of follow-up procedures in the medical record. Therefore, we have no indication that any bias toward higher colposcopy rates for women with positive cytology results exists. Although there are undoubtedly HPV-positive/ cytology-negative women who will go on to develop CIN undetected during the initial screening, we find it unlikely that this would affect our finding of unacceptably high false-negative rates for cervical cancer in the HPVnegative group of women. As for their contention that “a 91% sensitivity of cytology for CIN21 is really surprising,” we actually measured an endpoint of CIN31, not CIN21, at a threshold of atypical squamous cells of undetermined significance or higher. If we had used CIN21 at a threshold of atypical squamous cells of undetermined significance or higher, our sensitivity would have been 92%. This value is similar to pooled results from a large metaanalysis in which cytology had a sensitivity of 90.4% for CIN21. Rossi et al note that “1 of 1000 HPV-negative/ cytology-negative women in the study had an invasive cancer,” and they comment that perhaps “we should abandon both [HPV and Papanicolaou] tests as screening methods and simply periodically perform random cervical biopsies in the general population. ” We believe that their remark underscores a limited recognition of the difference between a randomized controlled trial and a retrospective, real-world review. The latter provides information about what clinicians actually see because of patient noncompliance, incomplete data, and provider nonconformity to guidelines. This is the essence of clinical practice, where we need to serve patients and not just write about them. We are encouraged that the significant difference between a study endpoint of invasive cervical cancer and CIN has been recognized. Available natural history studies document that most cases of CIN3 will never progress to cervical cancer. Only women with invasive cervical cancer are likely to harbor proven progressive precancerous lesions. In our opinion, this is why the observation of significant numbers of falsenegative HPV test results for women developing cervical cancer is so significant. Trials focusing on largely nonprogressive CIN2/3 lesions have yielded potentially misleading results. In conclusion, we believe that the data provide very important information about clinical practice and what might happen with an HPV primary testing scenario: 19% of cervical cancers could be missed.