Brown Patrick O, Palmer Chana
Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA.
PLoS Med. 2009 Jul;6(7):e1000114. doi: 10.1371/journal.pmed.1000114. Epub 2009 Jul 28.
Ovarian cancer kills approximately 15,000 women in the United States every year, and more than 140,000 women worldwide. Most deaths from ovarian cancer are caused by tumors of the serous histological type, which are rarely diagnosed before the cancer has spread. Rational design of a potentially life-saving early detection and intervention strategy requires understanding the lesions we must detect in order to prevent lethal progression. Little is known about the natural history of lethal serous ovarian cancers before they become clinically apparent. We can learn about this occult period by studying the unsuspected serous cancers that are discovered in a small fraction of apparently healthy women who undergo prophylactic bilateral salpingo-oophorectomy (PBSO).
We developed models for the growth, progression, and detection of occult serous cancers on the basis of a comprehensive analysis of published data on serous cancers discovered by PBSO in BRCA1 mutation carriers. Our analysis yielded several critical insights into the early natural history of serous ovarian cancer. First, these cancers spend on average more than 4 y as in situ, stage I, or stage II cancers and approximately 1 y as stage III or IV cancers before they become clinically apparent. Second, for most of the occult period, serous cancers are less than 1 cm in diameter, and not visible on gross examination of the ovaries and Fallopian tubes. Third, the median diameter of a serous ovarian cancer when it progresses to an advanced stage (stage III or IV) is about 3 cm. Fourth, to achieve 50% sensitivity in detecting tumors before they advance to stage III, an annual screen would need to detect tumors of 1.3 cm in diameter; 80% detection sensitivity would require detecting tumors less than 0.4 cm in diameter. Fifth, to achieve a 50% reduction in serous ovarian cancer mortality with an annual screen, a test would need to detect tumors of 0.5 cm in diameter.
Our analysis has formalized essential conditions for successful early detection of serous ovarian cancer. Although the window of opportunity for early detection of these cancers lasts for several years, developing a test sufficiently sensitive and specific to take advantage of that opportunity will be a challenge. We estimated that the tumors we would need to detect to achieve even 50% sensitivity are more than 200 times smaller than the clinically apparent serous cancers typically used to evaluate performance of candidate biomarkers; none of the biomarker assays reported to date comes close to the required level of performance. Overcoming the signal-to-noise problem inherent in detection of tiny tumors will likely require discovery of truly cancer-specific biomarkers or development of novel approaches beyond traditional blood protein biomarkers. While this study was limited to ovarian cancers of serous histological type and to those arising in BRCA1 mutation carriers specifically, we believe that the results are relevant to other hereditary serous cancers and to sporadic ovarian cancers. A similar approach could be applied to other cancers to aid in defining their early natural history and to guide rational design of an early detection strategy.
在美国，每年约有15000名女性死于卵巢癌，全球范围内这一数字超过140000人。大多数卵巢癌死亡是由浆液性组织学类型的肿瘤引起的，这类肿瘤在癌症扩散之前很少被诊断出来。合理设计一个可能挽救生命的早期检测和干预策略，需要了解我们为防止致命进展而必须检测的病变。对于致命性浆液性卵巢癌在临床上显现之前的自然史，我们知之甚少。通过研究一小部分接受预防性双侧输卵管卵巢切除术（PBSO）的表面健康女性中发现的意外浆液性癌，我们可以了解这个隐匿期。
我们基于对BRCA1突变携带者中通过PBSO发现的浆液性癌的已发表数据进行全面分析，建立了隐匿性浆液性癌生长、进展和检测的模型。我们的分析对浆液性卵巢癌的早期自然史得出了几个关键见解。首先，这些癌症在临床上显现之前，平均有超过4年处于原位癌、I期或II期癌症阶段，约1年处于III期或IV期癌症阶段。其次，在隐匿期的大部分时间里，浆液性癌直径小于1厘米，在对卵巢和输卵管进行大体检查时不可见。第三，浆液性卵巢癌进展到晚期（III期或IV期）时的中位直径约为3厘米。第四，为了在肿瘤进展到III期之前实现50%的检测敏感性，每年的筛查需要检测直径为1.3厘米的肿瘤；80%的检测敏感性则需要检测直径小于0.4厘米的肿瘤。第五，为了通过每年的筛查使浆液性卵巢癌死亡率降低50%，一项检测需要检测直径为0.5厘米的肿瘤。
我们的分析明确了成功早期检测浆液性卵巢癌的基本条件。尽管这些癌症的早期检测机会窗口持续数年，但开发一种足够敏感和特异的检测方法以利用这一机会将是一项挑战。我们估计，为了达到哪怕50%的敏感性，我们需要检测的肿瘤比通常用于评估候选生物标志物性能的临床上明显的浆液性癌小200多倍；迄今为止报道的生物标志物检测方法均未接近所需的性能水平。克服检测微小肿瘤时固有的信号噪声问题可能需要发现真正的癌症特异性生物标志物或开发超越传统血液蛋白生物标志物的新方法。虽然这项研究仅限于浆液性组织学类型的卵巢癌以及 specifically 在BRCA1突变携带者中发生的那些癌症，但我们认为这些结果与其他遗传性浆液性癌和散发性卵巢癌相关。类似的方法可应用于其他癌症，以帮助确定其早期自然史并指导早期检测策略的合理设计。
