The American Cancer Society has estimated that in 2021, about 21,410 women in the US will receive a new diagnosis of ovarian cancer (OC), and about 13,770 women will die from this disease. Ovarian cancer ranks 5th in cancer deaths among women, with a 1 in 78 chance of women developing this disease during their lifetime and a 1 in 108 chance of dying from the disease1 . Such a high mortality is mainly attributed to the minimal (or lack of) clinical symptoms in the early stages of the disease, leading to a diagnosis in advanced stages (International Federation of Obstetrics and Gynecology [FIGO] stage III and IV). Prognosis of patients diagnosed with early stage OC is excellent, since the disease can be treated before spreading to surrounding tissues. However, prognosis of patients at late stages, which occurs in ≥ 80% of cases2 , is poor. In these patients with advanced stage OC, the median survival is only 18 to 24 months2 , and sadly, it has been observed that despite optimal surgery and appropriate first-line chemotherapy, approximately 70%–80% of these patients will relapse within 5 years2–4 . As for patients with early stage OC (stage I or II), the relapse rate drops to 20%–25%5 . There is clearly an urgent need for the development of early detection methods capable of stratifying disease, monitoring response to therapy, and providing surveillance for post-surgical recurrence in women with OC6 .
Ovarian Cancer recurrence
Cancer recurrence (or relapse) is defined as the return of cancer after treatment, following a period of time when the cancer was not detected (American Cancer Society). The period in which no cancer is detected is typically referred to by physicians as “NED” (no evidence of disease), or “remission”7. Cancer recurrence after a period of remission can be difficult to differentiate from cancer progression (characterized by spreading or worsening of the cancer), especially when the time between completion of treatment with NED and the relapse is very short7 . Therefore, women who undergo initial treatment require additional follow-up care to monitor for recurrence7.
The chance of recurrence is much higher in patients with residual disease remaining after primary debulking surgery than those with no residual disease after surgery8 . Recurrent ovarian cancer (ROC) is linked to reductions in survival rates, and is generally considered incurable9 . Specifically, the 5-year and 12-year survival rates for recurrent ovarian cancer are less than 30% and 5%, respectively8.
One very important factor requiring continuous monitoring is patients’ symptoms. Symptoms can be both shortand long-term and patients should be educated on when to report them to the care provider. Specifically, if they are recurrent (occurring more than 12 times per month over a 12-month timeframe, as referenced by the American Cancer Society), it should be of heightened concern for the provider and followed-up with testing and development of appropriate treatment plans10.
Unfortunately, ROC symptoms (including pelvic pain, bloating, early satiety, obstruction, weight loss and fatigue) are usually nonspecific, and the scar tissue and fibrosis resulting from surgery and chemo/radiotherapy, can mimic tumor recurrence11 . Moreover, ROC usually presents as small implants in the abdomen and as normal-sized lymph node metastasis which are difficult to detect with traditional imaging technologies, such as ultrasound (US), computed tomography (CT) scans and magnetic resonance imaging (MRI)3.
Currently, the NCCN guidelines for monitoring and follow-up of EOC recommends scheduled clinical visits, physical examinations, radiological examination [including chest/abdominal/pelvic CT, MRI, FDG-PET/CT, FDG-PET scans (skull base to mid-thigh), and chest x-ray] and measurements of CA-125 levels (or other tumor biomarkers) if initially elevated12.
At present, the most adopted radiological exam during follow up is CT scan, with a sensitivity of 58–84% and a specificity of 60–100%. This technology has limitations, including its poor performance to identify peritoneal, mesenteric or intestinal wall lesions of less than 5 mm, which could remain undetected13 . The combination of PETCT provides the highest sensitivity and specificity (45–100% and 40–100%, respectively)14 and is mainly used in patients with increased CA-125 and a negative CT scan11.
Due to the above-mentioned limitations of imaging, biomarkers represent an effective early detection tool for ovarian cancer recurrence, leading to a higher likelihood of optimal secondary cytoreduction, and thus improved patient survival.
Biomarkers for monitoring Ovarian Cancer recurrence
Over the past few years, great efforts have been made to understand the key role of serum biomarkers to predict the risk of OC recurrence. Biomarkers can be used not only as a diagnostic tool but also as a prognostic indicator that gives the likelihood of disease recurrence and stratifies patients at different risk levels for specific outcomes15.
Cancer antigen 125 (CA125) is a heavily glycosylated transmembrane mucin (MUC16) which is overexpressed in 80% of epithelial ovarian cancers16 . First identified in 1981, CA125 became available on the US market in 1997 as a biomarker for monitoring disease progression, detection of residual, or OC recurrence.
CA125 is currently one of the most widely used cancer biomarkers in standard clinical practice for disease surveillance and its levels correlate with response to treatment15.
It has been established that a persistently rising CA125 level is a highly specific indicator of recurrent disease. Rustin et al showed that doubling in CA125 serum levels outside the normal range, detected disease relapse 4.8 months prior to any clinical sign and patient symptom17 . Doubling of baseline CA125 within the normal range prompts imaging to detect disease that might be resected during secondary cytoreduction16.
Earlier detection of OC recurrence allows physicians to start treatment while the patient is still asymptomatic16. CA125 has been shown to have a sensitivity of 67.39% and a specificity of 86.79% to detect early ovarian cancer recurrence with a threshold of 35 U/mL18. Furthermore, elevated postoperative serum CA125 values (>65 U/mL) are associated with a lower 5 years survival rate19 .
Rising CA125 serum levels represent a useful tool for the detection of relapse in women with OC. However, CA125 surveillance is also associated with a high false-negative rate, since not all cancers produce elevated levels of serum CA12515. Furthermore, CA125 appears elevated in other benign conditions including endometriosis, menstrual cycle and pregnancy20.
To allow patients to benefit from an early therapeutic intervention capable of prolonging the disease-free interval and improve overall survival, there is an urgent need for other sensitive biomarkers that can predict ovarian cancer recurrence in advance of the rise in CA12515.
Biomarkers including HE4, may contribute not only to earlier detection of primary ovarian cancer, but also to earlier detection of recurrent disease.
Human epididymis secretory protein E4 (HE4/WFDC2) has been available as a biomarker for monitoring of disease recurrence or progression since 2009. HE4 is present in the epithelium of fallopian tubes, the endometrium, and the endocervical glands, but not in the ovarian surface epithelium. Elevated expression levels of HE4 have been observed in 93-100% of serous, 80-100% of endometrioid and 50-83% of clear-cell carcinomas of the ovary, while being absent in mucinous ovarian cancer21,22.
In contrast to CA125, HE4 levels do not appear to be elevated in benign conditions in both pre- and postmenopausal women, indicating that this marker could be a valuable complement to distinguish malignant from benign ovarian tumors23,24. HE4 has also been found to be more sensitive (at preset specificity) than other single biomarkers for ovarian cancer (including CA125), especially in Stage I disease25. Interestingly, the combination of HE4 with CA125 generated the highest sensitivity (76.4% at a specificity of 95%) relative to other dual combination of biomarkers in a clinical trial of women presenting with an adnexal mass26. This result suggests that these two biomarkers combined, provide a more accurate assessment of malignancy than either alone16.
Besides its important role to assess pelvic masses, testing patients for serum HE4 levels is a valuable approach to monitor treatment and detect relapse24 . In a prospective study by Havrilesky and colleagues, 27 patients with advanced OC experienced recurrence following initial response to therapy. In 56% of these patients one or more biomarkers (HE4, glycodelin, MMP7) were elevated earlier (range 6–69 weeks) than CA-125 and prior to clinical evidence of recurrence27. A year later, a study by Anastasi and colleagues further supported the potential of HE4 as an OC relapse marker, indicating an increase in HE4 levels 5-8 months before CA125 in 62.5% of patients with OC2.
Plotti and colleagues also demonstrated in a prospective study that HE4 can indeed detect recurrent OC with 73.53% sensitivity (at a cutoff of 70pmol/L) compared to CA125 (sensitivity 35.29%). They also showed that by combining CA125 and HE4 (at a HE4 cut-off of 70 pmol/L), the overall sensitivity for detection of recurrent OC reached 76.47 % with a specificity of 100%28. These results suggest that HE4 can indeed predict OC recurrence earlier than CA125 alone, and that elevated levels of HE4 can be detected in those cancers that fail to express CA125. Furthermore, the combination of CA125 and HE4 can provide significantly better sensitivity to monitor treatment, while shortening the time to detect recurrent OC than either marker alone16.
Similarly, another study from 2012 highlighted the advantages of HE4 over CA125 to predict ovarian cancer recurrence. Specifically, HE4 could predict recurrence earlier than CA125, and was elevated in patients that do not express CA12529 A few years later, Piovano et al suggested that the prognostic role of HE4 could help clinicians personalize follow up programs, while its predictive role could help plan treatment for relapse30.
Finally, a more recent study also highlighted the role of HE4 in predicting recurrent epithelial ovarian cancer and suggested HE4 is potentially better than CA125 as a marker for this purpose31.
Taken together, these studies have provided evidence that HE4 may not only provide a valuable biomarker to discriminate benign versus malignant masses, but also represents a valuable monitoring tool able to foresee, in spite of treatment, the recurrence of OC.
Although ovarian cancer recurrence is a lethal and chronic disease, currently no surveillance strategies are well defined or standardized15 . Therefore, the identification of markers capable of following the remission from disease in response to therapy and detecting recurrence of the disease, is as important as identifying biomarkers for the detection of OC at early stages2.
Currently, biomarkers such as CA125 and HE4 have been used to monitor response to treatment and to detect recurrence15. Despite its high specificity, CA125 has not proven to be sufficiently sensitive to monitor a complete response to primary therapy. Studies have also highlighted the limited effectiveness of CA125 to detect disease recurrence only 4.8 months before signs and symptoms develop clinically15,17.
In recent years, HE4 has shown its potential and effectiveness as a biomarker not only for the early diagnosis of OC (since it has been found to be highly expressed in the early stages of the disease), but also for early detection of OC recurrence. Specifically, multiple studies have demonstrated the effectiveness of HE4 to predict OC recurrence months earlier than CA125, thus reinforcing the superiority of HE4 as a biomarker for disease relapse.
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