Andrea R. Hagemann, MD, MSCI

CASE New patient presents with a history of endometrial hyperplasia

A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A_1c [HbA_1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m²). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.

At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA_1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.

An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
 

Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.¹ These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.² General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.³

In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.⁴ As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.⁵ Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.

In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.

Continue to: Current use of endometrial ablation in the US...

In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.⁶ In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.⁷ The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.⁸ There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.

Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.⁹ The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.

Endometrial ablation complications: Late-onset procedure failure

A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.¹⁰ It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.¹¹ The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.

It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.¹² Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.¹³ The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.¹⁴

The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.¹⁵ One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.¹⁶

In the previously mentioned poll of SGO members,¹ 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.¹ While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.

Appropriate patient selection and contraindications

The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.¹⁷

What about patients who may be at increased risk for endometrial cancer?

There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,¹⁸ but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.¹⁹ It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.²⁰

In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m², compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).²¹ Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.^22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.

Continue to: Hysterectomy—A disincentivized option...

Hysterectomy—A disincentivized option

The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.²⁵ These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.²⁶ This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.

These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.²⁷ These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.²⁸ While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.

We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?

Post-ablation bleeding: Management by the gyn oncologist

Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.

Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.²⁹ A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.

Our recommendations

Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.³¹ Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.

Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.³² While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.

Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.

In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.

CASE Resolution

After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.

Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●

Acknowledgement

The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.

CASE New patient presents with a history of endometrial hyperplasia

A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A_1c [HbA_1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m²). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.

At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA_1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.

An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
 

Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.¹ These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.² General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.³

In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.⁴ As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.⁵ Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.

In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.

Continue to: Current use of endometrial ablation in the US...

In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.⁶ In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.⁷ The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.⁸ There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.

Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.⁹ The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.

Endometrial ablation complications: Late-onset procedure failure

A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.¹⁰ It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.¹¹ The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.

It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.¹² Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.¹³ The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.¹⁴

The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.¹⁵ One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.¹⁶

In the previously mentioned poll of SGO members,¹ 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.¹ While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.

Appropriate patient selection and contraindications

The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.¹⁷

What about patients who may be at increased risk for endometrial cancer?

There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,¹⁸ but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.¹⁹ It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.²⁰

In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m², compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).²¹ Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.^22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.

Continue to: Hysterectomy—A disincentivized option...

Hysterectomy—A disincentivized option

The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.²⁵ These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.²⁶ This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.

These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.²⁷ These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.²⁸ While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.

We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?

Post-ablation bleeding: Management by the gyn oncologist

Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.

Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.²⁹ A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.

Our recommendations

Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.³¹ Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.

Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.³² While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.

Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.

In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.

CASE Resolution

After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.

Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●

Acknowledgement

The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.

CASE New patient presents with a history of endometrial hyperplasia

A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A_1c [HbA_1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m²). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.

At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA_1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.

An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
 

Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.¹ These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.² General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.³

In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.⁴ As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.⁵ Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.

In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.

Continue to: Current use of endometrial ablation in the US...

In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.⁶ In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.⁷ The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.⁸ There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.

Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.⁹ The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.

Endometrial ablation complications: Late-onset procedure failure

A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.¹⁰ It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.¹¹ The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.

It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.¹² Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.¹³ The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.¹⁴

The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.¹⁵ One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.¹⁶

In the previously mentioned poll of SGO members,¹ 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.¹ While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.

Appropriate patient selection and contraindications

The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.¹⁷

What about patients who may be at increased risk for endometrial cancer?

There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,¹⁸ but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.¹⁹ It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.²⁰

In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m², compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).²¹ Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.^22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.

Continue to: Hysterectomy—A disincentivized option...

Hysterectomy—A disincentivized option

The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.²⁵ These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.²⁶ This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.

These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.²⁷ These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.²⁸ While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.

We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?

Post-ablation bleeding: Management by the gyn oncologist

Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.

Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.²⁹ A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.

Our recommendations

Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.³¹ Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.

Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.³² While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.

Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.

In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.

CASE Resolution

After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.

Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●

Acknowledgement

The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.

CASE Patient inquires about new technology to detect cancer

A 51-year-old woman (para 2) presents to your clinic for a routine gynecology exam. She is up to date on her screening mammogram and Pap testing. She has her first colonoscopy scheduled for next month. She has a 10-year remote smoking history, but she stopped smoking in her late twenties. Her cousin was recently diagnosed with skin cancer, her father had prostate cancer and is now in remission, and her paternal grandmother died of ovarian cancer. She knows ovarian cancer does not have an effective screening test, and she recently heard on the news about a new blood test that can detect cancer before symptoms start. She would like to know more about this test. Could it replace her next Pap, mammogram, and future colonoscopies? She also wants to know—How can a simple blood test detect cancer?

The power of genomics in cancer care

Since the first human genome was sequenced in 2000, the power of genomics has been evident across many aspects of medicine, including cancer care.¹ Whereas the first human genome to be sequenced took more than 10 years to sequence and cost over  $1 billion, sequencing of your entire genome can now be obtained for less than $400—with results in a week.²

Genomics is now an integral part of cancer care, with results having implications for both cancer risk and prevention as well as more individualized treatment. For example, a healthy 42-year-old patient with a strong family history of breast cancer may undergo genetic testing and discover she has a mutation in the tumor suppression gene BRCA1, which carries a 39% to 58% lifetime risk of ovarian cancer.³ By undergoing a risk-reducing bilateral salpingooophorectomy she will lower her ovarian cancer risk by up to 96%.^4,5 A 67-year-old with a new diagnosis of stage III ovarian cancer and a BRCA2 mutation may be in remission for 5+ years due to her BRCA2 mutation, which makes her eligible for the use of the poly(ADPribose) polymerase (PARP) inhibitor olaparib.⁶ Genetic testing as illustrated above has led to decreased cancer-related mortality and prolonged survival.⁷ However, many women with such germline mutations are faced with difficult choices about surgical risk reduction, with the potential harms of early menopause and quality of life concerns. Having a test that does not just predict cancer risk but in fact quantifies that risk for the individual would greatly help in these decisions. Furthermore, more than 75% of ovarian cancers occur without a germline mutation. 

Advances in genetic testing technology also have led to the ability to obtain genetic information from a simple blood test. For example, cell-free DNA (cfDNA), which is DNA fragments that are normally found to be circulating in the bloodstream, is routinely used as a screening tool for prenatal genetic testing to detect chromosomal abnormalities in the fetus.⁸ This technology relies on analyzing fetal free (non-cellular) DNA that is naturally found circulating in maternal blood. More recently, similar technology using cfDNA has been applied for the screening and characterization of certain cancers.⁹ This powerful technology can detect cancer before symptoms begin—all from a simple blood test, often referred to as a “liquid biopsy.” However, understanding the utility, supporting data, and target population for these tests is important before employing them as part of routine clinical practice. 

Continue to: Current methods of cancer screening are limited...

Current methods of cancer screening are limited 

Cancer is a leading cause of death worldwide, with nearly 10 million cancer-related deaths annually, and it may surpass cardiovascular disease as the leading cause over the course of the century.^10,11 Many cancer deaths are in part due to late-stage diagnosis, when the cancer has already metastasized.¹² Early detection of cancer improves outcomes and survival rates, but it is often difficult to detect early due to the lack of early symptoms with many cancers, which can limit cancer screening and issues with access to care.¹³

 Currently, there are only 5 cancers: cervical, prostate, breast, colon, and lung (for high-risk adults) that are screened for in the general population (see "Cancer screening has helped save countless lives" at the end of this article).¹⁴ The Pap test to screen for cervical cancer, developed in the 1940s, has saved millions of women’s lives and reduced the mortality of cervical cancer by 70%.¹⁵ Coupled with the availability and implementation of the human papillomavirus (HPV) vaccine, cervical cancer rates are decreasing at substantial rates.¹⁶ However, there are no validated screening tests for uterine cancer, the most common gynecologic malignancy in the United States, or ovarian cancer, the most lethal. 

Screening tests for cervical, prostate, breast, colon, and lung cancer have helped save millions of lives; however, these tests also come with high false-positive rates and the potential for overdiagnosis and overtreatment. For example, half of women undergoing mammograms will receive a false-positive result over a 10-year time period,¹⁷ and up to 50% of men undergoing prostate cancer screening have a positive prostate-specific antigen (PSA) test result when they do not actually have prostate cancer.¹⁸ Additionally, the positive predictive value of the current standard-of-care screening tests can be as low as <5%. Most diagnoses of cancer are made from a surgical biopsy, but these types of procedures can be difficult depending on the location or size of the tumor.¹⁹ 

The liquid biopsy. Given the limitations of current cancer screening and diagnostic tests, there is a great need for a more sensitive test that also can detect cancer from multiple organ sites. Liquid biopsy-based biomarkers can include circulating tumor cells, exosomes, microRNAs, and circulating tumor DNA (ctDNA). With advances in next-generation sequencing, ctDNA techniques remain the most promising.²⁰ 

Methylation-based MCED testing: A new way of  cancer screening 

Multi-cancer early detection (MCED) technology was developed to address the need for better cancer screening and has the potential to detect up to 50 cancers with a simple blood test. This new technology opens the possibility for early detection of multiple cancers before symptoms even begin. MCED testing is sometimes referred to as “GRAIL” testing, after the American biotechnology company that developed the first commercially available MCED test, called the Galleri test (Galleri, Menlo Park, California). Although other biotechnology companies are developing similar technology (Exact Sciences, Madison, Wisconsin, and Freenome, South San Francisco, California, for example), this is the first test of its kind available to the public.²¹

The MCED test works by detecting the cfDNA fragments that are released into the blood passively by necrotic or apoptotic cells or secreted actively from tumor cells. The DNA from tumor cells is also known as circulating tumor DNA (ctDNA). CtDNA is found in much lower quantities in the blood stream compared with cfDNA from cells, making it difficult to distinguish a cancer versus a noncancer cell and to determine the tumor site of origin.²²

Through innovation, the first example of detecting cancer through this method in fact came as a surprise result from an abnormal cfDNA test. A pregnant 37-yearold woman had a cfDNA result suggestive of aneuploidy for chromosomes 18 and 13; however, she gave birth to a normal male fetus. Shortly thereafter, a vaginal biopsy confirmed small-cell carcinoma with alterations in chromosomes 18 and 13.²³ GRAIL testing for this patient was subsequently able to optimize their methods of detecting both the presence of cancer cells and the tumor site of origin by utilizing next-generation genomic sequencing and methylation. Their development of a methylation-based assay combined with 46 machine-learning allowed the test to determine, first, if there is cancer present or not, and second, the tissue of origin prediction. It is important to note that these tests are meant to be used in addition to standard-of-care screening tests, not as an alternative, and this is emphasized throughout the company’s website and the medical literature.²⁴ 

Continue to: The process to develop and validate GRAIL’s blood-based cancer screening test...

The process to develop and validate GRAIL’s blood-based cancer screening test includes 4 large clinical trials of more than 180,000 participants, including those with cancer and those without. The Circulating Cell-Free Genome Atlas (CCGA) Study, was a prospective, case-controlled, observational study enrolling approximately 15,000 participants with 3 prespecified sub-studies. The first sub-study developed the machine-learning classifier for both early detection and tumor of origin detection.^25,26 

The highest performing assay from the first sub-study then went on to be further validated in the 2nd and 3rd sub-studies. The 3rd sub-study, published in the Annals of Oncology in 2021 looked at a cohort of 4,077 participants with and without cancer, and found the specificity of cancer signal detection to be 99.5% and the overall sensitivity to be 51.5%, with increasing sensitivity by cancer stage (stage I - 17%, stage II - 40%, stage III - 77%, and stage IV - 90.1%).²⁴ The false-positive rate was low, at 0.7%, and the true positive rate was 88.7%. Notably, the test was able to correctly identify the tumor of origin for 93% of samples.²⁴ The study overall demonstrated high specificity and accuracy of tumor site of origin and supported the use of this blood-based MCED assay. 

The PATHFINDER study was another prospective, multicenter clinical trial that enrolled more than 6,000 participants in the United States. The participants were aged >50 years with or without additional cancer risk factors. The goal of this study was to determine the extent of testing required to achieve diagnosis after a “cancer signal detected” result. The study results found that, when MCED testing was added to the standard-of-care screening, the number of cancers detected doubled when compared with standard cancer screening alone.^27,28 Of the 92 participants with positive cancer signals, 35 were diagnosed with cancer, and 71% of these cancer types did not have standard-ofcare screening. The tumor site of origin was correctly detected in 97% of cases, and there were less than 1% of false positives. Overall, the test led to diagnostic evaluation of 1.4% of patients and a cancer diagnosis in 0.5%. 

Currently, there are 2 ongoing clinical trials to further evaluate the Galleri MCED test. The STRIVE trial that aims to prospectively validate the MCED test in a population of nearly 100,000 women undergoing mammography,²⁹ and the SUMMIT trial,³⁰ which is similarly aiming to validate the test in a group of individuals, half of whom have a significantly elevated risk of lung cancer. 

With the promising results described above, the Galleri test became the first MCED test available for commercial use starting in 2022. It is only available for use in people who are aged 50 and older, have a family history of cancer, or are at an increased risk for cancer (although GRAIL does not elaborate on what constitutes increased risk). However, the Galleri test is only available through prescription—therefore, if interested, patients must ask their health care provider to register with GRAIL and order the test (https://www .galleri.com/hcp/the-galleri-test/ordering). Additionally, the test will cost the patient $949 and is not yet covered by insurances. Currently, several large health care groups such as the United States Department of Veterans Affairs, Cleveland Clinic, and Mercy hospitals have partnered with GRAIL to offer their test to certain patients for use as part of clinical trials. Currently, no MCED test, including the Galleri, is approved by the US Food and  Drug Administration. 

Incorporating MCED testing into clinical practice

The Galleri MCED test has promising potential to make multi-cancer screening feasible and obtainable, which could ultimately reduce late-stage cancer diagnosis and decrease mortality from all cancers. The compelling data from large cohorts and numerous clinical trials demonstrate its accuracy, reliability, reproducibility, and specificity. It can detect up to 50 different types of cancers, including cancers that affect our gynecologic patients, including breast, cervical, ovarian, and uterine. Additionally, its novel methylation-based assay accurately identifies the tumor site of origin in 97% of cases.²⁸ Ongoing and future clinical trials will continue to validate and refine these methods and improve the sensitivity and positive-predictive value of this assay. As mentioned, although it has been incorporated into various large health care systems, it is not FDA approved and has not been validated in the general population. Additionally, it should not be used as a replacement for recommended screening. 

CASE Resolved

The patient is eligible for the Galleri MCED test if ordered by her physician. However, she will need to pay for the test out-of-pocket. Due to her family history, she should consider germline genetic testing (either for herself, or if possible, for her father, who should meet criteria based on his prostate cancer).³ Panel testing for germline mutations has become much more accessible, and until MCED testing is ready for prime time, it remains one of the best ways to predict and prevent cancers. Additionally, she should continue to undergo routine screening for cervical, breast, and colon cancer as indicated. ●

CASE Patient inquires about new technology to detect cancer

A 51-year-old woman (para 2) presents to your clinic for a routine gynecology exam. She is up to date on her screening mammogram and Pap testing. She has her first colonoscopy scheduled for next month. She has a 10-year remote smoking history, but she stopped smoking in her late twenties. Her cousin was recently diagnosed with skin cancer, her father had prostate cancer and is now in remission, and her paternal grandmother died of ovarian cancer. She knows ovarian cancer does not have an effective screening test, and she recently heard on the news about a new blood test that can detect cancer before symptoms start. She would like to know more about this test. Could it replace her next Pap, mammogram, and future colonoscopies? She also wants to know—How can a simple blood test detect cancer?

The power of genomics in cancer care

Since the first human genome was sequenced in 2000, the power of genomics has been evident across many aspects of medicine, including cancer care.¹ Whereas the first human genome to be sequenced took more than 10 years to sequence and cost over  $1 billion, sequencing of your entire genome can now be obtained for less than $400—with results in a week.²

Genomics is now an integral part of cancer care, with results having implications for both cancer risk and prevention as well as more individualized treatment. For example, a healthy 42-year-old patient with a strong family history of breast cancer may undergo genetic testing and discover she has a mutation in the tumor suppression gene BRCA1, which carries a 39% to 58% lifetime risk of ovarian cancer.³ By undergoing a risk-reducing bilateral salpingooophorectomy she will lower her ovarian cancer risk by up to 96%.^4,5 A 67-year-old with a new diagnosis of stage III ovarian cancer and a BRCA2 mutation may be in remission for 5+ years due to her BRCA2 mutation, which makes her eligible for the use of the poly(ADPribose) polymerase (PARP) inhibitor olaparib.⁶ Genetic testing as illustrated above has led to decreased cancer-related mortality and prolonged survival.⁷ However, many women with such germline mutations are faced with difficult choices about surgical risk reduction, with the potential harms of early menopause and quality of life concerns. Having a test that does not just predict cancer risk but in fact quantifies that risk for the individual would greatly help in these decisions. Furthermore, more than 75% of ovarian cancers occur without a germline mutation. 

Advances in genetic testing technology also have led to the ability to obtain genetic information from a simple blood test. For example, cell-free DNA (cfDNA), which is DNA fragments that are normally found to be circulating in the bloodstream, is routinely used as a screening tool for prenatal genetic testing to detect chromosomal abnormalities in the fetus.⁸ This technology relies on analyzing fetal free (non-cellular) DNA that is naturally found circulating in maternal blood. More recently, similar technology using cfDNA has been applied for the screening and characterization of certain cancers.⁹ This powerful technology can detect cancer before symptoms begin—all from a simple blood test, often referred to as a “liquid biopsy.” However, understanding the utility, supporting data, and target population for these tests is important before employing them as part of routine clinical practice. 

Continue to: Current methods of cancer screening are limited...

Current methods of cancer screening are limited 

Cancer is a leading cause of death worldwide, with nearly 10 million cancer-related deaths annually, and it may surpass cardiovascular disease as the leading cause over the course of the century.^10,11 Many cancer deaths are in part due to late-stage diagnosis, when the cancer has already metastasized.¹² Early detection of cancer improves outcomes and survival rates, but it is often difficult to detect early due to the lack of early symptoms with many cancers, which can limit cancer screening and issues with access to care.¹³

 Currently, there are only 5 cancers: cervical, prostate, breast, colon, and lung (for high-risk adults) that are screened for in the general population (see "Cancer screening has helped save countless lives" at the end of this article).¹⁴ The Pap test to screen for cervical cancer, developed in the 1940s, has saved millions of women’s lives and reduced the mortality of cervical cancer by 70%.¹⁵ Coupled with the availability and implementation of the human papillomavirus (HPV) vaccine, cervical cancer rates are decreasing at substantial rates.¹⁶ However, there are no validated screening tests for uterine cancer, the most common gynecologic malignancy in the United States, or ovarian cancer, the most lethal. 

Screening tests for cervical, prostate, breast, colon, and lung cancer have helped save millions of lives; however, these tests also come with high false-positive rates and the potential for overdiagnosis and overtreatment. For example, half of women undergoing mammograms will receive a false-positive result over a 10-year time period,¹⁷ and up to 50% of men undergoing prostate cancer screening have a positive prostate-specific antigen (PSA) test result when they do not actually have prostate cancer.¹⁸ Additionally, the positive predictive value of the current standard-of-care screening tests can be as low as <5%. Most diagnoses of cancer are made from a surgical biopsy, but these types of procedures can be difficult depending on the location or size of the tumor.¹⁹ 

The liquid biopsy. Given the limitations of current cancer screening and diagnostic tests, there is a great need for a more sensitive test that also can detect cancer from multiple organ sites. Liquid biopsy-based biomarkers can include circulating tumor cells, exosomes, microRNAs, and circulating tumor DNA (ctDNA). With advances in next-generation sequencing, ctDNA techniques remain the most promising.²⁰ 

Methylation-based MCED testing: A new way of  cancer screening 

Multi-cancer early detection (MCED) technology was developed to address the need for better cancer screening and has the potential to detect up to 50 cancers with a simple blood test. This new technology opens the possibility for early detection of multiple cancers before symptoms even begin. MCED testing is sometimes referred to as “GRAIL” testing, after the American biotechnology company that developed the first commercially available MCED test, called the Galleri test (Galleri, Menlo Park, California). Although other biotechnology companies are developing similar technology (Exact Sciences, Madison, Wisconsin, and Freenome, South San Francisco, California, for example), this is the first test of its kind available to the public.²¹

The MCED test works by detecting the cfDNA fragments that are released into the blood passively by necrotic or apoptotic cells or secreted actively from tumor cells. The DNA from tumor cells is also known as circulating tumor DNA (ctDNA). CtDNA is found in much lower quantities in the blood stream compared with cfDNA from cells, making it difficult to distinguish a cancer versus a noncancer cell and to determine the tumor site of origin.²²

Through innovation, the first example of detecting cancer through this method in fact came as a surprise result from an abnormal cfDNA test. A pregnant 37-yearold woman had a cfDNA result suggestive of aneuploidy for chromosomes 18 and 13; however, she gave birth to a normal male fetus. Shortly thereafter, a vaginal biopsy confirmed small-cell carcinoma with alterations in chromosomes 18 and 13.²³ GRAIL testing for this patient was subsequently able to optimize their methods of detecting both the presence of cancer cells and the tumor site of origin by utilizing next-generation genomic sequencing and methylation. Their development of a methylation-based assay combined with 46 machine-learning allowed the test to determine, first, if there is cancer present or not, and second, the tissue of origin prediction. It is important to note that these tests are meant to be used in addition to standard-of-care screening tests, not as an alternative, and this is emphasized throughout the company’s website and the medical literature.²⁴ 

Continue to: The process to develop and validate GRAIL’s blood-based cancer screening test...

The process to develop and validate GRAIL’s blood-based cancer screening test includes 4 large clinical trials of more than 180,000 participants, including those with cancer and those without. The Circulating Cell-Free Genome Atlas (CCGA) Study, was a prospective, case-controlled, observational study enrolling approximately 15,000 participants with 3 prespecified sub-studies. The first sub-study developed the machine-learning classifier for both early detection and tumor of origin detection.^25,26 

The highest performing assay from the first sub-study then went on to be further validated in the 2nd and 3rd sub-studies. The 3rd sub-study, published in the Annals of Oncology in 2021 looked at a cohort of 4,077 participants with and without cancer, and found the specificity of cancer signal detection to be 99.5% and the overall sensitivity to be 51.5%, with increasing sensitivity by cancer stage (stage I - 17%, stage II - 40%, stage III - 77%, and stage IV - 90.1%).²⁴ The false-positive rate was low, at 0.7%, and the true positive rate was 88.7%. Notably, the test was able to correctly identify the tumor of origin for 93% of samples.²⁴ The study overall demonstrated high specificity and accuracy of tumor site of origin and supported the use of this blood-based MCED assay. 

The PATHFINDER study was another prospective, multicenter clinical trial that enrolled more than 6,000 participants in the United States. The participants were aged >50 years with or without additional cancer risk factors. The goal of this study was to determine the extent of testing required to achieve diagnosis after a “cancer signal detected” result. The study results found that, when MCED testing was added to the standard-of-care screening, the number of cancers detected doubled when compared with standard cancer screening alone.^27,28 Of the 92 participants with positive cancer signals, 35 were diagnosed with cancer, and 71% of these cancer types did not have standard-ofcare screening. The tumor site of origin was correctly detected in 97% of cases, and there were less than 1% of false positives. Overall, the test led to diagnostic evaluation of 1.4% of patients and a cancer diagnosis in 0.5%. 

Currently, there are 2 ongoing clinical trials to further evaluate the Galleri MCED test. The STRIVE trial that aims to prospectively validate the MCED test in a population of nearly 100,000 women undergoing mammography,²⁹ and the SUMMIT trial,³⁰ which is similarly aiming to validate the test in a group of individuals, half of whom have a significantly elevated risk of lung cancer. 

With the promising results described above, the Galleri test became the first MCED test available for commercial use starting in 2022. It is only available for use in people who are aged 50 and older, have a family history of cancer, or are at an increased risk for cancer (although GRAIL does not elaborate on what constitutes increased risk). However, the Galleri test is only available through prescription—therefore, if interested, patients must ask their health care provider to register with GRAIL and order the test (https://www .galleri.com/hcp/the-galleri-test/ordering). Additionally, the test will cost the patient $949 and is not yet covered by insurances. Currently, several large health care groups such as the United States Department of Veterans Affairs, Cleveland Clinic, and Mercy hospitals have partnered with GRAIL to offer their test to certain patients for use as part of clinical trials. Currently, no MCED test, including the Galleri, is approved by the US Food and  Drug Administration. 

Incorporating MCED testing into clinical practice

The Galleri MCED test has promising potential to make multi-cancer screening feasible and obtainable, which could ultimately reduce late-stage cancer diagnosis and decrease mortality from all cancers. The compelling data from large cohorts and numerous clinical trials demonstrate its accuracy, reliability, reproducibility, and specificity. It can detect up to 50 different types of cancers, including cancers that affect our gynecologic patients, including breast, cervical, ovarian, and uterine. Additionally, its novel methylation-based assay accurately identifies the tumor site of origin in 97% of cases.²⁸ Ongoing and future clinical trials will continue to validate and refine these methods and improve the sensitivity and positive-predictive value of this assay. As mentioned, although it has been incorporated into various large health care systems, it is not FDA approved and has not been validated in the general population. Additionally, it should not be used as a replacement for recommended screening. 

CASE Resolved

The patient is eligible for the Galleri MCED test if ordered by her physician. However, she will need to pay for the test out-of-pocket. Due to her family history, she should consider germline genetic testing (either for herself, or if possible, for her father, who should meet criteria based on his prostate cancer).³ Panel testing for germline mutations has become much more accessible, and until MCED testing is ready for prime time, it remains one of the best ways to predict and prevent cancers. Additionally, she should continue to undergo routine screening for cervical, breast, and colon cancer as indicated. ●

CASE Patient inquires about new technology to detect cancer

A 51-year-old woman (para 2) presents to your clinic for a routine gynecology exam. She is up to date on her screening mammogram and Pap testing. She has her first colonoscopy scheduled for next month. She has a 10-year remote smoking history, but she stopped smoking in her late twenties. Her cousin was recently diagnosed with skin cancer, her father had prostate cancer and is now in remission, and her paternal grandmother died of ovarian cancer. She knows ovarian cancer does not have an effective screening test, and she recently heard on the news about a new blood test that can detect cancer before symptoms start. She would like to know more about this test. Could it replace her next Pap, mammogram, and future colonoscopies? She also wants to know—How can a simple blood test detect cancer?

The power of genomics in cancer care

Since the first human genome was sequenced in 2000, the power of genomics has been evident across many aspects of medicine, including cancer care.¹ Whereas the first human genome to be sequenced took more than 10 years to sequence and cost over  $1 billion, sequencing of your entire genome can now be obtained for less than $400—with results in a week.²

Genomics is now an integral part of cancer care, with results having implications for both cancer risk and prevention as well as more individualized treatment. For example, a healthy 42-year-old patient with a strong family history of breast cancer may undergo genetic testing and discover she has a mutation in the tumor suppression gene BRCA1, which carries a 39% to 58% lifetime risk of ovarian cancer.³ By undergoing a risk-reducing bilateral salpingooophorectomy she will lower her ovarian cancer risk by up to 96%.^4,5 A 67-year-old with a new diagnosis of stage III ovarian cancer and a BRCA2 mutation may be in remission for 5+ years due to her BRCA2 mutation, which makes her eligible for the use of the poly(ADPribose) polymerase (PARP) inhibitor olaparib.⁶ Genetic testing as illustrated above has led to decreased cancer-related mortality and prolonged survival.⁷ However, many women with such germline mutations are faced with difficult choices about surgical risk reduction, with the potential harms of early menopause and quality of life concerns. Having a test that does not just predict cancer risk but in fact quantifies that risk for the individual would greatly help in these decisions. Furthermore, more than 75% of ovarian cancers occur without a germline mutation. 

Advances in genetic testing technology also have led to the ability to obtain genetic information from a simple blood test. For example, cell-free DNA (cfDNA), which is DNA fragments that are normally found to be circulating in the bloodstream, is routinely used as a screening tool for prenatal genetic testing to detect chromosomal abnormalities in the fetus.⁸ This technology relies on analyzing fetal free (non-cellular) DNA that is naturally found circulating in maternal blood. More recently, similar technology using cfDNA has been applied for the screening and characterization of certain cancers.⁹ This powerful technology can detect cancer before symptoms begin—all from a simple blood test, often referred to as a “liquid biopsy.” However, understanding the utility, supporting data, and target population for these tests is important before employing them as part of routine clinical practice. 

Continue to: Current methods of cancer screening are limited...

Current methods of cancer screening are limited 

Cancer is a leading cause of death worldwide, with nearly 10 million cancer-related deaths annually, and it may surpass cardiovascular disease as the leading cause over the course of the century.^10,11 Many cancer deaths are in part due to late-stage diagnosis, when the cancer has already metastasized.¹² Early detection of cancer improves outcomes and survival rates, but it is often difficult to detect early due to the lack of early symptoms with many cancers, which can limit cancer screening and issues with access to care.¹³

 Currently, there are only 5 cancers: cervical, prostate, breast, colon, and lung (for high-risk adults) that are screened for in the general population (see "Cancer screening has helped save countless lives" at the end of this article).¹⁴ The Pap test to screen for cervical cancer, developed in the 1940s, has saved millions of women’s lives and reduced the mortality of cervical cancer by 70%.¹⁵ Coupled with the availability and implementation of the human papillomavirus (HPV) vaccine, cervical cancer rates are decreasing at substantial rates.¹⁶ However, there are no validated screening tests for uterine cancer, the most common gynecologic malignancy in the United States, or ovarian cancer, the most lethal. 

Screening tests for cervical, prostate, breast, colon, and lung cancer have helped save millions of lives; however, these tests also come with high false-positive rates and the potential for overdiagnosis and overtreatment. For example, half of women undergoing mammograms will receive a false-positive result over a 10-year time period,¹⁷ and up to 50% of men undergoing prostate cancer screening have a positive prostate-specific antigen (PSA) test result when they do not actually have prostate cancer.¹⁸ Additionally, the positive predictive value of the current standard-of-care screening tests can be as low as <5%. Most diagnoses of cancer are made from a surgical biopsy, but these types of procedures can be difficult depending on the location or size of the tumor.¹⁹ 

The liquid biopsy. Given the limitations of current cancer screening and diagnostic tests, there is a great need for a more sensitive test that also can detect cancer from multiple organ sites. Liquid biopsy-based biomarkers can include circulating tumor cells, exosomes, microRNAs, and circulating tumor DNA (ctDNA). With advances in next-generation sequencing, ctDNA techniques remain the most promising.²⁰ 

Methylation-based MCED testing: A new way of  cancer screening 

Multi-cancer early detection (MCED) technology was developed to address the need for better cancer screening and has the potential to detect up to 50 cancers with a simple blood test. This new technology opens the possibility for early detection of multiple cancers before symptoms even begin. MCED testing is sometimes referred to as “GRAIL” testing, after the American biotechnology company that developed the first commercially available MCED test, called the Galleri test (Galleri, Menlo Park, California). Although other biotechnology companies are developing similar technology (Exact Sciences, Madison, Wisconsin, and Freenome, South San Francisco, California, for example), this is the first test of its kind available to the public.²¹

The MCED test works by detecting the cfDNA fragments that are released into the blood passively by necrotic or apoptotic cells or secreted actively from tumor cells. The DNA from tumor cells is also known as circulating tumor DNA (ctDNA). CtDNA is found in much lower quantities in the blood stream compared with cfDNA from cells, making it difficult to distinguish a cancer versus a noncancer cell and to determine the tumor site of origin.²²

Through innovation, the first example of detecting cancer through this method in fact came as a surprise result from an abnormal cfDNA test. A pregnant 37-yearold woman had a cfDNA result suggestive of aneuploidy for chromosomes 18 and 13; however, she gave birth to a normal male fetus. Shortly thereafter, a vaginal biopsy confirmed small-cell carcinoma with alterations in chromosomes 18 and 13.²³ GRAIL testing for this patient was subsequently able to optimize their methods of detecting both the presence of cancer cells and the tumor site of origin by utilizing next-generation genomic sequencing and methylation. Their development of a methylation-based assay combined with 46 machine-learning allowed the test to determine, first, if there is cancer present or not, and second, the tissue of origin prediction. It is important to note that these tests are meant to be used in addition to standard-of-care screening tests, not as an alternative, and this is emphasized throughout the company’s website and the medical literature.²⁴ 

Continue to: The process to develop and validate GRAIL’s blood-based cancer screening test...

The process to develop and validate GRAIL’s blood-based cancer screening test includes 4 large clinical trials of more than 180,000 participants, including those with cancer and those without. The Circulating Cell-Free Genome Atlas (CCGA) Study, was a prospective, case-controlled, observational study enrolling approximately 15,000 participants with 3 prespecified sub-studies. The first sub-study developed the machine-learning classifier for both early detection and tumor of origin detection.^25,26 

The highest performing assay from the first sub-study then went on to be further validated in the 2nd and 3rd sub-studies. The 3rd sub-study, published in the Annals of Oncology in 2021 looked at a cohort of 4,077 participants with and without cancer, and found the specificity of cancer signal detection to be 99.5% and the overall sensitivity to be 51.5%, with increasing sensitivity by cancer stage (stage I - 17%, stage II - 40%, stage III - 77%, and stage IV - 90.1%).²⁴ The false-positive rate was low, at 0.7%, and the true positive rate was 88.7%. Notably, the test was able to correctly identify the tumor of origin for 93% of samples.²⁴ The study overall demonstrated high specificity and accuracy of tumor site of origin and supported the use of this blood-based MCED assay. 

The PATHFINDER study was another prospective, multicenter clinical trial that enrolled more than 6,000 participants in the United States. The participants were aged >50 years with or without additional cancer risk factors. The goal of this study was to determine the extent of testing required to achieve diagnosis after a “cancer signal detected” result. The study results found that, when MCED testing was added to the standard-of-care screening, the number of cancers detected doubled when compared with standard cancer screening alone.^27,28 Of the 92 participants with positive cancer signals, 35 were diagnosed with cancer, and 71% of these cancer types did not have standard-ofcare screening. The tumor site of origin was correctly detected in 97% of cases, and there were less than 1% of false positives. Overall, the test led to diagnostic evaluation of 1.4% of patients and a cancer diagnosis in 0.5%. 

Currently, there are 2 ongoing clinical trials to further evaluate the Galleri MCED test. The STRIVE trial that aims to prospectively validate the MCED test in a population of nearly 100,000 women undergoing mammography,²⁹ and the SUMMIT trial,³⁰ which is similarly aiming to validate the test in a group of individuals, half of whom have a significantly elevated risk of lung cancer. 

With the promising results described above, the Galleri test became the first MCED test available for commercial use starting in 2022. It is only available for use in people who are aged 50 and older, have a family history of cancer, or are at an increased risk for cancer (although GRAIL does not elaborate on what constitutes increased risk). However, the Galleri test is only available through prescription—therefore, if interested, patients must ask their health care provider to register with GRAIL and order the test (https://www .galleri.com/hcp/the-galleri-test/ordering). Additionally, the test will cost the patient $949 and is not yet covered by insurances. Currently, several large health care groups such as the United States Department of Veterans Affairs, Cleveland Clinic, and Mercy hospitals have partnered with GRAIL to offer their test to certain patients for use as part of clinical trials. Currently, no MCED test, including the Galleri, is approved by the US Food and  Drug Administration. 

Incorporating MCED testing into clinical practice

The Galleri MCED test has promising potential to make multi-cancer screening feasible and obtainable, which could ultimately reduce late-stage cancer diagnosis and decrease mortality from all cancers. The compelling data from large cohorts and numerous clinical trials demonstrate its accuracy, reliability, reproducibility, and specificity. It can detect up to 50 different types of cancers, including cancers that affect our gynecologic patients, including breast, cervical, ovarian, and uterine. Additionally, its novel methylation-based assay accurately identifies the tumor site of origin in 97% of cases.²⁸ Ongoing and future clinical trials will continue to validate and refine these methods and improve the sensitivity and positive-predictive value of this assay. As mentioned, although it has been incorporated into various large health care systems, it is not FDA approved and has not been validated in the general population. Additionally, it should not be used as a replacement for recommended screening. 

CASE Resolved

The patient is eligible for the Galleri MCED test if ordered by her physician. However, she will need to pay for the test out-of-pocket. Due to her family history, she should consider germline genetic testing (either for herself, or if possible, for her father, who should meet criteria based on his prostate cancer).³ Panel testing for germline mutations has become much more accessible, and until MCED testing is ready for prime time, it remains one of the best ways to predict and prevent cancers. Additionally, she should continue to undergo routine screening for cervical, breast, and colon cancer as indicated. ●