Abstract
The management of hereditary breast and ovarian cancer (HBOC) in Japan has changed
drastically with the expansion of indications for poly ADP-ribose polymerase inhibitors,
the increase in diagnostic opportunities with the spread of companion diagnoses, and
partial insurance coverage of HBOC management. These circumstances require a response that
is coordinated across the entire hospital rather than from individual departments. In
April 2021, we established the HBOC Center, which is operated by nine departments:
Obstetrics and Gynecology, Reproduction, Surgery (breast group, hepato-pancreato-biliary
group), Urology, Dermatology, Neuropsychiatry, the Center for Medical Genetics, and the
Cancer Center. In addition to discussions of individual cases, our monthly conferences
have enabled us to establish indication criteria and appropriate items for surveillance,
visualize the examination flow in the hospital, construct a patient database, and provide
open lectures to educate the public. The future HBOC management system should not only
fulfill the existing requirements for risk-reducing surgery and facility standards but
also offer comprehensive and diversified attention based on the needs of patients and
their family members.
Introduction
Hereditary breast and ovarian cancer (HBOC) is a cancer predisposition syndrome in which a
pathogenic variant of the BRCA1/2 genes, a cancer suppressor gene, causes
loss of function and predisposes the carrier to the development of breast, ovarian,
pancreatic, and prostate cancers.1 In
addition to the treatment of individual cancers, surveillance for the risk of developing
other related tumors is conducted in cooperation with other clinical departments, and
information on genetic testing is provided not only to the carriers themselves but also to
their family members.2 In effect, patients
are treated in a comprehensive and cross-disciplinary treatment system that goes beyond the
conventional framework of cancer treatment.3 The management of HBOC in Japan has changed significantly with the
expansion of indications for poly ADP-ribose polymerase inhibitors, the increase in
diagnostic opportunities provided by the spread of companion diagnoses, and the partial
insurance coverage of HBOC management.4
Five years have passed since part of HBOC management was covered by insurance in April 2020,
and, in that time, HBOC management itself has become more widespread in clinical
practice.4 However, the HBOC practice
system that patients seek from hospitals has been transforming from simply being able to
diagnose HBOC through BRCA genetic testing to a wide range of management areas, including
subsequent surveillance and support for family members. While many hospitals in Japan have
been forced to manage the rapidly increasing number of HBOC patients, our hospital has taken
a pioneering approach in establishing and working on a comprehensive practice system in
which multiple departments collaborate across disciplines. Here, we characterize the future
requirements of HBOC management systems based on the activities of the Keio HBOC Center.
Methods
Medical records of patients who visited the Keio HBOC Center from April 2021 to March 2023
were retrospectively searched to collect the number of BRCA genetic tests performed and
their positivity rates. Details of the surgical procedures performed on patients who
underwent risk-reducing mastectomy or risk-reducing oophorectomy were also reviewed.
Moreover, the minutes of the monthly conferences held at the Keio HBOC Center were reviewed
retrospectively to ascertain the initiatives implemented within and outside the hospital
over a 2-year period.
Results
Achievements in clinical practice
The Keio HBOC Center was first established in April 2021 as a multidisciplinary and
comprehensive medical system. It originally included seven departments: Obstetrics and
Gynecology, Reproduction, Surgery (breast and hepato-pancreato-biliary groups), Urology,
the Center for Medical Genetics, and the Cancer Center. In October 2021, Dermatology and
Neuropsychiatry departments were added to the center to give a total of nine departments
(Fig. 1). While undergoing treatment for
cancer at our hospital, cases in which HBOC was suspected or a genetic diagnosis was
rendered were referred to the center. A similar process was used for referrals from other
hospitals. Furthermore, family relatives of patients diagnosed with HBOC by genetic
testing at the center were also referred to the center on request. The clinical
achievements of the HBOC Center from the time of its establishment up until March 2023 are
shown in Table 1. As of March 2023, a total of
395 patients had received genetic counseling. BRCA genetic testing was performed in 232
cases (48 with ovarian cancer, 93 with breast cancer, 68 with pancreatic cancer, 8 with
prostate cancer, and 15 were cancer-naive). In these tests, BRCA gene
pathogenic variants were detected (positive) in 31 cases (13.4%) overall, of which 12
cases (25.0%) were for ovarian cancer, 9 cases (9.7%) for breast cancer, 1 case (1.5%) for
pancreatic cancer, 1 case (12.5%) for prostate cancer, and 8 cases (53.3%) were
cancer-naive. Homologous recombination repair deficiency testing for ovarian cancer was
performed in 48 cases. Risk-reducing salpingo-oophorectomy (RRSO) was performed in 20
cases and risk-reducing mastectomy (RRM) in 9 cases, including 3 cases of simultaneous
surgery. Details and complications of RRSO and RRM surgeries are shown in Table 2. Of the 20 RRSO cases, 9 had a
hysterectomy performed at the same time at the patient’s request. We fully explained the
advantages and disadvantages of hysterectomy to the patients, and, if they agreed to pay
for the hysterectomy at their own expense, we performed hysterectomy in addition to RRSO
upon approval by the institutional review board. Although the operation time was longer
(136.4 min, mean) and blood loss increased (31.3 mL, mean) in the group of patients who
underwent hysterectomy, there was no difference in the hospitalization period or surgical
complications. During the evaluation period, no occult cancer was detected among the cases
in which RRSO was performed. Of the 9 cases that underwent RRM, 5 underwent total
mastectomy and 4 underwent nipple-sparing mastectomy (NSM). Operation time and blood loss
were worse in the group that underwent bilateral total mastectomy (146.0 min, 53.0 mL,
mean) than in the group that underwent unilateral total mastectomy (39.0 min, 10.0 mL,
mean). In 3 of the 4 cases involving NSM, immediate breast reconstruction was also
performed, resulting in increased operative time and blood loss (209.6 min, 78.1 mL,
mean). Notably, in the single case where autologous tissue reconstruction was performed,
the operative time was further prolonged. There were 3 cases in which RRSO and RRM were
performed simultaneously, and although the operation time was longer (190.3 min, mean)
than in cases in which RRSO or RRM were performed alone, this did not necessarily affect
blood loss (42.7 mL, mean), hospitalization period (7.0 days, mean), or the occurrence of
complications.
Table 1Achievements of HBOC Center in clinical practice from establishment to March
2023
| Examination item |
Cases examined |
BRCA positive |
| Genetic counseling |
395 |
|
| BRCA genetic testing |
232 |
31 (13.4) |
| Ovarian cancer |
48 |
12 (25.0) |
| Breast cancer |
93 |
9 (9.7) |
| Pancreas cancer |
68 |
1 (1.5) |
| Prostate cancer |
8 |
1 (12.5) |
| Cancer-naive |
15 |
8 (53.3) |
| Homologous recombination repair deficiency
testing |
48 |
|
| Risk-reducing surgery |
26 |
|
| RRSO |
20 |
|
| RRM |
9 |
|
Data given as number or number (percentage).
RRSO, risk-reducing salpingo-oophorectomy; RRM, risk-reducing mastectomy.
Table 2Details and complications of RRSO and RRM
| Surgical procedure |
Mean operation time (min) |
Mean blood loss (mL) |
Mean hospitalization period (days) |
Complication |
Occult cancer |
| RRSO (n=17) |
|
|
|
|
|
| RRSO (n=9) |
88.7 |
17.2 |
6.2 |
None |
None |
| RRSO + hysterectomy (n=8) |
136.4 |
31.3 |
6.4 |
None |
None |
| RRM (n=6) |
|
|
|
|
|
| Total mastectomy (n=3) |
|
|
|
|
|
| Bilateral (n=2) |
146 |
53 |
8 |
Hemorrhage |
None |
| Unilateral (n=1) |
39 |
10 |
9 |
None |
None |
| NSM (n=3) a |
209.6 |
78.1 |
10.4 |
None |
None |
| RRSO + RRM (n=3) b |
190.3 |
42.7 |
7 |
None |
None |
a Nipple-sparing mastectomy: three cases underwent breast
reconstruction.
b Including RRSO + contralateral RRM, RRSO + bilateral RRM (NSM), and
RRSO + hysterectomy + contralateral RRM.
At the monthly HBOC Center conference, we discussed the indications for risk-reducing
surgery on a case-by-case basis. In addition, we also established the criteria for
surveillance and the items to be performed, visualized the examination flow in the
hospital, constructed and populated a database, and held open lectures to educate the
public. For example, regarding the visualization of surveillance procedures, we determined
which examinations and at what intervals they can be performed continuously in the
hospital according to current guidelines based on joint discussion among the Gynecology,
Surgery (breast group, hepato-pancreato-biliary group), and Urology departments. For
women, breast surveillance includes monthly self-palpation, palpation by a physician every
6 months, yearly contrast-enhanced magnetic resonance imaging, and yearly mammography or
ultrasound. Ovarian surveillance includes vaginal ultrasound every 6 months and serum
CA125 every 6 months. Pancreatic surveillance includes endoscopic ultrasound or magnetic
resonance cholangiopancreatography every year. For malignant melanoma of the skin, a
overall skin checkup can be performed as appropriate. For men, breast surveillance
includes monthly self-palpation and yearly palpation by a physician. Prostate surveillance
includes an annual test for serum prostate-specific antigen. Pancreatic surveillance and
malignant melanoma of the skin are performed as described for female patients. This
approach has increased the knowledge of tests performed in other departments and has
contributed to better HBOC management in the hospital. In addition, we created an HBOC
surveillance plan chart to allow the patients to visualize and manage the schedule of
their examinations (Fig. 2). The chart also has
an educational purpose, because it serves to raise awareness of the importance of
surveillance. Furthermore, given the increasing number of patients with HBOC, the HBOC
Center has established, with the approval of the institutional review board, a database to
accumulate, share, and use medical data. Given that the database is stored on the hospital
network, each department can input the medical data for each case and share it among
departments, facilitating the academic activities on HBOC by each department.
We consider that the HBOC Center has an important responsibility to share information
with the general public as well as within the hospital. As a result, an open lecture was
presented to the public, based on a program that included ovarian and breast cancer,
genetics, pancreatic cancer, and prostate cancer, all of which were discussed in a manner
that was comprehensible to members of the public. Many patients expressed their wish that
such centers be established in university and general hospitals nationwide, because they
are currently forced to visit multiple hospitals. They also advocated for a higher level
of awareness on genetic diseases among medical professionals so that patients throughout
the country can be properly informed. Among the healthcare professionals assisting with
the initial lecture, requests were made for information on how to establish such a center
and as well as operational tips. Given the good reception toward the lecture and constant
requests for information sharing, we have decided to hold regular public lectures and to
make their content available to interested parties.
Discussion
The establishment of the Keio HBOC Center represents a significant advancement in the
management of HBOC in Japan. This multidisciplinary initiative has demonstrated the
feasibility and effectiveness of a comprehensive care model that spans multiple departments,
including obstetrics and gynecology, surgery, urology, dermatology, neuropsychiatry, and
genetics. It should be noted that the participation of neuropsychiatry in the center is
based on our strong awareness of the importance of treating the psychological burden of HBOC
patients.5 The integration of these
disciplines has not only facilitated collaborative decision-making but also improved patient
care through coordinated surveillance and risk-reducing strategies. The achievements of the
HBOC Center in clinical practice are noteworthy. With 395 patients receiving genetic
counseling and 232 undergoing BRCA testing, the detection of pathogenic
BRCA variants (13.4% overall) is consistent with global prevalence rates.
The particularly high positivity rate among cancer-naive patients (53.3%) underscores the
importance of genetic screening even in the absence of a personal cancer history,
highlighting a potential area for expanding population-based genetic testing programs.
The outcomes of risk-reducing surgeries, including RRSO and RRM, further validate the HBOC
Center’s commitment to patient-centered care. Despite the extended operative time associated
with simultaneous RRSO and hysterectomy, the absence of additional complications supports
the safety and feasibility of combined procedures when guided by patient preferences.
Although there was no case of occult carcinoma among the subjects in this study,
collaboration with a pathologist is very important because occult carcinoma or serous tubal
intraepithelial carcinoma can be detected in RRSO specimens.6 The experience with NSM and immediate reconstruction, while
leading to longer operative times, highlights the importance of preserving quality of life
through reconstructive options.
The internal initiatives of the HBOC Center, such as the visualization of surveillance
protocols and the creation of a shared medical database, have contributed to more efficient
multidisciplinary collaboration. The surveillance plan chart, in particular, serves as an
educational tool for patients, empowering them to participate actively in their long-term
care. The implementation of a hospital-wide HBOC surveillance plan and an educational chart
for patients aligns with survey findings of the Japan Society of Gynecologic Oncology
(JSGO), which emphasized the importance of clear, patient-friendly educational
materials.4 The development of a
centralized database further supports data-driven research and quality improvement efforts
across departments, addressing the JSGO survey’s identified need for information-sharing
platforms.4
The commitment of the HBOC Center to public education through open lectures has
successfully addressed a critical gap in genetic literacy. Feedback from attendees
underscores the demand for similar centers nationwide and highlights the broader societal
impact of information sharing. The positive reception from healthcare professionals also
points to the potential of the HBOC Center as a model for other institutions seeking to
develop similar multidisciplinary programs.
Despite the successes of the HBOC Center, several challenges and opportunities for
improvement remain. The surveillance management program is proceeding satisfactorily;
however, patients are encumbered by the necessity of undergoing each test at each department
on each visit date. Notably, patients who have not yet developed cancer are required to
undergo testing at their own expense. A system that would allow them to undergo all testing
in a single day is currently under consideration. Although the center has successfully
implemented risk-reducing surgeries, future efforts could focus on expanding access to
chemoprevention and lifestyle interventions. In addition, to address the feedback from
public lectures, the center should consider developing training programs aimed at healthcare
providers to promote HBOC awareness and competency across the medical community.
Conclusion
Future HBOC management systems should not only fulfill the existing requirements for
risk-reducing surgery and facility standards but also address the needs of patients and
their family members. We must listen to patients and their families, take the initiative in
hospital collaboration, and fulfill our responsibility to share information with the
community.
Acknowledgments
We thank all those who have supported the activities of the Keio HBOC Center.
Conflicts of Interest
The authors have declared that no conflict of interest exists.
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