As more women are concerned with their hereditary breast & Gyneacological cancer risk, the threshold for genetic testing is falling . Patients and family members should be supported & given information about chemoprevention, surveillance & risk-reducing surgery . The true challenge lies in translation of this knowledge into clinical practice, such that a definitive improvement in longevity and quality of life for patients and their families is realized.

1. Is Surgical Intervention in Women with
a Genetic Predisposition to
Gynaecological Cancers justified ??
Wafaa B. Basta
Consultant Gynaecology & Obstetrics at Mataria Teaching Hospital,
MRCOG
ERC MEMBER

7. 5% of endometrial carcinomas
20% of epithelial ovarian carcinomas
are
Hereditary
Gruber SB, Thompson WD. A population-based study of endometrial cancer and familial risk in younger women.
Cancer and Steroid Hormone Study Group. Cancer Epidemiol Biomarkers Prev 1996;5:411–7.

8. Autosomal Dominant Disorders
• Hereditary breast and ovarian cancer (HBOC)
• Lynch syndrome (formerly referred to as hereditary
non-polyposis colorectal carcinoma, HNPCC) .
Bewtra C, Watson P, Conway T, Read-Hippee C, Lynch HT. Hereditary ovarian cancer: a clinicopathological study. Int
J Gynecol Pathol 1992;11:180–7.

9. Rare Syndromes
• Cowden Syndrome
• Peutz-Jeghers Syndrome
• Li-Fraumeni Syndrome

10. Hereditary breast and ovarian cancer
The BRCA1 and BRCA2 genes were first identified
and cloned in the early 1990s.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer
susceptibility gene BRCA1. Science 1994;266:66–71.

11. Lifetime risk of by age 70 years
ovarian cancer breast cancer
BRCA1mutation 63% 85%
BRCA2carriers 27% 84%
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2
genes in breast cancer families. Am J Hum Genet 1998;62:676–89.

12. Who would be offered genetic
testing??

13. Identification of high-risk families
• According to family history of cancer , women are stratified into
categories of breast cancer risk.
Moderate risk of breast cancer.
High risk of breast cancer :
 with a 10% or lower probability of being a BRCA carrier.
 greater than 10% BRCA carrier probability .
NICE guideline Familial breast cancer: Classification and care of people at risk of familial breast cancer and management
of breast cancer and related risks in people with a family history of breast cancer [CG164] Published date: June 2013

14. Risk Assessment Tools
Are used to calculate a woman’s chance of
having a BRCA1 or BRCA2 gene mutation and
hence their lifetime breast and ovarian cancer
risk.
Examples :
– Manchester scoring system
– BOADICEA is a computer program .
National Institute for Health and Care Excellence. Familial breast cancer: classification and care of people at risk of familial breast
cancer and management of breast cancer and related risks in people with a family history of breast cancer. NICE clinical guideline 164.
Manchester: NICE; 2013.

20. Whom to offer genetic testing??
• A formal risk assessment has given risk estimates of:
– a 10% or greater chance of a gene mutation being harbored in
the family [new 2013]
– a greater than 8% risk of developing breast cancer in the next
10 years
– a 30% or greater lifetime risk of developing breast cancer.

21. Whom to offer genetic testing??
• Start with testing of an affected individual .
(mutation searching/ screening) to try to identify
a mutation in the appropriate gene
(such as BRCA1 BRCA2 or TP53)

22. Genetic testing
A diagnostic genetic test:
is a full screen of the gene normally undertaken
in an individual affected with cancer.
A predictive genetic test
is a targeted test for a specific mutation,
previously identified in another family
member, and usually undertaken in an
individual who has not had cancer.

23. Whom to offer genetic testing??
• Three or more breast and/or ovarian cancer cases with
at least one case in a woman aged younger than 50
years.
• Two breast cancer cases where younger than 40 years.
• Male breast cancer and an ovarian cancer or early-
onset female breast cancer case.
• Ashkenazi Jewish background with breast cancer in a
woman aged younger than 60 years.
• Young-onset bilateral breast cancer.
• Breast and ovarian cancer in the same patient.

24. Whom to offer genetic testing??
• Family history of any of the following, in
addition to breast cancers:
– sarcoma in a relative younger than age 45 years
– glioma or childhood adrenal cortical carcinomas
– complicated patterns of multiple cancers at a
young age.
– very strong paternal history (four relatives
diagnosed at younger than 60 years of age on the
father's side of the family).

25. Does histological confirmation alter the
risk category?
• Epithelial ovarian carcinoma are more likely to be associated
with BRCA1/2 mutations than borderline or non- epithelial
ovarian tumour
• High-grade serous and endometrioid carcinomas are more
likely to be associated with BRCA1/2 mutations than
mucinous ovarian carcinomas .
Kurman RJ, Shih leM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum
Pathol 2011;42:918–31.

26. Genetic testing for women with ovarian cancer
Historically,
a woman with ovarian carcinoma would only
be offered BRCA1 and BRCA2 gene testing if
she or a close relative had also been
diagnosed with breast or ovarian carcinoma.

27. Genetic testing for women with ovarian cancer
However, studies investigating the prevalence of
BRCA1 and BRCA2 mutations in epithelial
ovarian carcinoma patients unselected for
family history or ethnicity have found
pathological mutations in up to 17% of
women.

28. Genetic testing for women with ovarian cancer
As a result, it has been proposed that every
woman with epithelial ovarian, fallopian tube
and primary peritoneal carcinoma should be
offered BRCA1 and BRCA2 gene testing,
regardless of family history.

29. Management for women with
BRCA1 or BRCA2 carrier mutation

30. • Life style modification & advice.
• Screening for:
 breast cancer.
ovarian cancer.
• Chemoprevention
 Tamoxifen for breast cancer
 PARP inhibitors for ovarian cancer
• Risk-reducing Surgeries:
Risk –reducing breast surgery .
 Risk- reducing bilateral salpingo-oophorectomy
(RRBSO) .
Risk- reducing bilateral salpingectomy.

31. • Life style modification:
– Smoking & Alcohol cessation.
– Physical exercise .
– Appropriate diet& BMI.
– Encourage breast feeding.
– Advice regarding CC & HRT

32. Hormonal contraceptives (COCP)
– A family history of breast cancer is not a contra-
indication to hormonal contraception.
– over 35 years + family history of breast cancer ----
increased risk of breast cancer .
– BRCA1 mutations------ conflicting effects :
 potential increased risk of breast cancer under the age
of 40 .
 lifetime protection against ovarian cancer risk .
reduction in ovarian cancer risk may outweigh any
increase in risk of breast cancer.

33. Hormone replacement therapy (HRT)
– family history of breast cancer ----- increase in
breast cancer risk.
– If taken, restricted to short duration and low dose
, Oestrogen-only HRT.
– A woman having an early menopause ,HRT usage
if younger than age 50 .

34. Chemoprevention for breast cancer
• Tamoxifen or raloxifene for 5 years reduce the
risk of breast cancer in postmenopausal
women at increased risk of disease.

35. Chemoprevention of ovarian cancer
• Selective targeting of tumour cells by poly
ADP-ribose polymerase (PARP) inhibitors.
• Pre-clinical and clinical trials of PARP inhibition
in both sporadic and inherited ovarian
carcinomas are underway and the data from
these studies are promising.
Banerjee S, Kaye S. PARP inhibitors in BRCA gene-mutated ovarian cancer and beyond. Curr Oncol Rep 2011;13:442–9.

36. Breast screening for BRCA1/2 mutation
• 20-29ys: no MRI, no mamogram.
• 30-39ys: Annual MRI and consider annual mammography.
• 40-49ys: Annual MRI and annual mammography .
• 50-69ys: Annual mammography, Do not offer MRI unless
dense breast pattern.
• 70+ys: Mammography as part of the population screening
programme.

37. Screening for ovarian cancer
• In 13 studies evaluating ovarian cancer
screening in high-risk women:
( of the 70 tumours discovered, 24% were early stage.
The incidence of early-stage disease in unscreened
women in the general population is similar and
therefore it is unclear whether screening impacts on
mortality.)
Chan JK, Urban R, Cheung MK, Osann K, Husain A, Teng NN, et al. Ovarian cancer in younger vs older women:
a population-based analysis. Br J Cancer 2006;95:1314–20.

38. Screening for ovarian cancer
• A large prospective study :UK Familial Ovarian Cancer
Screening Study (UK FOCSS), which evaluated serial
ultrasound and CA125 measurement & its effect on
morbidity & mortality in this group of patients,
results are awaited.
• Until this , surveillance for ovarian carcinoma should
not be offered as an alternative to RRBSO.

39. Risk-reducing surgery

40. Risk-Reducing Bilateral Mastectomy
Breast Cancer Risk reduction of
at least 90%.
It is the most effective strategy for cancer breast
risk reduction in carriers of the BRCA
mutation.

41. RRBSO
BRCA1/2 mutation
Reduction in ovarian cancer risk 80%-96%
Reduction in overall mortality 60% -76%
Reduction in breast cancer risk for
premenopausal women
Up to 56% / Up to 46%
Management of Women with a Genetic Predisposition to Gynaecological Cancers
Scientific Impact Paper No. 48 February 2015
Can be performed laparoscopically

42. RRBSO
• Potential menopausal implications for
cardiovascular, bone and psychosexual health .
• If RRBSO is undertaken pre-menopausally:
– If no personal history of breast cancer -------Offer
HRT until the age of natural menopause(50 y).
– If personal history of breast cancer---- the use of
HRT is not recommended.

43. RRBSO
•surgery at 35–40
years
A BRCA1carrier chance
of developing ovarian
cancer increases
significantly during 40s-
•surgery may be
delayed until 45
years of age
The risk for BRCA2 does
not appear to increase
until later

44. RR Salpingectomy
• Tubal Hypothesis of
Epithelial Ovarian
Cancer Pathogenesis

45. Serous Tubal Intraepithelial Carcinoma (STIC)
The Distal Fallopian Tube as the Origin of Non-Uterine Pelvic High-Grade Serous Carcinomas.
Scientific Impact Paper No. 44. London: RCOG; 2014.

46. Serous Tubal Intraepithelial Carcinoma (STIC)
• STICs appear to shed malignant cells without
invading the tube.
• This explain:
– significant bulk of tumour on the ovary and
peritoneum with little tubal disease.
– residual risk of primary peritoneal cancer
following RRBSO.
Lewin SN, Kauff ND. Risk-reducing salpingo-oophorectomy for the prevention of inherited breast and
ovarian cancer. In: Lu KH, editor. Hereditary gynecologic cancer: risk, prevention, and management. New
York: Informa Healthcare; 2008. p. 79–91.

47. Risk-Reducing Bilateral Salpingectomy
• Allows conservation of the ovaries nearer to
the age of natural menopause, when a
delayed bilateral oophorectomy can be
performed.
• However, the long-term effect on ovarian
cancer incidence and mortality remains
unknown.
The Distal Fallopian Tube as the Origin of Non-Uterine Pelvic High-Grade Serous
Carcinomas. Scientific Impact Paper No. 44. London: RCOG; 2014.

48. Lynch syndrome
• formerly referred to as hereditary non-polyposis
colorectal carcinoma, HNPCC.
• Caused by germline mutations in the DNA
mismatch repair (MMR) genes (MSH2, MLH1,
MSH6, PMS2).
• Increased risk of early-onset cancer of multiple
types, including:
– colorectal, gastric, small bowel , hepat-obiliary ,
– brain, ureteric , renal pelvic cancers.
– Endometrial & ovarian
Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers
of DNA-mismatch-repair genes. Int J Cancer 1999;81:214–8.

49. Lynch syndrome
Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers
of DNA-mismatch-repair genes. Int J Cancer 1999;81:214–8.
Lynch syndrome General
population
The lifetime risk for
endometrial cancer
40–60% 3%
Life time risk for ovarian
carcinoma
10–12% 1.4%

50. Identification of at-risk families
• Refer at-risk women for genetic counseling
and testing:
– Endometrial cancer under 50 years +FDR with
another Lynch-related cancer( 23% MMR
mutation)
– two or more FDRs with endometrial cancer and no
family history of other cancers .( 8.7% chance)
Lu KH, Schorge JO, Rodabaugh KJ, Daniels MS, Sun CC, Soliman PT, et al. Prospective determination
of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol
2007;25:5158–64.

51. • Endometrial thickness by TVUS and biopsy
from 35– 40 years ----- early cancer detection
(part of a clinical trial).
• The good prognosis and early presentation
may offset survival advantage of screening.
Screening for
Lynch syndrome-associated cancers

52. Risk-reducing surgery for
Lynch syndrome-associated cancers
• Women are offered (TLHBSO) after completion of
their families.
• One study of 315 women with Lynch syndrome :
– No ovarian or endometrial cancer in women who
underwent risk-reducing surgery,
– 33% of women who did not have surgery
developed endometrial cancer and 5.5%
developed ovarian cancer.
Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, et al. Prophylactic surgery to reduce the
risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261–9.

53. Preventive therapy for
Lynch syndrome-associated cancers
• Regular intake of low-dose aspirin (75 mg daily) may
reduce the risk of colorectal cancer after 5 years of
use.
• Aspirin may also reduce the risk of developing the
other cancers associated with Lynch syndrome.
• A research study called CaPP3 (Cancer Prevention
Programme 3) is investigating the most effective
dose of aspirin for people with Lynch syndrome to
take (www.capp3.org).
Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal
cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010;376:1741–50.

54. Other rare syndromes
• Autosomal dominant genetic conditions.
 Cowden Syndrome
 Peutz-Jeghers Syndrome
 Li-Fraumeni Syndrome
• These conditions have specific cardinal
features that are recognizable and should
prompt a clinical genetics referral.

55. Cowden syndrome (CS)
• Germline mutations in the tumour suppressor
gene PTEN
• Autosomal dominant condition
• Macrocephaly, multiple hamartomas
• Increased risk of breast, thyroid and
endometrial cancers, but also colorectal,
melanoma and renal cell carcinoma.

56. Cowden syndrome (CS)
• The lifetime risk of endometrial cancer in CS
approaches 30%
• To date, no definitive evidence for
endometrial screening in CS, although some
have suggested annual endometrial biopsies.
• Risk-Reducing Hysterectomy may be
discussed ---------data regarding efficacy are
sparse.
Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with
germline PTEN mutations. Clin Cancer Res 2012;18:400–7.

57. Peutz-Jeghers syndrome (PJS)
• Germline mutations in the STK11 gene
• Autosomal dominant gastrointestinal
polyposis disorder .
• Characteristic pigmented lesions on the lips
and buccal mucosa .
Giardiello FM, Trimbath JD. Peutz-Jeghers syndrome and management recommendations. Clin
Gastroenterol Hepatol 2006;4:408–15.

58. Peutz-Jeghers syndrome (PJS)
• Increased risk of breast, gastrointestinal and
gynaecological tumours (sex cord stromal
tumours with annular tubules of the ovary
and adenoma malignum of the cervix) .
• Annual screening with Pap smear from age 18
years .
• Annual trans-vaginal ultrasound and CA125
starting from 25 years , although definitive
evidence for screening is lacking.
Giardiello FM, Trimbath JD. Peutz-Jeghers syndrome and management recommendations. Clin
Gastroenterol Hepatol 2006;4:408–15.

59. Li-Fraumeni syndrome (LFS)
• Caused by germline TP53 mutations.
• The cardinal features of the condition:
• young-onset sarcomas.
• breast cancer.
• adrenocortical carcinoma.
• childhood tumours.
• Gynaecological malignancies are unusual, the most
commonly diagnosed being epithelial ovarian
carcinoma.
Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, et al. A cancer family syndrome in twenty-
four kindreds. Cancer Res 1988;48:5358–62.

60. Conclusion
• As more women are concerned with their
hereditary breast & Gyneacological cancer risk,
the threshold for genetic testing is falling .
• Patients and family members should be
supported & given information about
chemoprevention, surveillance & risk-reducing
surgery .

61. Conclusion
• Until further evidence regarding chemo-
preventive measures , RR surgery is thought to
be an effective option.
• RR bilateral mastectomy protects against
breast cancer only. However, RRBSO decreases
both ovarian & breast cancer risk but not
without hazards.
• RR bilateral salpingectomy seems to be good
option to delay RRSO but still under trials.

62. Conclusion
• The management should involve a
multidisciplinary team that enables women to
have tailored management based on their
individual medical history and preferences.
• The true challenge lies in translation of this
knowledge into clinical practice, such that a
definitive improvement in longevity and
quality of life for patients and their families is
realized.

63. Thank
You