Management Of High Risk Population

Hereditary Breast Cancer

BRCA1 and BRCA 2

  • What is that stand for?!
    • BReast CAncer gene
  • What are they?
    • These are mutated genes.
    • They encode multifunctional proteins
  • Where are they?
    • BRCA1
      • Chromosome 17, Long arm
    • BRCA2
      • Chromosome 13, Long arm
  • What do they do?
    • They are functionally related.
    • Functions:
      • DNA recombination
      • Homologous Repair
      • Transcription
      • Chromatin remodeling
      • Centrosome Duplication
      • Cytokinesis
    • Both are in the class of CARETAKER genes.
    • They ensure genomic stability
  • Is there any associated syndrome with mutation in these genes?
    • Hereditary Breast/ovarian ca in BOTH
    • BRCA1
      • Bilat/multifocal breast ca;
      • Ovarian Cancer and fallopian tube ca
      • Risk of following cancers higher:
        • Prostate(in both)
        • Colon
        • Liver
        • Bone
    • BRCA2
      • D1 Fanconi Anemia <== bi-allelic mutation
      • Male breast Ca
      • Risk of following cancers:
        • Pancreas
        • Gallbladder
        • Pharynx
        • Stomach
        • melanoma
        • Prostate(in both)

What is the chance of Breast and Ovarioan Ca with BRCA1 and 2 mutation?

Breast > 50-80% life-time
Ovary
> 15-40%

Any difference between the cancer from BRCA1 vs BRCA2 vs sporadic?

  • BRCA1
    • more aggressive
    • more ER/PR neg
    • more high grade
    • behaves like basal-type(triple negative)
  • BRCA2
    • Mostly like sporadic
    • ER/PR + ; HER2 neg

Management of the High-Risk Patient

  • BRCA1 or BRCA2
  • Family history consistent with genetically transmitted breast cancer
  • Previous mantle irradiation
  • LCIS
  • Atypical hyperplasia
  • Variety of hormonal factors
    • Early menarche
    • Late age at first full-term pregnancy
    • Small effect on risk for any individual woman
  • Ashkenazic Jewish descent( higher risk for BRCA 1 and 2 )
    • 1 out 40 ashkenazic jewish women is BRCA+
  • Number of previous breast biopsies
  • First-degree female relatives

Options:

  • Monthly breast self-examination
  • Annual screening mammography
  • Clinical breast examinations once or twice
    • not clearly result in early detection in high-risk women.
  • Chemoprevention
    • Selective estrogen receptor modulators (SERMs)
    • Salpingo-Oophorectomy
      • After age 35 or once childbearing is completed
      • To reduce the risk of breast ca
        • Should be done before age of menopause
        • A prospective study! (6yr of F/U )
          • All-cause mortality > 3 vs 10%
          • Breast cancer-specific mortality> 2 vs 6%
          • Ovarian cancer-specific mortality 0.4 vs 3%
  • Prophylactic surgery
  • MRI
    • Cost-effective
    • recommended in BRCA1 and 2 patients

American Cancer Society Guidelines for Magnetic Resonance Imaging Screening

ANNUAL MRI RECOMMENDED BASED ON EVIDENCE
BRCA mutation
first degree relative with BRCA mutation
if life time of breast ca risk > 20-25%
ANNUAL MRI RECOMMENDED BASED ON EXPERT OPINION
Radiation to chest between age 10 and 30
Li-Fraumeni syndrome and first-degree relatives
Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives
INSUFFICIENT EVIDENCE TO RECOMMEND FOR OR AGAINST MRI
Lobular carcinoma in situ
Atypical hyperplasia (lobular or ductal)
Extremely or heterogeneously dense breasts on mammogram
Personal history of breast cancer, including DCIS

• Chemoprevention is an alternative to surveillance strategies. Two SERMs, tamoxifen and raloxifene, have been shown to reduce the incidence of ER-positive breast cancer. Four prospective, randomized trials have examined the effect of tamoxifen on breast cancer incidence. These studies and their outcomes are summarized in Tables 43.2.4 and 43.2.5.28,33,34,35 There is considerable heterogeneity in outcome among the trials, much of which can be attributed to differences in the populations studied. An Italian trial required women to have undergone a hysterectomy, but did not require an increase in breast cancer risk,34 while the Royal Marsden study used a family history of breast cancer as the determinant of risk status.33 In an overview of the four studies, tamoxifen produced a 38% reduction in breast cancer incidence (95% CI, 8% to 46%; P <.001), and a 48% reduction in the incidence of ER-positive breast cancers.36 No effect on the incidence of ER-negative cancers was seen in any of the trials, and the cancers occurring in women on tamoxifen were not found to have had more positive nodes or be larger in size than those in the placebo arm, providing reassurance that tamoxifen chemoprevention does not result in the occurrence of biologically more aggressive cancers.
• Table 43.2.4 A Comparison of Tamoxifen Chemoprevention Studies
• Study (Reference) • Age Range (y) • Family History (%) • HRT Use (%) • Lost to Follow-Up (%)
• Royal Marsden (33)
N = 2,471 • 30–70
median 47 • 100 • 26 • 11
• NSABP P1 (28)
N = 13,388 • >35
median NS • 76 • 0 • 1.6
• Italian (34)
N = 5,408 • 35–70
median 51 • 21 • 24.7 • 0.8
• IBIS (35)
N = 7,152 • 35–70
median 50.8 • 97 • 39.7 • NS
• HRT, hormone replacement therapy; NS, not stated; IBIS, International Breast Cancer Intervention Study; NSABP, National Surgical Adjuvant Breast and Bowel Project.

• In the largest of these studies, the NSABP P1 trial, a 49% risk reduction was seen with tamoxifen, with 43.4 cancers per 1,000 women occurring in the placebo arm compared to 22.0 per 1,000 in the tamoxifen arm.28 The benefits of tamoxifen were observed for both invasive and noninvasive carcinoma and were seen in women of all ages. A particular benefit was seen in those at risk due to atypical hyperplasia, with an 84% reduction in cancer incidence in this group. The risk reductions were similar in
• P.1611

those at risk on the basis of a family history of breast cancer and those at risk due to other factors. Controversy exists over the benefit of tamoxifen in BRCA mutation carriers. Only 19 of 288 women who developed breast cancer in the NSABP P1 study were found to have a BRCA1 or BRCA2 mutation. No evidence of tamoxifen benefit was seen in the eight BRCA1 carriers who received the drug. In contrast, a nonsignificant trend toward tamoxifen benefit was seen in BRCA2 carriers.37 These findings are consistent with observations that ER-positive cancers are more common in BRCA2 mutation carriers than BRCA1 mutation carriers, but the small sample size limits any conclusions. In a retrospective, case-controlled study of BRCA carriers who received tamoxifen for treatment of their initial carcinoma, Narod et al.38 reported a 50% reduction in the incidence of contralateral cancer. Benefit was seen in both BRCA1 and BRCA2 mutation carriers. These findings suggest that it is the likelihood of expressing the ER that determines the efficacy of tamoxifen as a chemopreventive rather than the presence of a BRCA mutation.
• The side effects of tamoxifen were well known from its use as a cancer treatment and were again observed in the prevention trials. In the combined analysis of the four studies, the relative risk of thromboembolic events in tamoxifen users was 1.9 (95% CI, 1.4 to 2.6; P <.0001) and the relative risk of endometrial cancer was 2.4 (95% CI, 1.5 to 4.0; P = .0005).36 Significant elevation in endometrial cancer and thromboembolic events was limited to postmenopausal women. Using this information, populations of women likely to have the most favorable risk-benefit ratio for tamoxifen can be identified. These include premenopausal women, younger postmenopausal women without a uterus, and those at risk on the basis of atypical hyperplasia or LCIS. In spite of this, use of tamoxifen for chemoprevention has been limited because of concerns about side effects.
• Table 43.2.5 Outcome of Tamoxifen Chemoprevention Studies
• Study (Reference) • Median Follow-Up (mo) • Total Cancers • Breast Cancer Rate (per 1,000 women-years) • RR (95% CI)
• Placebo • Tamoxifen
• Royal Marsden (ref. 33)
• 70 • 70 • 5.0 • 4.7 • 0.94 (0.59–1.43)
• NSABP P1 (ref. 28)
• 54.6 • 368 • 6.8 • 3.4 • 0.51 (0.39–0.66)
• Italian (ref. 34)
• 81.2 • 79 • 2.3 • 2.1 • 0.87 (0.62–2.14)
• IBIS (ref. 35)
• 50 • 170 • 6.7 • 4.6 • 0.68 (0.50–0.92)
• RR, relative risk tamoxifen to placebo; CI, confidence interval; NSABP, National Surgical Adjuvant Breast and Bowel Project; IBIS, International Breast Cancer Intervention Study.

• Raloxifene is another SERM that was initially approved for the treatment and prevention of osteoporosis by the U.S. Food and Drug Administration (FDA). Studies of raloxifene in osteoporotic women demonstrated a reduction in the incidence of breast cancer, a secondary end point. Like tamoxifen, raloxifene reduces the incidence of ER-positive breast cancer and has no effect on the incidence of ER-negative breast cancer. The NSABP P2 trial, the Study of Tamoxifen and Raloxifene (STAR) directly compared the chemopreventive actions and side effects of tamoxifen and raloxifene in 19,747 postmeno-pausal women at increased risk of breast cancer development.39 After a mean follow-up of 3.9 years, no difference in the incidence of invasive cancer was seen between women taking tamoxifen and those taking raloxifene (RR 1.02; 95% CI, 0.82 to 1.28). More cases of noninvasive cancer were noted in the raloxifene group (RR 1.40; 95% CI, 0.98 to 2.00), with a cumulative incidence of 11.7 per 1,000 compared to 8.1 per 1,000 in the tamoxifen group at 6 years (P = .052). A more favorable side-effect profile was seen for raloxifene, with an 84% reduction in endometrial hyperplasia and a statistically significant reduction in the number of hysterectomies compared to tamoxifen.
• P.1612

The number of endometrial cancers was also reduced in the raloxifene group (RR 0.62; 95% CI, 0.35 to 1.08), although the difference did not reach statistical significance. Significantly fewer thromboembolic events and cataracts occurred with raloxifene. The results of this study indicate that raloxifene is a viable alternative to tamoxifen for the chemoprevention of breast cancer in postmenopausal women at increased risk for the disease. In addition, the use of raloxifene in women with osteoporosis has the potential to lower breast cancer incidence in a group of women not considered high risk. Trials of aromatase inhibitors for breast cancer prevention are ongoing based on the findings from adjuvant therapy trials (discussed later in this chapter) that show that aromatase inhibitors produce a greater reduction in contralateral breast cancer incidence than is seen with tamoxifen treatment. The reduction in cancer incidence seen with aromatase inhibitors is also limited to ER-positive cancers. At present, there are no chemopreventive agents that have been proven to be effective in reducing the incidence of ER-negative breast cancer.
• Prophylactic surgery, in the form of bilateral mastectomy or bilateral salpingo-oophorectomy, is another option for breast cancer risk reduction. The efficacy of prophylactic mastectomy has never been studied in a prospective, randomized trial. Data on the benefits of the procedure are derived from retrospective reviews and case control studies. Hartmann et al.40 identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy between 1960 and 1993. Women were characterized as high risk if their family history was suggestive of an autosomal dominant predisposition to breast cancer. The expected incidence of cancer in this group was estimated using the age-specific incidence of breast cancer in their sisters. The remaining 425 women were classified as moderate risk, and the predicted incidence of breast cancer was derived from the Gail et al. model.26 A 90% to 94% reduction in breast cancer incidence (95% CI, 71% to 99%) and an 81% to 100% reduction in breast cancer mortality were observed with prophylactic mastectomy. In a prospective study of 139 BRCA mutation carriers with a mean follow-up of 3 years, Meijers-Heijboer et al.41 observed no breast cancers in the group undergoing prophylactic mastectomy compared to a 2.5% per year incidence in those opting for surveillance. Rebbeck et al.42 reported a mixed retrospective and prospective study of 483 BRCA mutation carriers. In this study, prophylactic mastectomy reduced breast cancer incidence by 90% to 95%. Studies of prophylactic mastectomy are summarized in Table 43.2.6.
• Although bilateral prophylactic mastectomy is an effective form of breast cancer risk reduction, even in women at risk due to BRCA mutations, it is an intervention that is unacceptable to many women. Prophylactic bilateral salpingo-oophorectomy is an alternative risk-reduction strategy in women at risk on the basis of BRCA mutations, which has the added benefit of reducing the risk of ovarian carcinoma, a disease for which effective screening is not available. In a case control study of 241 women, which included 99 women who had undergone prophylactic oophorectomy at a mean age of 42 years, the risk of breast carcinoma was reduced to 0.47 (95% CI, 0.29 to 0.77) with the procedure.43 A 96% reduction in ovarian cancer incidence was also noted. In a prospective study of the benefits of prophylactic salpingo-oophorectomy in 170 BRCA mutation carriers, Kauff et al.13 observed that the hazard ratio for breast cancer was reduced to 0.32 (95% CI, 0.08 to 1.20) and that for gynecologic cancer to 0.25 (95% CI, 0.08 to 0.74) at a mean follow-up of 24 months.
• Table 43.2.6 Outcome of Bilateral Prophylactic Mastectomy in High-Risk Women
• Author (Reference) • Population • No. of Women • Follow-Up • Risk Reduction
• Hartmann et al. (40)
• Women with a family history of breast cancer • 639 • 14 years (median) • 90%–94%
• Meijers-Heijboer et al. (41)
• BRCA1/2 mutation carriers • 139 • 3 years (mean) • 100%
• Rebbeck et al. (42)
• BRCA1/2 mutation carriers • 105 • 6.4 years (mean) • 90%–95%