BRCA Risk factors

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BRCA Risk factors

• White
• Age
• FH (M, S, D)
• BRCA12
• Endometrial Ca, fibrocystic disease, BRCA
• Early menarche (lt12), late menopause (gt50)
• Nulliparous or late first pregnancy

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Breast lesions
ADH DCIS (Preinvasive Malignant) ALH LCIS
ER 90 45 90 90
HER2 1 25 2
Risk 4-fold 8-10-fold 6-10-fold (1 per year) 6-10-fold (1 per year)
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Major trials on tamoxifen in DCIS

• NSABP B-24
• UK/ANZ
• NSABP B-35 (tamoxifen and anastrozole)
• NSAPB P-1 50 decrease in invasive breast cancer
  for LCIS and 86 decrease for ADH

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First events in NSABP B-24 trial(Lancet. 1999
353)
Type of event Placebo (n899) Tamoxifen (n899) P
Breast and non-breast cancer 16.7 (169) 12.6 (126) 0.006
Total breast 13.4 (130) 8.2 (84) 0.0009 By 5
Invasive 7.2 (70) 4.1 (41) 0.004 By 3
Non-invasive 6.2 4.2 0.08
Endometrial cancer 0.45 (2) 1.53 (7) 0.20
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B-24 trial

• Tamoxifen decreases the cumulative incidence of
  breast-cancer events in women with DCIS
• Most pronounced effect in younger patients (lt50
  yo)
• Among the ER () DCIS lesions, tamoxifen reduced
  the incidence of all breast cancer events by 50
• (Breast Cancer Res. Treat. 2002 76)

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Events in UK/ANZ trial(Lancet. 2003 362)
Events Control (n782) Tamoxifen (n794) P
Total 18 14 0.13
DCIS 11 7 0.03
Invasive 6 7 0.59
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UK/ANZ

• Tamoxifen did not produce additional benefit over
  and above that provided by radiotherapy (in a
  group of 316 patients, data not shown)

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B-24 vs UK/ANZ trial
B24 UK/ANZ
Tested hypothesis TRS more effective than RS Comparison of S, SR, ST, SRT
Randomization Full Partial
Size of TRS group 899 316
Age Younger (33.5 lt50 yo) Older (9.5 lt50yo)
Margins Positive and negative Negative only
ER expression Analyzed ?
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• B-24 there is evidence that tamoxifen has some
  positive benefit in addition to surgery and
  radiotherapy
• UK/ANZ it is indeterminate that tamoxifen does
  not have benefit in addition to surgery and
  radiotherapy

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Is it worth waiting?

• B-24 all event rate (per 100 per year)
• Placebo Tamoxifen
• All BRCA 2.9 1.8
• Invasive 1.6 0.9
• There is a 1 risk of a new event per year of
  observation
• NNT19 to avoid an event, not to save a life

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HER2/neu

• Human epidermal GFR2
• TK activity
• Transforms cells in vitro
• HER2 BRCAs have worse prognosis
• 15-20 invasive tumors HER2 positive

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Primary end-point disease-free survival. Events

• Recurrence of BRCA at any site
• Ipsi- or contralateral BRCA (DCIS but not LCIS)
• Non-breast Ca (not Ba/Sq skin, not cervix)
• Death from any cause.

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Exclusion criteria

• Distant Mts
• Previous Invasive BRCA
• Other neoplasms (excluding the above)
• T4 tumors, inflammatory, supraclavicular LNs,
  suspicious int mamm nodes, prior mediastinal
  irradiation
• Cardiac (CHF, Q wave, angina, uHTN, unstable
  arrhythmias, valvular disease, EFlt55)

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Limitations

• Length of follow-up risks
• Length of follow-up brain mets (1/3)
• Length of follow-up hormone status
• ? Correlation with HER2 expression
• ? Resistance to Herceptin

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Primary guides

• Was the assignment of patients to treatments
  randomized?
• Were pts properly accounted for?
• Follow up complete?
• Intention to treat?

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Secondary guides

• Pts, healthcare workers, personnel blind?
• Groups similar?
• Were groups treated equally?
• Statistics appropriate?

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Results

• Null hypothesis accepted/rejected?
• How large was the treatment effect?
• How precise was the estimate of effect?