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Modern Breast Cancer Treatment:
With an Emphasis on Breast Ca
Susceptibility Genes BRCA1,2
and the 5 Molecular Subtypes of Breast Ca
Mark Graham MD
Waverly Hematology-Oncology
Cary, NC
At Lafayette College
Easton, PA
October 20, 2011
BRCA1 and BRCA2 Founder Mutations
in the Ashkenazi Jewish Population
An estimated 1 in 40 Ashkenazi Jews
carries a BRCA1 or BRCA2 mutation
BRCA1
187 del AG
Prevalence = ~1%
5382 ins C
Prevalence = ~0.15%
BRCA2
BRCA2 Icelandic
founder mutation
999 del 5
6174 del T
Prevalence = ~1.5%
Roa BB et al. Nat Genet 14:185, 1996
Oddoux C et al. Nat Genet 14:188, 1996
Struewing JP. N Engl J Med 336:1401, 1997
Patient WP
- Sister w/ Bilateral
breast Ca at ages
44, 47
- Prompted BRCA1,2
testing: + for two
base pair deletion in
BRCA2: frame shift,
“1006 del GA”
T
++
+
+
- In turn, prompted
family testing 2009,
including proband
WP: patient’s two
children and WP +,
niece -.
Bilateral Br Ca: 44, 47
T
_
+
+ +
+
2
-Oct 2009:
Recommend
heightened
screening and
eventual BPM, BSO
for trhe Proband
Patient WP
- Negative
Mammography 4/09,
physical exam 10/09
- Pt palpated Right
superior peri-areolar
mass, April 2010
- D. Eddleman: Core
Bx + for up to 0.8 cm
ILCA, no LVI or DCIS
_
- ER+, PgR+, HER2-
New ILCA,
April 2010, age 52
++
- Pt elected Bilateral
Mastectomies w/ gene
mutation
+
+
Bilateral Br Ca: 44, 47
_ _
+
+
++
- Additional Family
members tested, incl.
Proband’s mother
- Paternal
transmission proven
Rotterdam Study of 139 BRCA 1, 2 Carriers:
“Self-Randomization” to Surveillance or
Bilateral Prophylactic Mastectomy (BPM)
63 (45%) chose Close Surveillance
76 (55%) chose BPM
• 3.0 years mean F/U
• 8 / 63 developed Breast
Ca
• Actuarial BrCa incidence
17% at 5 years
• Annual rate of 2.5%
BrCa
• 2.9 years mean F/U
• 0 / 76 with Breast Ca
• p = 0.003 vs. the
Close Surveillance
Group
Meijers-Heijboer H, et al. N Engl J Med 2001;345:159 -164
Patient TS
- Prostate, Breast, Ca
Unknown Primary in the
previous generation
- Sister w/ Br Ca at age
40, two paternal 1st
cousins w/ Br Ca at 45
and 40
- Prompted BRCA1,2
sequencing in Pt’s sister,
one Paternal 1st cousin:
Both Negative for
deleterious mutation
_
Male Br Ca: 49, living at 53
_
?
Sister,
Pat. 1st Cousin:
“Negative
BRCA1,2
Testing”
?
?
?
- 2006: Pt developed
male Breast Ca, at 49:
2 LN+, Grade 3,
ER+, PgR-, HER2-.
- Right MRM, W. Cannon;
Adjuvant TAC x 4 fol. By
Taxol x 4; Tamoxifen to
the present.
Patient TS
- 2010: Dr. Wm Dunlap
Referred TS for
reconsideration of “any
further genetic testing
that might prove
beneficial”.
- Prompted
BRCA1,2Associated
Rearrangement
or “BART”
- Showed large deletion
in BRCA2, including all
of Exons 1 and 2
Male Br Ca: 49, living at 53
_
_?
?
?
++
Sister,
Pat. 1st Cousin:
“Negative
BRCA1,2
Sequencing”
+
+
?
?
?
?
Testing,
?
Patient:
Tested for
“BART”:
Positive for
BRCA2 2-Exon
Deletion
- Sisters, Cousins,
Brother, Daughters can
now have correct
assignment of risk
1st of 3 daughters has
now tested and carries
the deleterious mutation
Mayo Clinic Study of Well Women Undergoing
Bilateral Prophylactic Mastectomy (BPM)
Group
N
Breast
Cancers (%)
High-risk women
with mastectomy
214
E: 83 (38.7%)
O: 3 (1.4%)
Their full sisters w/
no mastectomy
403
O: 156 (38.7%)
96% reduction in BrCa
Hartmann et al. N Engl J Med 1999;340:77-84.
Patient LA
- Pt 44 palpated on the left a
high Tail of Spence nodule.
Previous basal cell of scalp, 23.
- Family Hx Br Ca in Paternal GM
at 38, father w/ multiple basal
cells in 50’s.
- Core Bx, Excision with Sentinel
LN by G. Paschal removed
1.1 cm Grade 3 Triple Negative
_
Triple Negative Br Ca: 44
- Prompted BRCA1,2
sequencing with “Reflex to
BART”.
- Negative for any deleterious
mutation.
BRCA1,2 Neg.: Sequencing and “BART”
- Continued with adjuvant
chemoRx; Radiation
(Not Quite)
Getting to 100% in BRCA 1,2 testing
Another 5-6 %
discovered
by BART
90-92% of mutations found by sequencing
The last 4-5 % appear
not to be discoverable
by current methods.
3 Breast Cancer “Events”
that might affect me in the future,
if I do not carry a mutation in
BRCA1/2
1. Same Breast or Regional Recurrence
2. New Second Primary Breast Cancer in the
Opposite Breast, or elsewhere in the Same
breast
– 30% lifetime risk at age 35 (7 / 1000 / year)
– Cut in half by hormonal therapy in ER+ Breast Ca
*3. Life-threatening Bone, Lung, Liver
Recurrences
3 Breast Cancer “Events”
that might affect me in the future –
and a 4th if I do carry a mutation in BRCA1/2
1. Same Breast Recurrence
2. New 2nd Primary Breast Ca in the Opposite
Breast
– 60% at age 35 vs. 30% if no mutation
*3. Life-threatening Bone, Lung, Liver Recurrences
4. Increased Lifetime Risk for Ovarian Ca
– 50 % if BRCA1 +;
30 % if BRCA2 +; vs.
– 1 – 1.5 % in the General Population
I have a more favorable type of breast cancer
in that my underarm LN’s are negative.
Higher-Risk for
recurrence and death
Lower-Risk for
recurrence and death
LN’s
Positive
LN’s
Negative
Locally
Advanced
Tumor in the
Breast
Spread to Bone,
Lung or Liver
At Time of
Presentation
*
My tumor
5/23/2017
In the modern era, we recognize
5 distinct subtypes of Breast Cancer
HER2/neu +
*
ER-,
PgR-,
HER2/neu +
HER2/neu “Basal”
ER-,
PgR-,
HER2/neu -
ER-
*
ER+,
PgR +/-,
HER2/neu +
HER2/neu + Breast Ca
5/23/2017
“Luminal A:”
ER+,
PgR +,
HER2/neu -
“Luminal B:”
ER+,
PgR +/-,
HER2/neu -
ER+
Standard Adjuvant Rx for HER2+ Breast Ca:
Carbo/Taxotere x 6 q 3 wk + Herceptin 52 wk;
Radiation and Hormonal Rx, as indicated
Carboplatin / Taxotere
6 cycles, every 3 wks
1st 18 wks
XRT
Herceptin 52 wks,
Given IV every 3 wks
Multiple yr. daily oral hormonal Rx
In the modern era, we recognize
5 distinct subtypes of Breast Cancer
HER2/neu +
ER-,
PgR-,
HER2/neu +
HER2/neu “Basal”
ER-,
PgR-,
HER2/neu -
* Triple Negative
ER-
ER+,
PgR +/-,
HER2/neu +
5/23/2017
“Luminal A:”
ER+,
PgR +,
HER2/neu -
“Luminal B:”
ER+,
PgR +/-,
HER2/neu -
ER+
Triple Negative Breast Cancer
Common in younger African American
women
Associated with mutations in Breast-Ovarian Ca
susceptibility gene BRCA1, but not BRCA2
Treated with good success with modern
ChemoRx
20% are resistant and have no good treatments,
an area of intense investigation
Standard Adjuvant Rx for HER2- Breast Cancer:
Adriamycin/Cytoxan (AC) x 4 every 2 or 3 weeks
followed by Weekly Taxol for 12 weeks.
Radiation and Hormonal Rx, if indicated
Adria / Cytoxan
4 cycles,
every 2 or 3 wks
Taxol every week for
12 weeks
XRT (if indicated)
Oral hormonal Rx
(If indicated)
In the modern era, ER+ and HER2-, LNBreast Cancer is specially studied
HER2/neu +
ER-,
PgR-,
HER2/neu +
HER2/neu “Basal”
ER-,
PgR-,
HER2/neu -
ER-
ER+,
PgR +/-,
HER2/neu +
“Luminal B:”
ER+,
PgR +/-,
HER2/neu -
“Luminal A:”
ER+,
PgR +,
HER2/neu -
*
5/23/2017
ER+
I have one of two types of hormoneresponsive ER+, HER2- breast cancer
Potential
Treatments
Hormonal
Therapy
Only
(HT only)
“Luminal A:”
ER+,
PgR +,
HER2/neu -
*
5/23/2017
Hormonal
Therapy
after
ChemoTherapy
(CT →HT)
“Luminal B:”
ER+,
PgR +/-,
HER2/neu -
*
ER+
OncotypeDx in 2011:
A tool to help us think about
the biologic risk of your
ER+, LN- Breast Cancer,
and to assign the correct treatment
(HT only vs. HT after CT)
without subjecting you
to unnecessary or ineffective treatments.
The 16 gene Oncotype Dx assay:
Stored tumors from B-14 and B-20 were used
to select genes predictive of outcome
w/ no treatment, with HT and with HT + CT
Recurrence Score (RS) = the sum of the scores
assigned to each of the 16 selected genes,
weighted so that for each gene, a lower score
represents a more favorable outcome and
greater response to HT.
Group 1: RS 1 to 17
Group 2: RS 18 to 30
Group 3: RS 31 and up
RS and Breast Cancer Death in
NSABP B-14 and B-20
Low Risk (RS < 18)
Intermediate Risk (RS 18 - 30)
HIgh Risk (RS > 31)
NO SYSTEMIC RX
B14
No Tam
B14 No Tam
HORMONAL RX
B-14 Tam
B-20 Tam
B14 Tam
B20 Tam
HORM + CHEMO
B-20
Tam + CT
B20 Tam + CT
0
5
10
15
20
25
30
35
40
10 Yr Absolute Risk BC Death (%) (95% CI)
68
Largest Tamoxifen Benefit Observed in Low- and
Intermediate-Risk Recurrence Score Groups
Low Risk (RS < 18)
Intermediate Risk (RS 18 - 30)
HIgh Risk (RS > 31)
NO SYSTEMIC RX
B14
No Tam
B14 No Tam
TAMOXIFEN
BENEFIT
HORMONAL RX
B-14 Tam
B-20 Tam
B14 Tam
B20 Tam
HORM + CHEMO
B-20
Tam + CT
B20 Tam + CT
0
5
10
15
20
25
30
35
10 Yr Absolute Risk BC Death (%) (95% CI)
40
69
Largest Chemotherapy Benefit Observed in
High-Risk Recurrence Score Group
Low Risk (RS < 18)
Intermediate Risk (RS 18 - 30)
HIgh Risk (RS > 31)
NO SYSTEMIC RX
B14
No Tam
B14 No Tam
HORMONAL RX
B-14 Tam
B-20 Tam
B14 Tam
B20 Tam
HORM + CHEMO
B-20
Tam + CT
CHEMOTHERAPY
BENEFIT
B20 Tam + CT
0
5
10
15
20
25
30
35
40
10 Yr Absolute Risk BC Death (%) (95% CI)
70
Thanks very much for your
attention, and thanks to all of the
science teachers at Lafayette
A firm grounding
in the scientific method
is the underpinning of all progress in
scientific and medical research