Reviewing the Genetic Component

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Very little is known about the effect of a BRCA1 or BRCA2 mutation with respect to treatment outcomes, although there are some traits of hereditary breast cancer in women with a BRCA1 mutation that indeed do suggest a poor outcome. Investigators do know that two of the characteristics associated with a poor prognosis in hereditary breast cancer occurring in younger women are high-grade tumors and tumors that do not have estrogen receptors.^1,2

Expert Commentary

For women with BRCA-associated breast cancers, the ultimate tumor prognosis appears to be the same as when matched to similar tumors in non- BRCA carriers.
Women with BRCA mutations are at greater risk for contralateral tumors and ovarian cancer, and merit special surveillance and consideration of prophylactic surgery to lower risk of those cancers.

To better understand the inconsistent evidence concerning the effect of a BRCA1 or BRCA2 mutation on the prognosis of hereditary breast cancer, investigators analyzed 10-year survival rates in a national group of Israeli women with invasive breast cancer. They chose this specific population because the leading cause of all deaths from cancer among Israeli women is breast cancer, with 3800 diagnosed with this disease each year.³ Within this population, 28% are diagnosed before the age of 50 years.³ The findings of this study were published in a July 2007 article in The New England Journal of Medicine.

Dr. Gad Rennert and his colleagues at the National Cancer Control Center, Carmel Medical Center in Haifa, Israel, reviewed data on 2514 patients with invasive breast cancer who were diagnosed between January 1, 1987 and December 31, 1988. Pathology records for 1794 and medical records for 1545 of the subjects were reviewed and DNA from tumor specimens was analyzed for presence of three originator mutations in the BRCA1 and BRCA2 genes. After each of the 1794 subjects was assigned a mutational status, demographic and clinical features were compared between BRCA carriers and noncarriers, utilizing several statistical tests—chi-square test, Fisher’s exact test, Mann-Whitney test, or t-test. The result of this comparison showed that all but 46 of the subjects were Jewish women and no mutation was detected in the group of 46. However, among the 1748 Jewish women, a mutation was detected in 135 specimens.

Table 1. Characteristics of Jewish and Non-Jewish Women with Breast Cancer*

Variable	Ashkenazi Jews	Iraqi Jews	Sephardi Jews	Other Jews †	All Jews ‡	Non-Jews
No. of subjects	1102	87	418	131	1748	46
Age at Diagnosis
Mean—yr	62.1 ± 13.5	56.2 ± 11.0	54.7 ± 13.2	46.9 ± 11.7	58.8 ± 14.0	49.7 ± 9.9
< 50 yr—%	20	26	37	67	29	46
Tumor Size
Median (interquartile range) —cm	2.0 (1.5-3.0)	2.5 (1.8-3.0)	2.5 (1.8-3.5)	2.0 (1.5-3.0)	2.0 (1.5-3.0)	3.0 (2.4-5.0)
< 2 cm—%	34	29	27	43	33	16
2-5 cm—%	56	60	58	47	56	58
> 5 cm—%	10	11	14	9	11	26
Missing data—no.	157	15	88	25	287	8
Nodal Status
Positive— %	47	44	54	56	49	81
Negative— %	53	56	46	44	51	19
Missing data—no.	127	3	37	18	186	4
Stage
I—%	31	32	26	30	30	7
II—%	46	43	47	50	46	53
III—%	16	20	19	16	17	33
IV—%	6	4	8	3	6	7
Missing data—no.	76	4	17	16	114	1
Estrogen-receptor status
Strongly positive—%	30	27	18	15	26	25
Mildly positive—%	33	29	34	36	33	25
Negative — %	37	44	48	48	41	50
Missing Data—no.	417	25	153	71	669	18
Excluded—no. §	92	10	41	8	152	0
Alive at 10 yr—%	50	53	51	57	51	52
Mutational status
No mutation—no. (%)	997 (91)	81 (93)	414 (99)	111 (85)	1613 (92)	46 (100)
BRCA1—no. (%)	55 (5)	6 (7)	2 (<1)	15 (11)	78 (4)	0
BRCA2—no. (%)	47 (4)	0	1 (<1)	5 (4)	53 (3)	0
Both mutations—no.	3	0	1	0	4	0

* Plus-minus values are means ±SD. Percentages may not total 100 because of rounding.
† Women in this category were born in Israel but were of unclassified ethnic origin.
‡ This category includes 10 Jewish women with an unknown country of birth and origin.
§ Data were excluded for patients who were treated at one institution for which estrogen-receptor results were determined to be unreliable.
Reprinted from Rennert G, et al. N Engl J Med. 2007;357:115-123. Copyright © 2007, Massachusetts Medical Society. All rights reserved.

Pathology reports from all participants were used to compare the tumors in the 131 Jewish women who had a mutation to the tumors in the 1189 Jewish women who had no mutation. The results of this comparison showed that the average age of diagnosis of breast cancer was lower in BRCA1 carriers than in noncarriers (52 years versus 61 years [P <.001]). The researchers also found that estrogen-receptor–positive tumors were less likely to be found in BRCA1 carriers than in noncarriers, who exhibited strong evidence of estrogen-receptor–positive tumors.

The 1794 subjects were followed for 10 years, after which survival rates were 67% for BRCA1 carriers, 56% for BRCA2 carriers, and 67% for noncarriers (P = .25 for the comparison between carriers of either mutation and noncarriers by the log-rank test with 2 degrees of freedom.) During the 10 years, there were 24 deaths from breast cancer among BRCA1 carriers, with 21 (88%) occurring within 5 years after diagnosis. Within the same time period, there were 22 deaths from breast cancer among BRCA2 carriers, with 17 (77%) occurring within 5 years of diagnosis. In the noncarrier group, 244 of 361 (68%) deaths occurred within 5 years of diagnosis (P = .04 for the comparison between carriers of either mutation and noncarriers.) After hazard ratios were adjusted, breast cancer death rates in women who were carriers of BRCA mutations did not differ from death rates in women who were noncarriers of BRCA mutations.

A comparison of BRCA1 carriers and noncarriers who received chemotherapy with those who did not receive chemotherapy during the 10 years revealed survival rates for women who did not receive chemotherapy to be 76% in BRCA1 carriers and 74% in noncarriers (hazard ratio, 0.93; 95% CI, 0.43–2.02; P = .86). In the group that received chemotherapy, the survival rate after 10 years was 71% for BRCA1 carriers and 46% for noncarriers (hazard ratio, 0.48; 95% CI, 0.19–1.21; P = .12). The results of this comparison clearly indicated that the relationship between BRCA1 mutation status and the use of chemotherapy was only apparent in overall survival.

Table 2. Ten-Year Survival Rates and Adjusted Hazard Ratios for Death, According to the Use or Nonuse of Chemotherapy and Genetic Subgroup.*

Group	No. of Subjects		Death from Any Cause			Death from Breast Cancer		*P Value for Interaction between BRCA* Status and Chemotherapy**
		10-Year Survival	Adjusted Hazard Ratio (95% CI) †	P Value	10-Year Survival	Adjusted Hazard Ratio (95% CI) †	P Value
		%			%
Noncarriers		51	1.0		67	1.0
No chemotherapy	757	56	1.0		74	1.0
Chemotherapy	235	42	1.0		46	1.0
BRCA1 Carriers								OS, .02; BCS, .21
No chemotherapy	42	45	1.59 (1.01-2.50)	.04	76	0.93 (0.43-2.02)	.86
Chemotherapy	25	68	0.56 (0.24-1.29)	.17	71	0.48 (0.19-1.21)	.12
BRCA2 Carriers								OS, .97; BCS, .70
No chemotherapy	29	59	1.14 (0.58-2.24)	.69	67	1.40 (0.61-3.21)	.43
Chemotherapy	17	41	1.04 (0.54-2.01)	.90	47	1.06 (0.52-2.11)	.87

*Chemotherapy drugs used in combination were cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide, mitoxantrone, and fluorouracil. Data regarding chemotherapy were not available for all study patients. OS denotes overall survival, and BCS breast-cancer-specific survival.
† Data were adjusted for age (<50, 50-70, or >70 yr), tumor size (≤2 or >2 cm), lymph-node status (positive or negative), and status with respect to metastasis (yes or no).
Reprinted from Rennert G, et al. N Engl J Med. 2007;357:115-123. Copyright © 2007, Massachusetts Medical Society. All rights reserved.

The investigators then looked at the influence of age, tumor stage and size, and lymph-node status on breast cancer mortality. The findings suggested that tumor size and lymph-node status were important predictors of mortality in noncarriers, and the interrelationship between tumor size and carrier status was important as a predictor of mortality in BRCA1 mutation subjects but not for BRCA2 mutation subjects. They did not find age to be a predictor of survival in either noncarriers or carriers of the mutations.

The goal of the hereditary breast cancer investigation performed by Dr. Rennert and colleagues was to assess survival rates for women who were carriers of a BRCA1 or BRCA2 mutation, compared with noncarriers of a mutation. Estimations of survival are important to women with hereditary breast cancer who carry a BRCA mutation because they may be faced with the decision to undergo preventive surgery or to opt for demanding observation only. The results of this investigation showed that the size of the tumor was not a predictor of mortality but lymph-node status showed borderline significance as a predictor, and that BRCA1 or BRCA2 mutation influence on the response to chemotherapy was not deemed noteworthy.

In conclusion, Dr. Rennert and colleagues found no clear survival difference between the BRCA mutations; however, potentially important differences were seen when the investigators analyzed the data according to tumor size and the use or nonuse of chemotherapy.⁴

References

Johannsson OT, Idvall I, Anderson C, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer. 1997;33:362-371.
Karp SE, Tonin PN, Begin LR, et al. Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer. 1997;80:435-441.
Parkin DM, Whelan SL, Ferlay J, et al, eds. Cancer incidence in five continents. Vol. VII. Lyon, France: IARC Press, 2000. (IARC scientific publications no. 155.)
Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Eng J Med. 2007;357:115-123.

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Reviewing the Genetic Component

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Reviewing the Genetic Component

By Carol Pierini Expert Commentary by Harold J. Burstein, MD, PhD

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By Carol Pierini
Expert Commentary by Harold J. Burstein, MD, PhD