Association of Genetic Testing Results With Mortality Among Women With Breast Cancer or Ovarian Cancer

Allison W. Kurian, MD, MSc; Paul Abrahamse, MA; Irina Bondarenko, MS; Ann S. Hamilton, PhD; Dennis Deapen, DrPH; Scarlett L. Gomez, PhD; Monica Morrow, MD; Jonathan S. Berek, MD, MMSc; Timothy P. Hofer, MD, MSc; Steven J. Katz, MD, MPH; Kevin C. Ward, PhD, MPH

Disclosures

J Natl Cancer Inst. 2022;114(2):245-253.

Abstract and Introduction

Abstract

Background: Breast cancer and ovarian cancer patients increasingly undergo germline genetic testing. However, little is known about cancer-specific mortality among carriers of a pathogenic variant (PV) in BRCA1/2 or other genes in a population-based setting.

Methods: Georgia and California Surveillance Epidemiology and End Results (SEER) registry records were linked to clinical genetic testing results. Women were included who had stages I-IV breast cancer or ovarian cancer diagnosed in 2013–2017, received chemotherapy, and were linked to genetic testing results. Multivariable Cox proportional hazard models were used to examine the association of genetic results with cancer-specific mortality.

Results: 22 495 breast cancer and 4320 ovarian cancer patients were analyzed, with a median follow-up of 41 months. PVs were present in 12.7% of breast cancer patients with estrogen and/or progesterone receptor-positive, HER2-negative cancer, 9.8% with HER2-positive cancer, 16.8% with triple-negative breast cancer, and 17.2% with ovarian cancer. Among triple-negative breast cancer patients, cancer-specific mortality was lower with BRCA1 (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.35 to 0.69) and BRCA2 PVs (HR = 0.60, 95% CI = 0.41 to 0.89), and equivalent with PVs in other genes (HR = 0.65, 95% CI = 0.37 to 1.13), vs noncarriers. Among ovarian cancer patients, cancer-specific mortality was lower with PVs in BRCA2 (HR = 0.35, 95% CI = 0.25 to 0.49) and genes other than BRCA1/2 (HR = 0.47, 95% CI = 0.32 to 0.69). No PV was associated with higher cancer-specific mortality.

Conclusions: Among breast cancer and ovarian cancer patients treated with chemotherapy in the community, BRCA1/2 and other gene PV carriers had equivalent or lower short-term cancer-specific mortality than noncarriers. These results may reassure newly diagnosed patients, and longer follow-up is ongoing.

Introduction

Genetic testing for inherited pathogenic variants (PVs) in cancer susceptibility genes has an established role in cancer treatment^[1] and is relevant for secondary cancer risk reduction and testing of relatives.^[2] We and others reported that patients diagnosed with breast and/or ovarian cancer increasingly undergo germline sequencing of many genes.^[3–6] In this context, patients may experience a positive genetic test result as a worrisome second diagnosis^[7,8] and wonder whether having a PV increases their chance of dying from their cancer. It is important to know whether cancer mortality is associated with germline PVs to inform treatment decision-making and how clinicians counsel p atients about prognosis.

Prior studies have investigated breast and ovarian cancer-specific mortality among carriers of PVs in BRCA1 and/or BRCA2 (BRCA1/2), with mixed results. Some showed lower cancer-specific mortality in BRCA1/2 PV carriers, particularly among cohorts treated with chemotherapy, which may reflect a greater chemosensitivity of BRCA1/2 PV carriers vs noncarriers due to dysfunctional DNA repair.^[9–12] Additional studies showed higher cancer-specific mortality in BRCA1/2 PV carriers,^[13–16] whereas others showed no difference from patients who tested negative.^[17–23] Several prior studies were from single institutions or academic networks, which may introduce selection bias. Few studies analyzed results according to breast cancer subtypes or looked beyond BRCA1/2 to consider the many other genes now evaluated in clinical practice.

We studied cancer-specific mortality among a population-based cohort comprising all women diagnosed with breast cancer or ovarian cancer in Georgia or California and reported to statewide Surveillance Epidemiology and End Results (SEER) cancer registries from 2013 to 2017, together with their results of clinical germline genetic sequencing provided by testing laboratories. Given concerns that SEER underreports chemotherapy,^[24] we excluded patients with no chemotherapy reported, because of uncertainty about their actual treatment history; thus, we limited the study to patients with documented chemotherapy receipt. Based on studies suggesting high chemosensitivity in BRCA1/2 PV carriers,^{[9–11,13,22,25]} our hypothesis was that patients with a PV in BRCA1/2 or another cancer susceptibility gene would have lower cancer-specific mortality than patients having negative or uncertain genetic testing results.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Characteristics of tested breast cancer patients and ovarian cancer patients who received chemotherapy
Characteristic	Breast cancer No. (%)^a	Ovarian cancerNo. (%)^a
State
California	15 390 (68.4)	3129 (72.4)
Georgia	7105 (31.6)	1191 (27.6)
Age at cancer diagnosis, y
20–29	588 (2.6)	47 (1.1)
30–39	3549 (15.8)	184 (4.3)
40–49	8086 (35.9)	642 (14.9)
50–59	5641 (25.1)	1189 (27.5)
60–69	3475 (15.4)	1287 (29,8)
70–79	1059 (4.7)	765 (17.7)
80 and older	97 (<1)	206 (4.8)
Race and ethnicity
Non-Hispanic White	13 043 (58.0)	2916 (67.5)
Black	3324 (14.8)	319 (7.4)
Native American or Alaskan Native	71 (<1)	10 (<1)
Asian or Pacific Islander	2406 (10.7)	464 (10.7)
Hispanic	3651 (16.2)	611 (14.1)
Poverty level
High (poverty ≥20%)	4970 (22.1)	894 (20.7)
Medium (10%-19%)	7248 (32.2)	1403 (32.5)
Low (poverty <10%)	10 277 (45.7)	2023 (46.8)
Marital status
Married	14 123 (62.8)	2433 (56.3)
Not married	8372 (37.2)	1887 (43.7)
Stage
I	5530 (24.6)	667 (15.4)
II	11 188 (49.7)	392 (9.1)
III	4563 (20.3)	2046 (47.4)
IV	1214 (5.4)	1215 (28.1)
Grade^b
1	1474 (6.6)	199 (5.8)
2	8125 (36.1)	398 (11.6)
3	12 896 (57.3)	1370 (39.9)
4 (ovarian cancer only)	NA	1465 (42.7)
Subtype (breast cancer only)
ER/PR-positive, HER2-negative	10,956 (48.7)	NA
HER2-positive, any hormone receptor status	6078 (27.0)	NA
ER/PR-negative and HER2-negative (triple-negative)	5461 (24.3)	NA
Histology (ovarian cancer only)
Serous	NA	3099 (71.7)
Mucinous	NA	104 (2.4)
Endometrioid	NA	438 (10.1)
Clear cell	NA	310 (7.2)
Other adenocarcinoma	NA	369 (8.6)

^aPercentages may not sum to 100 because of rounding. ER = estrogen receptor; PR = progesterone receptor; NA = not applicable.
^bGrade was missing for 888 ovarian cancer patients.

Table 2. Genetic testing results, treatment, and mortality of tested breast cancer patients and ovarian cancer patients treated with chemotherapy
Characteristic	Breast cancer, No. (%)			Ovarian cancer No. (%)
Characteristic	ER/PR-positive, HER2-negative	HER2-positive, any ER/PR status	ER/PR-negative, HER2-negative (triple-negative)	Ovarian cancer No. (%)
Total No.	10 946	6089	5460	4320
Genetic testing results
Negative	7549 (69.0)	4286 (70.4)	3619 (66.3)	2737 (63.4)
BRCA1 PV	320 (2.9)	90 (1.5)	517 (9.5)	328 (7.6)
BRCA2 PV	499 (4.6)	142 (2.3)	217 (4.0)	242 (5.6)
Other gene^a PV	567 (5.2)	363 (6.0)	182 (3.3)	174 (4.0)
VUS	2011 (18.4)	1208 (19.8)	925 (16.9)	839 (19.4)
Surgery, breast
Breast-conserving surgery	3718 (34.0)	2148 (35.3)	2214 (40.5)	NA
Unilateral mastectomy	2866 (26.2)	1359 (22.3)	1042 (19.1)	NA
Bilateral mastectomy	2785 (25.4)	1528 (25.1)	1359 (24.9)	NA
Other surgery	894 (8.2)	496 (8.1)	376 (6.9)	NA
No surgery	683 (6.2)	558 (9.2)	469 (8.6)	NA
Surgery, ovarian
Debulking surgery	NA	NA	NA	2287 (52.9)
Other surgery^b	NA	NA	NA	1675 (38.8)
No surgery	NA	NA	NA	358 (8.3)
Radiation therapy	6549 (59.8)	3073 (50.5)	2920 (53.5)	47 (1.1)
Other systemic therapy
Endocrine therapy	8117 (74.2)	3149 (51.7)	276 (5.1)	55 (1.3)
HER2-directed therapy	433 (4.0)	5090 (83.6)	141 (2.6)	209 (4.8)
Died from cancer^c	662 (6.0)	246 (4.0)	765 (14.0)	1244 (28.8)
Average time at risk, days	1156	1158	1111	1034

^aOther genes in which PVs were found are listed in Supplementary Table 1 (available online). ER = estrogen receptor; NA = not applicable; PR = progesterone receptor; PV = pathogenic variant; VUS = variant of uncertain significance.
^bOther surgeries recorded by Surveillance Epidemiology and End Results (SEER) for ovarian cancer treatment include local tumor destruction not otherwise specified, total removal of tumor or single ovary, unilateral or bilateral salpingo-oophorectomy with or without hysterectomy, and unilateral or bilateral salpingo-oophorectomy with omentectomy (SEER codes 17, 25–28, 35–37, 50–52, 55–57).
^cMedian follow-up was 41 months (range = 1–85 months).

Table 3. Treatments received by genetic test results among tested breast cancer patients and ovarian cancer patients treated with chemotherapy
Treatment	Genetic test result					P ^b
Treatment	Negative No. (%)	VUS only No. (%)	BRCA1 PV No. (%)	BRCA2 PV No. (%)	Other gene^a PV No. (%)	P ^b
Breast cancer
Surgery						<.001
No surgery	1151 (8.0)	330 (8.0)	74 (8.0)	73 (8.5)	87 (7.8)
Lumpectomy	5942 (41.5)	1582 (38.2)	119 (12.8)	113 (13.2)	311 (28.0)
Unilateral mastectomy	3631 (25.4)	990 (23.9)	170 (18.3)	200 (23.3)	265 (23.8)
Bilateral mastectomy	3588 (25.1)	908 (21.9)	453 (48.9)	383 (44.6)	352 (31.7)
Other surgery	1142 (8.0)	334 (8.1)	111 (12.0)	89 (10.4)	97 (8.7)
Radiation therapy	8943 (62.5)	2406 (58.1)	304 (32.8)	369 (43.0)	524 (47.1)	<.001
Other systemic therapy
Endocrine therapy	7930 (55.4)	2269 (54.8)	238 (25.7)	443 (51.6)	674 (60.6)	<.001
HER2-directed therapy	3921 (27.4)	1168 (28.2)	95 (10.2)	136 (15.9)	342 (30.8)	<.001
Ovarian Cancer
Surgery						.01
No surgery	227 (1.6)	81 (2.0)	15 (1.6)	24 (2.8)	11 (1.0)
Debulking surgery	1458 (10.2)	416 (10)	203 (21.9)	126 (14.7)	84 (7.6)
Other surgery	1052 (7.4)	342 (8.3)	110 (11.9)	92 (10.7)	79 (7.1)
Radiation therapy	29 (0.2)	13 (0.3)	4 (0.4)	0 (0)	1 (0.1)	.31
Other systemic therapy
Endocrine therapy	33 (0.2)	13 (0.3)	3 (0.3)	2 (0.2)	4 (0.4)	.60
HER2-directed therapy	127 (0.9)	42 (1.0)	20 (2.2)	11 (1.3)	9 (0.8)	.83

^aOther genes in which PVs were found are listed in Supplementary Table 1 (available online). PV = pathogenic variant; VUS = variant of uncertain significance.
^bA 2-sided χ² test was used to calculate the P values.

Table 4. Breast cancer-specific mortality of patients in a multivariable proportional hazards survival model, by breast cancer subtype ^a
Characteristic	ER/PR-positive, HER2-negative HR (95% CI)	HER2-positive, any ER/PR status HR (95% CI)	ER/PR-negative, HER2-negative (triple-negative) HR (95% CI)
Genetic testing results
Negative	1 (Referent)	1 (Referent)	1 (Referent)
BRCA1 PV	1.06 (0.71 to 1.58)	0.92 (0.29 to 2.91)	0.49 (0.35 to 0.69)
BRCA2 PV	0.73 (0.50 to 1.04)	0.39 (0.12 to 1.24)	0.60 (0.41 to 0.89)
Other gene^b PV	0.73 (0.49 to 1.10)	0.59 (0.26 to 1.32)	0.65 (0.37 to 1.13)
VUS only	0.81 (0.64 to 1.02)	0.70 (0.49 to 1.01)	0.79 (0.64 to 0.98)
Age (per 10-year difference)	1.06 (0.99 to 1.14)	1.04 (0.93 to 1.16)	0.95 (0.90 to 1.02)
Race and ethnicity
Non-Hispanic White	1 (Referent)	1 (Referent)	1 (Referent)
Native American or Alaskan Native	2.40 (0.77 to 7.54)	–^c	0.56 (0.14 to 2.26)
Asian or Pacific Islander	0.91 (0.68 to 1.21)	1.20 (0.80 to 1.79)	0.66 (0.47 to 0.93)
Black	1.43 (1.14 to 1.79)	2.03 (1.43 to 2.88)	1.02 (0.84 to 1.23)
Hispanic	1.07 (0.84 to 1.37)	1.16 (0.79 to 1.71)	0.94 (0.75 to 1.16)
Poverty level
Low (poverty <10%)	1 (Referent)	1 (Referent)	1 (Referent)
Medium (10%-19%)	0.95 (0.79 to 1.14)	1.03 (0.75 to 1.43)	1.07 (0.89 to 1.28)
High (poverty ≥20%)	1.11 (0.90 to 1.36)	1.59 (1.15 to 2.20)	1.35 (1.12 to 1.62)
Married (vs not married)	0.77 (0.65 to 0.90)	0.90 (0.69 to 1.17)	0.95 (0.82 to 1.11)
Stage
I	1 (Referent)	1 (Referent)	1 (Referent)
II	1.36 (0.96 to 1.92)	1.63 (0.99 to 2.68)	1.99 (1.51 to 2.63)
III	4.42 (3.13 to 6.23)	4.67 (2.81 to 7.78)	6.89 (5.16 to 9.20)
IV	16.59 (11.38 to 24.17)	11.38 (6.69 to 19.38)	16.58 (11.89 to 23.12)
Grade
1	1 (Referent)	1 (Referent)	1 (Referent)
2	1.58 (1.07 to 2.31)	1.12 (0.40 to 3.10)	1.04 (0.38 to 2.83)
3	4.13 (2.84 to 6.01)	1.80 (0.66 to 4.88)	1.23 (0.46 to 3.29)
Surgery
Breast conserving	1 (Referent)	1 (Referent)	1 (Referent)
Unilateral mastectomy	2.03 (1.58 to 2.62)	2.02 (1.32 to 3.09)	2.26 (1.80 to 2.83)
Bilateral mastectomy	1.60 (1.22 to 2.09)	1.42 (0.90 to 2.26)	1.70 (1.35 to 2.14)
No surgery	3.70 (2.68 to 5.09)	3.13 (1.95 to 5.03)	4.26 (3.24 to 5.61)
Other surgery	1.59 (1.08 to 2.34)	3.34 (1.96 to 5.69)	2.07 (1.49 to 2.88)
Radiotherapy (vs none)	1.25 (1.03 to 1.51)	1.44 (1.08 to 1.93)	1.32 (1.12 to 1.57)
Endocrine therapy (vs none)	0.79 (0.65 to 0.94)	0.47 (0.35 to 0.63)	1.08 (0.80 to 1.47)
HER2-directed therapy (vs none)	0.82 (0.60 to 1.13)	0.61 (0.44 to 0.84)	1.21 (0.86 to 1.69)
Year of diagnosis	1.05 (0.98 to 1.13)	1.15 (1.02 to 1.29)	1.04 (0.98 to 1.10)
California (vs Georgia)	0.83 (0.69 to 1.01)	0.86 (0.63 to 1.18)	0.78 (0.66 to 0.93)

^aResults presented are from a single multivariable proportional hazards model for each breast cancer subtype. CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; PR = progesterone receptor; PV = pathogenic variant; VUS = variant of uncertain significance.
^bOther genes in which PVs were found are listed in Supplementary Table 1 (available online).
^cNo observations for this group.

Table 5. Ovarian cancer-specific mortality of patients in a multivariable proportional hazards survival model
Characteristic	Hazard ratio (95% CI)
Genetic testing results
Negative	1 (Referent)
BRCA1 PV	0.85 (0.68 to 1.07)
BRCA2 PV	0.35 (0.25 to 0.49)
Other gene PV^a	0.47 (0.32 to 0.69)
VUS only	0.84 (0.72 to 0.98)
Age (per 10-year difference)	1.16 (1.09 to 1.22)
Race and ethnicity
Non-Hispanic White	1 (Referent)
Black	0.86 (0.69 to 1.07)
Native American or Alaskan Native	2.88 (1.18 to 6.99)
Asian or Pacific Islander	0.89 (0.72 to 1.10)
Hispanic	0.91 (0.75 to 1.10)
Poverty level
Low (poverty <10%)	1 (Referent)
Medium (10%-19%)	1.08 (0.95 to 1.23)
High (poverty ≥20%)	0.97 (0.82 to 1.14)
Married (vs not married)	0.93 (0.83 to 1.04)
Stage
I	1 (Referent)
II	1.85 (1.18 to 2.90)
III	5.88 (4.10 to 8.42)
IV	8.18 (5.69 to 11.77)
Grade^b
1	1 (Referent)
2	1.12 (0.76 to 1.64)
3	1.16 (0.82 to 1.65)
4	1.19 (0.83 to 1.69)
Serous (vs not serous)^c	0.80 (0.69 to 0.94)
Surgery
No surgery	1 (Referent)
Debulking surgery	0.61 (0.50 to 0.73)
Other surgery^d	0.47 (0.38 to 0.57)
Year of diagnosis	1.07 (1.02 to 1.12)
California (vs Georgia)	0.82 (0.73 to 0.93)

^aOther genes in which PVs were found are listed in Supplementary Table 1 (available online). CI = confidence interval; PV = pathogenic variant; VUS = variant of unknown significance.
^bMultiple imputation was used for grade because 22% of patients had missing grade data.
^cCollapsed to serous vs not serous because of smaller numbers in subgroups of nonserous histology.
^dOther surgeries recorded by Surveillance Epidemiology and End Results (SEER) for ovarian cancer treatment include local tumor destruction not otherwise specified, total removal of tumor or single ovary, unilateral or bilateral salpingo-oophorectomy with or without hysterectomy, and unilateral or bilateral salpingo-oophorectomy with omentectomy (SEER codes 17, 25–28, 35–37, 50–52, 55–57).

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Association of Genetic Testing Results With Mortality Among Women With Breast Cancer or Ovarian Cancer

Abstract and Introduction

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