Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab

Figures & data

Figure 1  Study population. ^aTotal number of patients meeting the inclusion and exclusion criteria for the study. ^bDe novo staging according to SEER. ^cIdentification of distant recurrence according to Medicare claims. ^dTrastuzumab part of the first treatment regimen after diagnosis of metastatic breast cancer. ^eTrastuzumab part of second or subsequent treatment after diagnosis of metastatic breast cancer.

Table 1  Patient Characteristics

		De Novo Stage of Breast Cancer^a
		Stage 0–III (n = 356)		Stage IV (n = 254)		All Patients (n = 610)		p Value^b
Age at diagnosis of metastatic breast cancer	66–69	51	14.3%	73	28.7%	124	20.3%	<.0001
	70–74	121	34.0%	74	29.1%	195	32.0%
	75–79	88	24.7%	67	26.4%	155	25.4%
	80–84	69	19.4%	27	10.6%	96	15.7%
	≥85	27	7.6%	13	5.1%	40	6.6%
Race/ethnicity	White	298	83.7%	191	75.2%	489	80.2%	.03
	Black	30	8.4%	39	15.4%	69	11.3%
	Hispanic	16	4.5%	11	4.3%	27	4.4%
	Other	12	3.4%	13	5.1%	25	4.1%
Year of metastatic breast cancer diagnois	2000	16	4.5%	28	11.0%	44	7.2%	<.0001
	2001	41	11.5%	37	14.6%	78	12.8%
	2002	46	12.9%	34	13.4%	80	13.1%
	2003	50	14.0%	42	16.5%	92	15.1%
	2004	69	19.4%	66	26.0%	135	22.1%
	2005–2006	134	37.6%	47	18.5%	181	29.7%
Estrogen(ER) and progesterone (PR) receptor status	ER^+ and PR^+	83	23.3%	68	26.8%	151	24.8%	.54
	ER^+ or PR^+	55	15.4%	42	16.5%	97	15.9%
	ER^− and PR^− or unknown	218	61.2%	144	56.7%	362	59.3%
National Cancer Institute Comorbidity Index	0	313	87.9%	226	89.0%	539	88.4%	.90
	≥1	43	12.1%	28	11.0%	71	11.6%
Prior surgery for breast cancer		342	96.1%	124	48.8%	466	76.4%	<.0001
Radiation		192	53.9%	159	62.6%	351	57.5%	0.03
Prior inpatient admission		217	61.0%	114	44.9%	331	54.3%	<.0001
Prior emergency department Visit		37	10.4%	27	10.6%	64	10.5%	.93
Claim for durable medical equipment		141	39.6%	46	18.1%	187	30.7%	<.0001

^aDe Novo Stage could be either Stage IV or Stage 0–III. However, all patients initially diagnosed with Stage 0–III had a distant recurrence documented in their Medicare claims to be included in the study.

^bAll tests of significance performed using Chi Square analysis. Comparisons are de novo Stage IV to de novo Stage 0–III.

Table 2  Patterns of Trastuzumab use

		De Novo Stage of Breast Cancer^a.
		Stage 0–III (n = 356)		Stage IV (n = 254)		All Patients (n = 610)		p Value^b.
Metastatic breast cancer diagnosis to first trastuzumab (days)	Mean (SD^c)	172.8	(304.5)	176.8	(227.0)	174.5	(274.7)	.85
	Median (IQR^d)	42	(14–173)	78	(47–189)	63	(26–183)
Months of trastuzumab (months)	Mean (SD)	11.0	(10.5)	15.7	(14.7)	12.9	(12.6)	<.0001
	Median (IQR)	8.0	(3.0–15.0)	12.0	(4.0–22.0)	10.0	(4.0–18.0)
Trastuzumab administrations per month	Mean (SD)	2.1	(1.0)	2.1	(1.0)	2.1	(1.0)	.30
	Median (IQR)	2	(1.1–2.9)	2.0	(1.25–3.0)	2.0	(1.16–3.0)

^aDe novo Stage could be either Stage IV or Stage 0–III. However, all patients initially diagnosed with Stage 0–III had a distant recurrence documented in their Medicare claims to be included in the study.

^bAll tests of significance performed on means using t-test. Comparisons are de novo Stage IV to de novo Stage 0–III.

^cSD—Standard deviation.

^dIQR—Interquartile range.

Table 3  Trastuzumab Regimens

	De Novo Stage of Breast Cancer^a
Treatment Regimens	Stage 0–III (n = 356)	Stage IV (n = 254)	All Patients (n = 610)	p Value^b
First-line trastuzumab (70% of cohort)	59.3 (252)	40.7 (173)	100 (425)
Trastuzumab regimen [%(n)]				.02
Trastuzumab alone	36.5 (92)	23.7 (41)	31.3 (133)
Trastuzumab plus taxane	44.4 (112)	53.2 (92)	48.0 (204)
Trastuzumab plus other	19.1 (48)	23.1 (40)	20.7 (88)
Delayed Trastuzumab (30% of cohort)	56.2 (104)	43.8 (81)	100 (185)	.07
Initial chemotherapy regimen [%(n)]
Anthracycline and/or cyclophosphamide	41.4 (43)	56.8 (46)	48.1 (89)
Taxane and/or vinorelbine	19.2 (20)	18.5 (15)	18.9 (35)
Other (neither of the above)	39.4 (41)	24.7 (20)	33.0 (61)
Trastuzumab Regimen [%(n)]				.71
Trastuzumab alone	34.6 (36)	35.8 (29)	35.1 (65)
Trastuzumab plus taxane	43.3 (45)	46.9 (38)	44.9 (83)
Trastuzumab plus other	22.1 (23)	17.3 (14)	20.0 (37)

^aDe novo Stage could be either Stage IV or Stage 0–III. However, all patients initially diagnosed with Stage 0–III had a distant recurrence documented in their Medicare claims to be included in the study.

^bAll tests of significance performed using Chi Square analysis. Comparisons are de novo Stage IV to de novo Stage 0–III.

Figure 2  Patterns of trastuzumab use. Each row of data represents a single patient. Each colored rectangle within each row represents one month, ordered chronologically following the beginning of trastuzumab therapy, up to a maximum of 24 months. Dark blue rectangles indicate more administrations of trastuzumab in that month; light blue rectangles indicate fewer administrations; orange rectangles indicate no administrations of trastuzumab while the patient was still observed in the data set; and clear rectangles indicate that the patient was no longer observed in the data because of death or the end of the observation period. Within each of the four figures, patients are ordered from high (top of figure) to low number of trastuzumab administrations during 48 months following the beginning of therapy, a measure of both the intensity and duration of trastuzumab therapy. MBC—Metastatic breast cancer

Table 4  Multivariate Survival Analysis-all Patients, by Cause of Death

		All Cause Mortality				Cancer Mortality				NonCancer Mortaltiy
Patient Characteristic		95% Confidence Interval				95% Confidence Interval				95% Confidence Interval
		Hazard Ratio	Lower	Upper	p Value	Hazard Ratio	Lower	Upper	p Value	Hazard Ratio	Lower	Upper	p Value
Trastuzumab regimen included chemotherapy	No
Without chemotherapy	Yes					Reference Category
With chemotherapy		0.63	0.49	0.80	<.001	0.67	0.51	0.88	<.01	0.64	0.25	1.64	.35
Trastuzumab timing
First-line						Reference Category
Delayed		0.74	0.55	1.01	.06	0.70	0.49	0.98	.04	1.44	0.45	4.64	.54
Age at diagnosis of metastatic breast cancer	66–69					Reference Category
	70–74	1.23	0.80	1.90	.34	1.25	0.79	1.98	.35	1.98	0.25	15.89	.52
	75–79	1.34	0.83	2.17	.23	1.30	0.77	2.21	.33	2.58	0.33	19.94	.36
	80–84	3.11	1.48	6.51	<.01	2.51	1.06	5.92	.04	1.02	0.07	15.99	.99
	≥85	5.22	1.63	16.75	<.01	3.58	1.05	12.15	.04	NA^a	NA	NA	NA
Race	White					Reference Category
	Black	1.51	1.08	2.12	.02	1.15	0.77	1.70	.51	4.99	1.36	18.32	.02
	Hispanic	1.10	0.57	1.83	.95	1.01	0.53	1.91	.99	1.63	0.18	14.91	.67
	Other	1.09	0.66	1.81	.74	1.20	0.67	2.17	.54	NA	NA	N/A	NA
Stage at breast cancer de novo diagnosis	0–III					Reference Category
	IV	1.03	0.78	1.36	.83	0.97	0.71	1.32	.84	1.00	0.34	2.93	.99
National Cancer Institute Comorbidity Index	0					Reference Category
	1	1.16	0.74	1.81	.52	1.12	0.68	1.85	.65	0.30	0.02	4.25	.37
	2	1.00	0.51	1.97	.10	1.05	0.50	2.23	.89	2.31	0.21	24.81	.49
	≥3	1.23	0.29	5.17	.78	0.68	0.09	5.02	.70	NA	NA	NA	NA
Year trastuzumab therapy began	2000					Reference Category
	2001	0.87	0.48	1.56	.63	0.95	0.49	1.83	.87	0.11	0.01	1.95	.04
	2002	1.01	0.58	1.75	.98	1.04	0.56	1.94	.90	0.84	0.16	4.43	.83
	2003	1.27	0.74	2.21	.39	1.35	0.73	2.52	.34	0.52	0.09	3.02	.46
	2004	1.03	0.60	1.77	.92	1.06	0.57	1.96	.85	0.23	0.04	1.52	.13
	2005	0.72	0.41	1.28	.26	0.78	0.41	1.48	.45	0.36	0.06	2.31	.28
	2006	0.65	0.30	1.40	.27	0.78	0.34	1.77	.55	0.40	0.03	5.92	.50
Estrogen (ER) and progesterone (PR) receptor status	ER^−/PR^−					Reference Category
	ER^+/PR^+	0.82	0.62	1.08	.15	0.78	0.58	1.06	.11	1.17	0.39	3.47	.78
	ER^+/PR^−	0.69	0.50	0.96	.03	0.74	0.52	1.06	.10	0.42	0.08	2.13	.29
	ER^−/PR^+	0.82	0.38	1.79	.62	0.73	0.30	1.80	.49	4.46	0.37	54.01	.24
Prior surgery for breast cancer	No					Reference Category
	Yes	0.78	0.58	1.05	.10	0.67	0.49	0.94	.02	0.81	0.20	3.27	.77
Radiation	No					Reference Category
	Yes	1.04	0.82	1.31	.77	1.08	0.83	1.40	.59	0.42	0.15	1.15	.09
Inpatient admission	No					Reference Category
	Yes	1.54	1.20	1.97	<.01	1.53	1.16	2.01	<.01	2.13	0.76	5.95	.15
Durable medical equipment	No					Reference Category
	Yes	0.90	0.70	1.17	.44	0.90	0.67	1.19	.45	0.68	0.22	2.10	.50
Emergency department visit	No					Reference Category
	Yes	1.00	0.70	1.45	.99	1.03	0.69	1.53	.91	0.19	0.02	2.07	.17
Outpatient visit	No					Reference Category
	Yes	3.52	1.24	9.95	.02	2.64	0.92	7.55	0.07	NA	NA	NA	NA

^aNot applicable-insufficient patients in this group to calculate estimate.

Table 5  Multivariate Survival Analysis, Cancer Mortality Stratified by First-line Versus Delayed Trastuzumab

		First-Line Trastuzumab				Delayed Trastuzumab
			95% Confidence Interval				95% Confidence Interval
Patient Characteristic		Hazard Ratio	Lower	Upper	p Value	Hazard Ratio	Lower	Upper	p Value
Trastuzumab regimen included chemotherapy	No				Reference Category
	Yes	0.54	0.39	0.74	<.001	1.44	0.77	2.69	.25
Age at diagnosis of metastatic breast cancer	66–69				Reference Category
	70–74	1.28	0.71	2.34	.41	1.04	0.42	2.57	.93
	75–79	1.10	0.59	2.02	.77	1.58	0.40	6.28	.52
	80–84	2.58	0.96	6.94	.06	16.61	1.04	265.20	.05
	≥85	4.54	1.18	17.53	.03	NA^a.	NA	NA	NA
Race/ethnicity	White				Reference Category
	Black	1.18	0.72	1.93	.51	0.95	0.41	2.22	.90
	Hispanic	1.12	0.59	2.12	.72	0.54	0.12	2.49	.43
	Other	1.05	0.40	2.72	.92	1.18	0.42	3.37	.75
Stage at breast cancer de novo diagnosis	0–III				Reference Category
	IV	0.91	0.61	1.37	.66	1.26	0.65	2.45	.49
National Cancer Institute Comorbidity Index	0				Reference Category
	1	1.38	0.76	2.51	.29	0.44	0.13	1.51	.19
	2	1.03	0.45	2.35	.94	1.52	0.17	13.83	.71
	≥3	0.59	0.08	4.45	.61	NA	NA	NA	NA
Year trastuzumab therapy began	2000				Reference Category.
	2001	1.24	0.58	2.67	.58	0.53	0.11	2.52	.42
	2002	1.20	0.58	2.47	.62	1.10	0.25	4.79	.90
	2003	1.49	0.72	3.09	.28	1.31	0.31	5.59	.71
	2004	1.19	0.58	2.44	.64	1.18	0.27	5.11	.83
	2005	0.85	0.40	1.78	.66	0.54	0.12	2.40	.42
	2006	1.14	0.45	2.87	.78	0.17	0.01	1.93	.15
Estrogen (ER) and Progesterone (PR) receptor status	ER^−/PR^−				Reference Category
	ER^+/PR^+	0.59	0.41	0.86	.01	1.68	0.88	3.21	.12
	ER^+/PR^−	0.64	0.41	0.99	.04	0.61	0.28	1.32	.21
	ER^−/PR^+	0.58	0.20	1.66	.31	1.13	0.08	16.29	.93
Prior surgery for breast cancer	No				Reference Category
	Yes	0.74	0.50	1.12	.15	0.34	0.17	0.70	<.01
Radiation	No				Reference Category
	Yes	0.97	0.72	1.31	.84	1.54	0.78	3.02	.21
Inpatient admission	No				Reference Category
	Yes	1.37	0.97	1.93	.07	1.59	0.94	2.69	.09
Emergency department visit	No				Reference Category.
	Yes	1.24	0.77	1.20	.38	1.24	0.47	3.32	.66
Outpatient visit	No				Reference Category
	Yes	2.43	0.69	8.60	.17	5.57	0.63	49.02	.12
Durable medical equipment	No				Reference Category
	Yes	0.91	0.66	1.27	.59	1.11	0.54	2.27	.78

^aNot applicable-insufficient patients in this group to calculate estimate.

Figure 3  Sensitivity of trastuzumab hazard ratio to changes in the multivariate survival analysis. This figure presents the results of three sets (all patients, patients receiving first-line trastuzumab, patients receiving delayed trastuzumab) of nine multivariate survival analyses (three each for all-cause, cancer, and noncancer mortality) designed to test the sensitivity of the findings reported in Tables 4 and 5 to changes in the approach to multivariate analysis. Standard multivariate survival analyses (S) were performed with all individual patient variables included in the model. Propensity multivariate survival analyses were performed with either propensity score quintile (PQ) included in the model as a substitute for all patient variables except trastuzumab plus chemotherapy, or using propensity score as a weight (PSW). The y-axis indicates the hazard ratio for trastuzumab plus chemotherapy compared with trastuzumab alone. Triangles represent the estimated hazard ratio for trastuzumab plus chemotherapy compared with trastuzumab alone from the corresponding model on the x-axis. Bars around each triangle represent the upper and lower bounds of the 95% confidence interval for the hazard ratio. Confidence intervals that overlap the horizontal line at the hazard ratio of 1.0 indicate that the estimated hazard ratio for trastuzumab plus chemotherapy is not significant at p = .05.