SHORT COMMUNICATION
Trastuzumab Beyond Progression for HER2 Positive Metastatic Breast Cancer: Progression-Free Survival on First-Line Therapy Predicts Overall Survival Impact Daniel Rayson, MD,* Sarah Lutes, BSc Pharm,† Gordon Walsh, MSc,‡ Marlene Sellon, BSc Pharm,‡ Bruce Colwell, MD,* Mark Dorreen, MD,* Arik Drucker, MD,* Alwin Jeyakumar, MBBS,* and Tallal Younis, MBBCH* *Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre and Atlantic Clinical Cancer Research Unit, Halifax, NS, Canada; †Department of Pharmacy, Tom Baker Cancer Centre, Calgary, Alberta, Canada; ‡Cancer Care Nova Scotia and Atlantic Clinical Cancer Research Unit, Halifax, NS, Canada
n
Abstract: Trastuzumab beyond first progression in the metastatic setting has been adopted based on limited data suggesting improved outcomes compared to second-line chemotherapy alone although predictive factors for preferential benefit remain elusive. We conducted a retrospective review of all patients receiving trastuzumab for HER2 + metastatic disease between Jan 1, 1999–June 15, 2011. Univariate and time to event analyses described treatment and survival patterns. Median duration of each line of therapy and overall survival times for covariates, including treatment era (pre versus post Jan 1, 2005), lines of trastuzumab-based therapy (1 versus 2 versus 3 + ), first-line chemotherapy partner (docetaxel/paclitaxel versus other) and median exposure to first-line trastuzumab-based therapy (=/> versus < cohort median) were estimated. A total of 119 patients received a median of two lines of trastuzumab-based therapy (range 1–8). Median overall survival was 21.8 months (95% CI = 14.5–27.1 m), by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumab-based therapy received was 10.6 m (95% CI = 5.3–17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) (p = 0.0014). Median overall survival was significantly longer for those receiving taxanes with trastuzumab compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median overall survival with duration of first-line trastuzumab-based therapy =/> cohort median was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m for shorter durations (95% CI = 6.9–15.6 m; p < 0.0001). Our observations support progression-free survival on first-line trastuzumab-based therapy as a clinically relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy. n Key Words: metastatic breast cancer, trastuzumab, treatment beyond progression
S
ince publication of the pivotal trials comparing chemotherapy alone to chemotherapy with trastuzumab for metastatic, HER2 + breast cancer, trastuzumab-based systemic therapy has been a treatment cornerstone for this patient subset (1). Continuation of trastuzumab beyond first disease progression in the metastatic setting has increasingly been adopted based on data from small randomized trials and case series suggesting improved outcomes compared to secondline chemotherapy alone (2–5). Limited clinical data
Address correspondence and reprint requests to: Daniel Rayson, MD FRCPC FACP, Division of Medical Oncology, Atlantic Clinical Cancer Research Unit, Room 460 Bethune Bldg., 1276 South Park Street, Halifax NS B3H 2Y9, Canada, or e-mail: [email protected] This work was presented in part at IMPAKT 2013, Brussels. Belgium, May 2–4, 2013. DOI: 10.1111/tbj.12284 © 2014 Wiley Periodicals, Inc., 1075-122X/14 The Breast Journal, Volume 20 Number 4, 2014 408–413
in the context of lack in understanding of mechanisms of resistance, coupled with absence of cumulative toxicity, has resulted in the adoption of ongoing HER2targeting in multiple sequential lines of systemic therapy for HER2 + metastatic breast cancer although identification of a patient subset most likely to benefit from this strategy remains problematic (6). The aim of our study was to describe treatment characteristics, response rates and survival outcomes along the entire duration of trastuzumab exposure among a consecutive cohort of patients with metastatic, HER2 + breast cancer treated at a single Canadian institution.
METHODS The Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia is the largest tertiary cancer care
Trastuzumab Beyond Progression • 409
facility in Atlantic Canada. Trastuzumab-based systemic therapy has been an approved and funded therapeutic option since Jan 1, 1999 with no restriction on number of lines of therapy potentially offered to patients with HER2 + metastatic disease. All patients receiving at least one dose of trastuzumab-based therapy for HER2 + metastatic disease with first treatment between Jan 1, 1999 and June 15, 2011 were included in this retrospective review. Univariate and time to event analyses were used to describe treatment and survival patterns for all cases. Time to event analysis was used to estimate survival outcomes using the Kaplan–Meier method. The log-rank test was used to compare differences in the survival distribution among the study covariates. All analyses were conducted using SAS 9.2 (SAS Institute, Cary, NC). RESULTS A total of 119 consecutive patients were included in the analysis. Clinical and pathologic characteristics Table 1. Clinical-Pathologic Characteristics Median age at diagnosis (years, range) Median tumor size (cms, range) Grade (%) I II III LVI positive Nodal involvement ER and/or PR positive HER2/neu status* (%) IHC positive FISH positive Adjuvant therapies (%) Trastuzumab Chemotherapy Radiation Endocrine therapy
50 (26–76) 2.6 (1.1–14) 1.2 27.9 70.9 51 62 47.5 84.9 13.5 10.8 60 50 31.7
*See text for details. Two cases missing testing methodology information.
of the primary invasive malignancy as well as adjuvant therapies received are described in Table 1. Fifty seven patients (47.5%) had endocrine-sensitive disease and 13 patients (10.8%) had received adjuvant trastuzumab, The median disease-free interval between date of initial breast cancer diagnosis and start of first-line trastuzumab-based therapy for metastatic disease was 32.9 months (range: 0.6–227.3 months). Median follow-up time from diagnosis of primary invasive breast cancer was 56 months (range: 10.2– 242.3 months) and from time of first trastuzumabbased therapy for metastatic disease was 17.3 months (range: 0.1–134.7 months). The median lines of trastuzumab-based therapy received were 2 (range: 1–8). Median durations of each line of trastuzumab-based therapy as well as best response to each line of therapy as described by the treating clinician and abstracted from the relevant patient charts are described in Table 2. The median duration of first-line trastuzumab-based therapy was 8.9 months (range: 0.1–100.6 months) with 25 patients (24.5%) receiving single agent trastuzumab alone. All were treated until disease progression with 5 (4.3%) discontinuing first-line therapy due to asymptomatic cardiac toxicity. Median duration of lines 2 through 5 ranged between 5.5 (5th line) and 6.6 months (3rd line). Durations of therapy were generally shorter for lines 6 and beyond, although there were patients who experienced prolonged exposure to trastuzumab-based therapy even in these advanced treatment settings. Objective response rates (ORR), as assessed by the treating physician, were highest for first-line therapy at 32.8% with a clinical benefit response (CR+PR+SD) rate of 75.9%. ORR was lower with subsequent lines of trastuzumab-based therapy ranging from 0% (lines 5 and 8) to 15.8% for second-line therapy. Rates of
Table 2. Duration, clinician-described best response, and toxicity leading to trastuzumab discontinuation per treatment line Best response (%) Line of therapy 1 2 3 4 5 6 7 8+
N (%) 119 78 47 31 20 10 7 5
(100) (65.5) (39.5) (26.1) (16.8) (8.4) (5.9) (4.2)
Median duration; months (range) 8.1 6.3 6.6 6.2 5.5 3.6 4.9 11.0
(0.1–100.6) (0.4–38.1) (0.8–72.6) (0.7–25.3) (1.2–23.3) (0.9–8.6) (1.4–17.0) (2.1–36.1)
CR + PR (%)
SD (%)
Progression (%)
Toxicity (%)
32.8 15.8 9.1 9.7 0.0 10.0 14.3 0.0
43.1 54.0 63.6 51.6 50 20.0 28.6 60.0
18.1 27.6 27.3 38.7 50 70.0 57.1 40.0
6.0 2.6 0.0 0.0 0.0 0.0 0.0 0.0
410 • rayson et al.
disease stability as best response for lines 2–5 however ranged from 50% to 63.6% resulting in a clinical benefit rate ranging between 50% and 72.7% for these lines of therapy. Kaplan–Meier estimates of median overall survival (OS) for the entire cohort as well as by treatment era (pre versus post Jan 1, 2005), lines of trastuzumab-based therapy received (1 versus 2 versus 3 + ), chemotherapy partner in first line (taxane versus other) and duration of first line trastuzumab exposure (>versus < cohort median) are presented in Figs. 1–5.
Median OS time was 21.8 months (95% CI = 14.5–27.1 m). Median OS time by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumabbased therapy received was 10.6 m (95% CI = 5.3– 17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) for 1 versus 2 versus 3 + lines respectively (p = 0.0014). Median time to first disease relapse was significantly longer for those receiving adjuvant trastuzumab (818.5 d. versus 582 d. p < .0001). Median OS for those receiving adjuvant trastuzumab was not reached but 5 year OS estimates
Figure 1. Median overall survival from first cycle of trastuzumab-based therapy for metastatic disease was 21.8 months (95% CI = 14.5–27.1 m).
Figure 2. Median overall survival by treatment era pre versus post Jan 1, 2005 was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m) respectively; p = 0.11.
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Figure 3. Median overall survival by 1 versus 2 versus 3 + lines of trastuzumab-based therapy received was 10.6 m (95% CI = 5.3– 17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) respectively; p = 0.0014.
Figure 4. Median overall survival by chemotherapy partner received with trastuzumab in first-line setting, docetaxel or paclitaxel versus other was 26.1 m (95% CI = 17.8– 31.4 m) versus 14.5 m (95% CI = 9.4–21.9 m) respectively; p = 0.02.
were 75% versus 50.4% favoring adjuvant trastuzumab receipt (p = 0.05). Median duration of first-line therapy for those receiving docetaxel or paclitaxel (n = 69) was 10.6 m compared to 6.2 m with other agents (n = 50) and significantly more patients receiving taxanes experiencing duration of first-line therapy greater than the overall median time of 8.9 m (p = 0.006). Median OS was also observed to be significantly longer for those receiving either taxane compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median OS time for those experiencing duration of first-line trastuzumab-based therapy equal to or greater than
the cohort median was 31.9 m (95% CI = 26.2– 52.2 m) versus 10.3 m (95% CI = 6.9–15.6 m) for those with duration less than the cohort median (p < 0.0001). There were 10 cases (8.4%) of asymptomatic cardiac toxicity, all recovering upon discontinuation of trastuzumab with none observed beyond second-line therapy. DISCUSSION There remains a paucity of robust level I evidence supporting the concept of continuing trastuzumab beyond first disease progression in the metastatic set-
412 • rayson et al.
Figure 5. Median overall survival by duration of first-line trastuzumab-based therapy equal to or longer than cohort median of 8.9 months versus shorter duration was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m (95% CI = 6.9–15.6 m) respectively; p < 0.0001.
ting. Due to preclinical data suggesting additive or synergistic effects with multiple relevant chemotherapeutic agents, lack of clearly understood mechanisms of resistance and absence of cumulative toxicity, continuation of trastuzumab beyond progression became a clinically relevant treatment strategy in advance of supportive data (6). Randomized controlled trials examining this hypothesis have been notoriously difficult to complete as planned or powered due to a number of factors including lack of clinical equipoise regarding randomization to a nontrastuzumab containing treatment arm. Data from GBG26/BIG3-05, along with that of the observational Hermine study which suggested an overall survival benefit favoring treatment beyond progression, have resulted in this strategy becoming supported by consensus guidelines (2,3,7). In our cohort, we observed a significant survival advantage for the group receiving three or more lines of trastuzumab-based therapy. It remains unclear whether this represents an epiphenomenon whereby those patients who remain alive continue to receive trastuzumab simply due to continuing survival, or whether it supports the concept of a HER2 + disease subset that is preferentially HER2-driven and for whom ongoing trastuzumab-based therapy may be maximally clinically efficacious. We also observed a significant correlation between overall survival outcomes and duration of first-line trastuzumab-based therapy. A previous Italian multiinstitutional analysis of 69 patients treated at four institutions dividing the cohort into those with median
time to progression on first-line therapy >/= versus < 8 months observed a significant effect on postprogression survival (31.7 m versus 21.8 m, p = 0.04) (8). A second, single institutional study from Japan examined 76 patients and observed significantly longer postprogression survival for those experiencing a time to progression on first-line therapy greater than the observed median of 8.6 m (24.3 m versus 15.4 m, p = 0.024) (9). We observed a similar impact on overall survival when we divided our cohort by duration of exposure to first-line trastuzumab-based therapy as being longer or shorter than the overall median of 8.9 months. The group with duration of first-line therapy equal to or greater than the median experienced significantly longer overall survival compared to those experiencing shorter duration first-line therapy (10.3 m; 95% CI = 6.9–15.6 m versus 31.9 m; 95% CI = 26.3– 52.2 m, p < 0.0001). Of note, the median duration of first-line therapy we observed was comparable to those observed in the two studies noted above as well as that of the observational Hermine study. Study strengths include the fact that all consecutive patients receiving at least one dose of trastuzumab for metastatic disease since approval of trastuzumab in 1999 were included, thus minimizing patient selection bias. As well, our institution has utilized a consistent HER2 testing platform and quality assurance algorithm, minimizing risk of false-positive HER2 results. Study limitations include those inherent in all retrospective, single institution reviews. In particular, our observations regarding chemotherapy partner in first-
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line therapy and overall survival may have been biased by more robust patients with better performance status receiving these agents preferentially. Our results add to the evidence supporting clinically assessed progression-free survival on first-line trastuzumab-based therapy as a relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy. Our results, and those of others, also suggest significant heterogeneity in the clinical course of HER2 positive metastatic breast cancer. In the absence of a robust molecular predictive marker and the low likelihood of further level I evidence regarding the role of trastuzumab beyond progression forthcoming, duration of first-line therapy may be an important surrogate marker for overall survival benefit from a treatment beyond progression strategy. This may be of potential relevance in the adoption of sequential HER2-based treatments and should be further investigated with both survival and cost-effectiveness end points. Acknowledgment This study was funded through an unrestricted research grant provided by Roche Canada. The funder had no involvement in the design, analysis, interpretation, or conclusions related to this study and was not involved in any aspect of manuscript development nor approval. CONFLICT OF INTEREST No conflicts of interest declared by any of the authors.
REFERENCES 1. Slamon DL, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med 2001; 344:783–92. 2. vonMinckwitz G, Schwedler K, Schmidt M, et al. Trastuzumab beyond progression: overall survival analysis of the GBG26/ BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer 2011;47:2273–81. 3. Extra JM, Antoine EC, Vincent-Salomon A, et al. Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine study. Oncologist 2010;15:799–809. 4. Mannoci A, De Feo E, de Waure C, et al. Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies. Tumori 2010; 96:385–91. 5. Petrelli F, Barni S. A polled analysis of 2618 patients treated with trastuzumab beyond progression for advanced breast cancer. Clin Breast Cancer 2012;13:81–7. 6. Wong YN, Ottesen RA, Hughes ME, et al. Continued use of trastuzumab beyond disease progression in the National Comprehensive Cancer Network: should we practice ahead of the evidence? Oncologist 2011;16:559–65. 7. National Comprehensive Cancer Network guidelines version 2.2013. Breast Cancer MS-51, 2013. 8. Metro G, Giannarelli D, Gemma D, et al. Time to first tumor progression as outcome predictor of a second trastuzumab-based therapy beyond progression in HER-2 positive metastatic breast cancer. Breast J 2010;16:66–72. 9. Hayashi M, Okumura Y, Osako T, et al. Time to first tumor progression as a predictor of efficacy of continued treatment with trastuzumab beyond progression in human epidermal growth factor receptor 2-positive metastatic breast cancer. Int J Clin Oncol 2011;16:694–700.
Trastuzumab Beyond Progression for HER2 Positive Metastatic Breast Cancer: Progression-Free Survival on First-Line Therapy Predicts Overall Survival Impact Daniel Rayson, MD,* Sarah Lutes, BSc Pharm,† Gordon Walsh, MSc,‡ Marlene Sellon, BSc Pharm,‡ Bruce Colwell, MD,* Mark Dorreen, MD,* Arik Drucker, MD,* Alwin Jeyakumar, MBBS,* and Tallal Younis, MBBCH* *Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre and Atlantic Clinical Cancer Research Unit, Halifax, NS, Canada; †Department of Pharmacy, Tom Baker Cancer Centre, Calgary, Alberta, Canada; ‡Cancer Care Nova Scotia and Atlantic Clinical Cancer Research Unit, Halifax, NS, Canada
n
Abstract: Trastuzumab beyond first progression in the metastatic setting has been adopted based on limited data suggesting improved outcomes compared to second-line chemotherapy alone although predictive factors for preferential benefit remain elusive. We conducted a retrospective review of all patients receiving trastuzumab for HER2 + metastatic disease between Jan 1, 1999–June 15, 2011. Univariate and time to event analyses described treatment and survival patterns. Median duration of each line of therapy and overall survival times for covariates, including treatment era (pre versus post Jan 1, 2005), lines of trastuzumab-based therapy (1 versus 2 versus 3 + ), first-line chemotherapy partner (docetaxel/paclitaxel versus other) and median exposure to first-line trastuzumab-based therapy (=/> versus < cohort median) were estimated. A total of 119 patients received a median of two lines of trastuzumab-based therapy (range 1–8). Median overall survival was 21.8 months (95% CI = 14.5–27.1 m), by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumab-based therapy received was 10.6 m (95% CI = 5.3–17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) (p = 0.0014). Median overall survival was significantly longer for those receiving taxanes with trastuzumab compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median overall survival with duration of first-line trastuzumab-based therapy =/> cohort median was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m for shorter durations (95% CI = 6.9–15.6 m; p < 0.0001). Our observations support progression-free survival on first-line trastuzumab-based therapy as a clinically relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy. n Key Words: metastatic breast cancer, trastuzumab, treatment beyond progression
S
ince publication of the pivotal trials comparing chemotherapy alone to chemotherapy with trastuzumab for metastatic, HER2 + breast cancer, trastuzumab-based systemic therapy has been a treatment cornerstone for this patient subset (1). Continuation of trastuzumab beyond first disease progression in the metastatic setting has increasingly been adopted based on data from small randomized trials and case series suggesting improved outcomes compared to secondline chemotherapy alone (2–5). Limited clinical data
Address correspondence and reprint requests to: Daniel Rayson, MD FRCPC FACP, Division of Medical Oncology, Atlantic Clinical Cancer Research Unit, Room 460 Bethune Bldg., 1276 South Park Street, Halifax NS B3H 2Y9, Canada, or e-mail: [email protected] This work was presented in part at IMPAKT 2013, Brussels. Belgium, May 2–4, 2013. DOI: 10.1111/tbj.12284 © 2014 Wiley Periodicals, Inc., 1075-122X/14 The Breast Journal, Volume 20 Number 4, 2014 408–413
in the context of lack in understanding of mechanisms of resistance, coupled with absence of cumulative toxicity, has resulted in the adoption of ongoing HER2targeting in multiple sequential lines of systemic therapy for HER2 + metastatic breast cancer although identification of a patient subset most likely to benefit from this strategy remains problematic (6). The aim of our study was to describe treatment characteristics, response rates and survival outcomes along the entire duration of trastuzumab exposure among a consecutive cohort of patients with metastatic, HER2 + breast cancer treated at a single Canadian institution.
METHODS The Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia is the largest tertiary cancer care
Trastuzumab Beyond Progression • 409
facility in Atlantic Canada. Trastuzumab-based systemic therapy has been an approved and funded therapeutic option since Jan 1, 1999 with no restriction on number of lines of therapy potentially offered to patients with HER2 + metastatic disease. All patients receiving at least one dose of trastuzumab-based therapy for HER2 + metastatic disease with first treatment between Jan 1, 1999 and June 15, 2011 were included in this retrospective review. Univariate and time to event analyses were used to describe treatment and survival patterns for all cases. Time to event analysis was used to estimate survival outcomes using the Kaplan–Meier method. The log-rank test was used to compare differences in the survival distribution among the study covariates. All analyses were conducted using SAS 9.2 (SAS Institute, Cary, NC). RESULTS A total of 119 consecutive patients were included in the analysis. Clinical and pathologic characteristics Table 1. Clinical-Pathologic Characteristics Median age at diagnosis (years, range) Median tumor size (cms, range) Grade (%) I II III LVI positive Nodal involvement ER and/or PR positive HER2/neu status* (%) IHC positive FISH positive Adjuvant therapies (%) Trastuzumab Chemotherapy Radiation Endocrine therapy
50 (26–76) 2.6 (1.1–14) 1.2 27.9 70.9 51 62 47.5 84.9 13.5 10.8 60 50 31.7
*See text for details. Two cases missing testing methodology information.
of the primary invasive malignancy as well as adjuvant therapies received are described in Table 1. Fifty seven patients (47.5%) had endocrine-sensitive disease and 13 patients (10.8%) had received adjuvant trastuzumab, The median disease-free interval between date of initial breast cancer diagnosis and start of first-line trastuzumab-based therapy for metastatic disease was 32.9 months (range: 0.6–227.3 months). Median follow-up time from diagnosis of primary invasive breast cancer was 56 months (range: 10.2– 242.3 months) and from time of first trastuzumabbased therapy for metastatic disease was 17.3 months (range: 0.1–134.7 months). The median lines of trastuzumab-based therapy received were 2 (range: 1–8). Median durations of each line of trastuzumab-based therapy as well as best response to each line of therapy as described by the treating clinician and abstracted from the relevant patient charts are described in Table 2. The median duration of first-line trastuzumab-based therapy was 8.9 months (range: 0.1–100.6 months) with 25 patients (24.5%) receiving single agent trastuzumab alone. All were treated until disease progression with 5 (4.3%) discontinuing first-line therapy due to asymptomatic cardiac toxicity. Median duration of lines 2 through 5 ranged between 5.5 (5th line) and 6.6 months (3rd line). Durations of therapy were generally shorter for lines 6 and beyond, although there were patients who experienced prolonged exposure to trastuzumab-based therapy even in these advanced treatment settings. Objective response rates (ORR), as assessed by the treating physician, were highest for first-line therapy at 32.8% with a clinical benefit response (CR+PR+SD) rate of 75.9%. ORR was lower with subsequent lines of trastuzumab-based therapy ranging from 0% (lines 5 and 8) to 15.8% for second-line therapy. Rates of
Table 2. Duration, clinician-described best response, and toxicity leading to trastuzumab discontinuation per treatment line Best response (%) Line of therapy 1 2 3 4 5 6 7 8+
N (%) 119 78 47 31 20 10 7 5
(100) (65.5) (39.5) (26.1) (16.8) (8.4) (5.9) (4.2)
Median duration; months (range) 8.1 6.3 6.6 6.2 5.5 3.6 4.9 11.0
(0.1–100.6) (0.4–38.1) (0.8–72.6) (0.7–25.3) (1.2–23.3) (0.9–8.6) (1.4–17.0) (2.1–36.1)
CR + PR (%)
SD (%)
Progression (%)
Toxicity (%)
32.8 15.8 9.1 9.7 0.0 10.0 14.3 0.0
43.1 54.0 63.6 51.6 50 20.0 28.6 60.0
18.1 27.6 27.3 38.7 50 70.0 57.1 40.0
6.0 2.6 0.0 0.0 0.0 0.0 0.0 0.0
410 • rayson et al.
disease stability as best response for lines 2–5 however ranged from 50% to 63.6% resulting in a clinical benefit rate ranging between 50% and 72.7% for these lines of therapy. Kaplan–Meier estimates of median overall survival (OS) for the entire cohort as well as by treatment era (pre versus post Jan 1, 2005), lines of trastuzumab-based therapy received (1 versus 2 versus 3 + ), chemotherapy partner in first line (taxane versus other) and duration of first line trastuzumab exposure (>versus < cohort median) are presented in Figs. 1–5.
Median OS time was 21.8 months (95% CI = 14.5–27.1 m). Median OS time by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumabbased therapy received was 10.6 m (95% CI = 5.3– 17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) for 1 versus 2 versus 3 + lines respectively (p = 0.0014). Median time to first disease relapse was significantly longer for those receiving adjuvant trastuzumab (818.5 d. versus 582 d. p < .0001). Median OS for those receiving adjuvant trastuzumab was not reached but 5 year OS estimates
Figure 1. Median overall survival from first cycle of trastuzumab-based therapy for metastatic disease was 21.8 months (95% CI = 14.5–27.1 m).
Figure 2. Median overall survival by treatment era pre versus post Jan 1, 2005 was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m) respectively; p = 0.11.
Trastuzumab Beyond Progression • 411
Figure 3. Median overall survival by 1 versus 2 versus 3 + lines of trastuzumab-based therapy received was 10.6 m (95% CI = 5.3– 17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) respectively; p = 0.0014.
Figure 4. Median overall survival by chemotherapy partner received with trastuzumab in first-line setting, docetaxel or paclitaxel versus other was 26.1 m (95% CI = 17.8– 31.4 m) versus 14.5 m (95% CI = 9.4–21.9 m) respectively; p = 0.02.
were 75% versus 50.4% favoring adjuvant trastuzumab receipt (p = 0.05). Median duration of first-line therapy for those receiving docetaxel or paclitaxel (n = 69) was 10.6 m compared to 6.2 m with other agents (n = 50) and significantly more patients receiving taxanes experiencing duration of first-line therapy greater than the overall median time of 8.9 m (p = 0.006). Median OS was also observed to be significantly longer for those receiving either taxane compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median OS time for those experiencing duration of first-line trastuzumab-based therapy equal to or greater than
the cohort median was 31.9 m (95% CI = 26.2– 52.2 m) versus 10.3 m (95% CI = 6.9–15.6 m) for those with duration less than the cohort median (p < 0.0001). There were 10 cases (8.4%) of asymptomatic cardiac toxicity, all recovering upon discontinuation of trastuzumab with none observed beyond second-line therapy. DISCUSSION There remains a paucity of robust level I evidence supporting the concept of continuing trastuzumab beyond first disease progression in the metastatic set-
412 • rayson et al.
Figure 5. Median overall survival by duration of first-line trastuzumab-based therapy equal to or longer than cohort median of 8.9 months versus shorter duration was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m (95% CI = 6.9–15.6 m) respectively; p < 0.0001.
ting. Due to preclinical data suggesting additive or synergistic effects with multiple relevant chemotherapeutic agents, lack of clearly understood mechanisms of resistance and absence of cumulative toxicity, continuation of trastuzumab beyond progression became a clinically relevant treatment strategy in advance of supportive data (6). Randomized controlled trials examining this hypothesis have been notoriously difficult to complete as planned or powered due to a number of factors including lack of clinical equipoise regarding randomization to a nontrastuzumab containing treatment arm. Data from GBG26/BIG3-05, along with that of the observational Hermine study which suggested an overall survival benefit favoring treatment beyond progression, have resulted in this strategy becoming supported by consensus guidelines (2,3,7). In our cohort, we observed a significant survival advantage for the group receiving three or more lines of trastuzumab-based therapy. It remains unclear whether this represents an epiphenomenon whereby those patients who remain alive continue to receive trastuzumab simply due to continuing survival, or whether it supports the concept of a HER2 + disease subset that is preferentially HER2-driven and for whom ongoing trastuzumab-based therapy may be maximally clinically efficacious. We also observed a significant correlation between overall survival outcomes and duration of first-line trastuzumab-based therapy. A previous Italian multiinstitutional analysis of 69 patients treated at four institutions dividing the cohort into those with median
time to progression on first-line therapy >/= versus < 8 months observed a significant effect on postprogression survival (31.7 m versus 21.8 m, p = 0.04) (8). A second, single institutional study from Japan examined 76 patients and observed significantly longer postprogression survival for those experiencing a time to progression on first-line therapy greater than the observed median of 8.6 m (24.3 m versus 15.4 m, p = 0.024) (9). We observed a similar impact on overall survival when we divided our cohort by duration of exposure to first-line trastuzumab-based therapy as being longer or shorter than the overall median of 8.9 months. The group with duration of first-line therapy equal to or greater than the median experienced significantly longer overall survival compared to those experiencing shorter duration first-line therapy (10.3 m; 95% CI = 6.9–15.6 m versus 31.9 m; 95% CI = 26.3– 52.2 m, p < 0.0001). Of note, the median duration of first-line therapy we observed was comparable to those observed in the two studies noted above as well as that of the observational Hermine study. Study strengths include the fact that all consecutive patients receiving at least one dose of trastuzumab for metastatic disease since approval of trastuzumab in 1999 were included, thus minimizing patient selection bias. As well, our institution has utilized a consistent HER2 testing platform and quality assurance algorithm, minimizing risk of false-positive HER2 results. Study limitations include those inherent in all retrospective, single institution reviews. In particular, our observations regarding chemotherapy partner in first-
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line therapy and overall survival may have been biased by more robust patients with better performance status receiving these agents preferentially. Our results add to the evidence supporting clinically assessed progression-free survival on first-line trastuzumab-based therapy as a relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy. Our results, and those of others, also suggest significant heterogeneity in the clinical course of HER2 positive metastatic breast cancer. In the absence of a robust molecular predictive marker and the low likelihood of further level I evidence regarding the role of trastuzumab beyond progression forthcoming, duration of first-line therapy may be an important surrogate marker for overall survival benefit from a treatment beyond progression strategy. This may be of potential relevance in the adoption of sequential HER2-based treatments and should be further investigated with both survival and cost-effectiveness end points. Acknowledgment This study was funded through an unrestricted research grant provided by Roche Canada. The funder had no involvement in the design, analysis, interpretation, or conclusions related to this study and was not involved in any aspect of manuscript development nor approval. CONFLICT OF INTEREST No conflicts of interest declared by any of the authors.
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