International Journal of Clinical Oncology

, Volume 16, Issue 6, pp 694–700 | Cite as

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

  • Mitsuhiro Hayashi
  • Yasuhiro Okumura
  • Tomofumi Osako
  • Yasuo Toyozumi
  • Nobuyuki Arima
  • Hirotaka Iwase
  • Reiki Nishimura
Original Article

Abstract

Background

Trastuzumab demonstrates significant clinical benefits in HER2-positive metastatic breast cancer (MBC), and recent clinical trials suggest that trastuzumab should be continued in combination with other chemotherapy beyond progression. There is an urgent need to assess if patients could substantially benefit from continuing trastuzumab-based therapy.

Methods

We reviewed 91 patients with HER2-positive MBC treated with trastuzumab and investigated correlations between survival and clinical response to first trastuzumab-based therapy and biological markers, time to first tumor progression (1st TTP), response rate (RR), estrogen receptor (ER), Ki-67, and p53 overexpression.

Results

With a median follow-up of 33 months, 76 patients had received two or more lines of consecutive trastuzumab-based therapy. Median 1st TTP was 8.6 months; patients who received trastuzumab with chemotherapy had a longer 1st TTP and better RR than those without chemotherapy. In terms of survival after first progression, patients with a longer 1st TTP (≥8.6 months) had significantly better survival compared with those who had a shorter 1st TTP (24.3 months vs. 15.4 months, P = 0.024), and multivariate analysis revealed that 1st TTP was a significant prognostic factor (HR 0.44, 95% CI 0.23–0.82, P = 0.01). There were no correlations between survival and ER or Ki-67; however, there was a correlation with p53 overexpression (HR 1.92, 95% CI 1.01–3.64, P = 0.045).

Conclusions

1st TTP is a significant prognostic factor for patients who receive subsequent trastuzumab-based therapy. This factor should be considered when determining the efficacy of continuing trastuzumab or switching to another anti-HER2 therapy beyond progression.

Keywords

Trastuzumab Time to progression Treatment beyond progression Human epidermal growth factor receptor 2 Metastatic breast cancer p53 overexpression 

Introduction

Overexpression of human epidermal growth factor receptor type 2 (HER2), a transmembrane glycoprotein receptor with tyrosine kinase activity, occurs in 20–30% of breast cancers and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody that targets the extracellular domain of HER2, demonstrates significant clinical benefits in patients with HER2-positive breast cancer [1]. Patients with metastatic breast cancer are unlikely to be cured by any means. Nevertheless, trastuzumab-based therapy provides improvement in objective response, resulting in increased survival times for HER2-positive metastatic breast cancer patients [2, 3, 4].

Switching the treatment regimen at disease progression is a general principle in conventional systemic therapies such as cytotoxic chemotherapy and endocrine therapy. However, a preclinical study has suggested that continuing trastuzumab therapy is required for sustained tumor control in a breast cancer xenograft model [5], and recent prospective studies have supported the clinical efficacy and safety of continuing trastuzumab with other chemotherapies beyond disease progression, i.e., restoring trastuzumab and changing the combination agent [6, 7]. The clinical benefits of novel molecular targeting agents such as lapatinib, a tyrosine kinase inhibitor of HER1/HER2, have also been reported in HER2-positive metastatic breast cancer [8], and thus we could be pressed to decide whether to continue trastuzumab therapy or to change to other molecular targeting agents beyond disease progression.

Despite the improvement in survival provided by these molecular targeting agents, sometimes patients with HER2-postive breast cancer display primary or acquired resistance to systemic treatment, even with trastuzumab-based therapy. Numerous molecular mechanisms of trastuzumab resistance have been described, for example, the formation of p95HER2, hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway, phosphatase and tensin homolog (PTEN) deficiency, and overexpression of insulin-like growth factor-1 receptor (IGF-1R) [9, 10, 11]. These molecular mechanisms play an important role in clinical practice, and it would be extremely useful if we could diagnose primary trastuzumab resistance from the patients’ actual clinical data during the early treatment stages.

To assess patients for continuation of trastuzumab-based therapy, we hypothesized that the clinical response at initiation of trastuzumab-based therapy would reflect the subsequent efficacy of continuing trastuzumab beyond disease progression. One retrospective study of 67 patients in Italy that mainly analyzed second trastuzumab-based therapy beyond disease progression suggested that time to first tumor progression (1st TTP) may be a useful tool [12]. Therefore, we performed a retrospective analysis of the survival of HER2-positive metastatic breast cancer patients treated with two or more lines of consecutive trastuzumab-based therapy in Japan.

Patients and methods

We reviewed 91 patients with HER2-positive metastatic breast cancer treated with trastuzumab as a first- or second-line treatment at Kumamoto City Hospital in Japan from August 2000 to May 2010. Of these, 76 patients had received two or more lines of consecutive trastuzumab-based therapy beyond disease progression, whereas 15 patients were receiving the first trastuzumab-based therapy. Therefore, 76 patients were enrolled in the study. We investigated the correlation between patient survival and clinical or biological factors by reviewing a prospectively maintained database. Informed consent was obtained from all patients.

The trastuzumab-based therapies administered were as follows: trastuzumab monotherapy; trastuzumab with concurrent chemotherapy agents such as paclitaxel, docetaxel, vinorelbine, capecitabine, fluorouracil, and gemcitabine; trastuzumab with concurrent endocrine therapy such as tamoxifen, an aromatase inhibitor, luteinizing hormone-releasing hormone (LHRH) analogue, and medroxyprogesterone, according to the hormone receptor-positive patient’s menopausal status. Trastuzumab was administered weekly at a dose of 2 mg/kg after a first infusion loading dose of 4 mg/kg over 90 min. Breast cancer oncologists determined the appropriate treatment regimens for patients with HER2-positive metastatic breast cancer until the palliative care stage. If chemotherapy-related severe adverse events occurred, trastuzumab was usually continued with dose reduction or omission of the companion agents.

Clinical response was evaluated using the Response Evaluation Criteria in Solid Tumors [13]. 1st TTP was calculated from the start of the first trastuzumab-based therapy to the date of first disease progression. After the first progression, survival was determined as the time elapsed from disease progression after the first trastuzumab-based therapy to the date of last contact or death from any cause. The period between 1st TTP and the final assessment of overall survival was considered a useful marker for analyzing the efficacy of continuing trastuzumab beyond progression. We used the median 1st TTP as a cutoff value to identify two groups of patients, longer and shorter 1st TTP group.

Biological markers were examined at primary surgery or diagnosis using breast cancer samples. The variables of interest were estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67 labeling index, and p53 overexpression. Immunohistochemical staining was performed according to a protocol described previously [14]. Hormone receptor positivity was defined by positive staining for estrogen- and/or progesterone-positive receptors in at least 10% of tumor cell nuclei. HER2 expression was initially evaluated using the Hercep Test (Dako, Glostrup, Denmark). HER2 positivity was indicated by 3+ staining intensity. HER2 equivocal (2+ staining) was tested using fluorescence in situ hybridization with a threshold ratio of more than 2.0 for positive HER2:CEP17. Proliferation activity was assessed by immunostaining with the Ki-67 antibody (Dako). The proportion of proliferating cells was determined by counting at least 500 tumor cells, and the Ki-67 index was determined to be low if the proportion of cells was <20%, intermediate if the proportion was 20–49%, and high if the proportion was ≥50% [15]. Expression of p53 was also evaluated by immunostaining with the mouse monoclonal anti-p53 antibody (clone DO7; Dako). The staining pattern of the p53 protein was divided into three groups, 2+ (homogeneous and diffuse staining), 1+ (heterogeneous or focal staining in >5% of tumor cells), and negative (focal staining in <5% of tumor cells). In this study, p53 overexpression was indicated by 2+ staining.

Statistical comparisons between groups were performed using the chi-square and Fisher’s exact tests. Time-to-event data (TTP and survival after first progression) were analyzed using the Kaplan–Meier method; differences between curves were evaluated by the log-rank test. The Cox proportional hazards model was used to identify prognostic factors. A two-sided P value <0.05 was considered to be statistically significant. The JMP 8.0 software package (SAS Institute, Cary, NC, USA) was used for statistical analysis.

Results

Patient characteristics at initiation of trastuzumab-based therapy are shown in Table 1. The median 1st TTP was 8.6 months [95% confidence interval (CI), 6.5–9.9 months] among all patients after a median follow-up period of 33 months. Trastuzumab was prescribed as a first-line treatment in 58 (76%) patients and as a second-line treatment in 18 (24%) patients. Trastuzumab was administered in combination with chemotherapy in 50 (66%) patients, and taxane accounted for 88% of those combination regimens. Patients treated with trastuzumab and chemotherapy had a longer 1st TTP and better response rate (RR) than those without chemotherapy (1st TTP, 9.4 vs. 6.3 months, P = 0.026; RR, 82.0% vs. 38.5%, P = 0.001, respectively) (Fig. 1). There were no significant correlations between the 1st TTP and biological markers such as ER, PgR, Ki-67, and p53 status in this analysis.
Table 1

Patient characteristics at initiation of trastuzumab treatment

Characteristics

All patients (n = 76):

1st TTP ≥8.6 months (n = 39):

1st TTP <8.6 months (n = 37):

no. of patients (%)

no. of patients (%)

no. of patients (%)

Age (years)

 Median

53

54

52

 Range

29–72

29–72

32–70

Hormone receptor

 ER and/or PgR positive

30 (39)

19 (49)

11 (70)

 ER and PgR negative

45 (59)

19 (49)

26 (30)

 Unknown

1 (1)

1 (3)

0 (0)

Ki67 index

 Median, % (range)

38 (8–95)

38 (22–68)

39.5 (8–95)

 Low–intermediatea

56 (74)

28 (72)

28 (76)

 Higha

13 (17)

7 (18)

6 (16)

 Unknown

7 (9)

4 (10)

3 (8)

p53 overexpression

 Positive

27 (36)

14 (36)

13 (35)

 Unknown

9 (12)

4 (10)

5 (14)

Metastatic sites

 Liver

36 (47)

17 (44)

19 (51)

 Lung

26 (34)

14 (36)

12 (32)

 Brain

9 (12)

4 (10)

5 (14)

PS 0 or 1

65 (86)

33 (85)

32 (86)

Timing of initiation of T

 First line

58 (76)

30 (77)

28 (76)

 Second line

18 (24)

9 (23)

9 (24)

First T treatment

 With chemotherapy

50 (66)

29 (74)

21 (57)

 Monotherapy

22 (29)

9 (23)

13 (35)

 With endocrine therapy

4 (5)

1 (3)

3 (8)

Use of lapatinibb

12 (16)

7 (18)

5 (14)

1st TTP, time to first tumor progression; ER, estrogen receptor; PgR, progesterone receptor; PS, Eastern Cooperative Oncology Group performance status; T, trastuzumab

aKi67 index was considered low if the proportion of cells was <20%, intermediate if the proportion was 20–49%, and high if the proportion was ≥50%

bLapatinib was approved in April 2009 in Japan

Fig. 1

Comparison of the time to first tumor progression (TTP) among patients who received trastuzumab with and without chemotherapy. 1st TTP, time to first tumor progression; CI, confidence interval; T, trastuzumab

To assess the patients that could substantially benefit from continuing trastuzumab-based therapy beyond disease progression, we identified two different groups of patients by the 1st TTP period: 39 patients with a longer 1st TTP (≥8.6 months) and 37 patients with a shorter 1st TTP (<8.6 months) (see Table 1). In terms of clinical response to the initiation of trastuzumab-based therapy, the complete response rate among all patients was 12%, 13% in the longer 1st TTP group (1st TTP, ≥8.6 months), and 11% in the shorter 1st TTP group (1st TTP, <8.6 months). The RR was 67% among all patients, 85% for the longer 1st TTP group, and 49% for the shorter 1st TTP group (Table 2).
Table 2

Clinical response to initiation of trastuzumab-based treatment

Response

All patients (n = 76):

1st TTP ≥8.6 months (n = 39):

1st TTP <8.6 months (n = 37):

no. of patients (%)

no. of patients (%)

no. of patients (%)

CR

9 (12)

5 (13)

4 (11)

PR

42 (55)

28 (72)

14 (38)

SD

15 (20)

6 (15)

9 (24)

PD

10 (13)

0 (0)

10 (27)

1st TTP, time to first tumor progression; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

The most important factor was survival after the first progression. Those patients in the longer 1st TTP group had significantly better survival compared with those in the shorter 1st TTP group (median, 24.3 vs. 15.4 months, P = 0.024) (Fig. 2). The overall survival was also significantly better in the longer 1st TTP group (median, 40.0 months, 95% CI, 29.4–70.0; vs. 20.9 months, 95% CI, 16.3–24.6; P < 0.0001). Moreover, multivariate analysis revealed that the 1st TTP was the most significant prognostic factor for predicting survival after first progression [hazard ratio (HR), 0.44, 95% CI, 0.23–0.82, P = 0.01] (Table 3). We also found that p53 overexpression was correlated with poor prognosis in patients in whom trastuzumab treatment was continued (HR, 1.92, 95% CI, 1.0–3.64, P = 0.045). On the other hand, there were no significant correlations between patient survival and ER, PgR, and Ki-67 status in HER2-positive metastatic breast cancer with continuation of trastuzumab-based therapy.
Fig. 2

Survival after first progression based on the 1st TTP. Patients who continued trastuzumab-based therapy beyond disease progression were classified into two groups: longer 1st TTP group if the patients received trastuzumab for longer than 8.6 months from initiation of trastuzumab-based therapy and shorter 1st TTP group if patients received trastuzumab for less than 8.6 months. The median 1st TTP among all patients was 8.6 months. 1st TTP, time to first tumor progression; CI, confidence interval

Table 3

Univariate and multivariate analysis of factors influencing survival after first progression

Factor

Univariate

Multivariate

HR (95% CI)

P value

HR (95% CI)

P value

ER positive

0.85 (0.46–1.50)

0.57

  

PgR positive

0.77 (0.38–1.46)

0.44

  

Ki67 higha

0.65 (0.27–1.38)

0.28

  

p53 overexpression

2.12 (1.13–3.94)

0.02

1.92 (1.01–3.64)

0.045

Liver metastasis

1.36 (0.77–2.40)

0.28

  

Lung metastasis

1.18 (0.64–2.11)

0.59

  

Brain metastasis

1.08 (0.41–2.35)

0.86

  

PS 0 or 1

0.63 (0.31–1.46)

0.26

  

T as first-line therapy

0.64 (0.35–1.22)

0.17

  

Initiation of T with chemotherapy

1.94 (1.04–3.88)

0.04

1.94 (0.99–4.05)

0.054

Response to initiation of Tb

1.05 (0.58–1.98)

0.88

  

Longer 1st TTPc

0.53 (0.30–0.93)

0.03

0.44 (0.23–0.82)

0.010

1st TTP, time to first tumor progression; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PgR, progesterone receptor; PS, Eastern Cooperative Oncology Group performance status; T, trastuzumab

aProportion was ≥50%

bComplete response and partial response

c8.6 months or longer

Discussion

The current study showed that the patients who had a longer 1st TTP (≥8.6 months) at initiation of trastuzumab-based therapy could clinically benefit from continuing trastuzumab beyond disease progression. The trastuzumab-based therapy improved the prognosis for patients with HER2-positive metastatic breast cancer at first-line treatment [3, 4]. Moreover, our results further support the suitability of continuing trastuzumab-based therapy, i.e., retaining trastuzumab beyond disease progression and switching combination agents.

Preclinical data suggest that trastuzumab exerts a cytostatic rather than cytotoxic action, and that prolonged trastuzumab exposure is necessary for continued tumor suppression [5]. Evaluating various trastuzumab effects, such as the activation of antibody-dependent cellular cytotoxicity, prevention of HER2-activated intracellular signaling, inhibition of HER2-regulated angiogenesis, and prevention of shedding of the extracellular domain (ECD) of HER2 [1, 16, 17], it is clear why many oncologists have continued to use trastuzumab in clinical practice. Recently, two randomized studies and one large observational study were conducted to investigate continuation of trastuzumab-based therapy. A German Phase III randomized study comparing trastuzumab and capecitabine with capecitabine alone in 156 patients who had progressed during trastuzumab-based therapy (German Breast Group; GBG-26) reported that continuing trastuzumab was associated with a significantly longer TTP (8.2 vs. 5.6 months, P = 0.03) without any increased toxicity [7]. In a study comparing trastuzumab and lapatinib, which is an orally active dual HER1/HER2 tyrosine kinase inhibitor, with lapatinib alone in 296 patients who experienced progression after prior trastuzumab-based therapy (EGF 104900), continuation of trastuzumab-based therapy significantly improved progression-free survival (median, 12.0 vs. 8.1 months, HR, 0.73, P = 0.008) [6]. The Hermine study, an observational study conducted in France to evaluate outcomes of trastuzumab treatment in routine clinical practice that compared overall survival in 177 patient who continued or discontinued trastuzumab therapy, also suggested that continuing trastuzumab beyond disease progression offered a survival benefit (median overall survival, >27.8 months vs. 16.8 months, P < 0.001) [18]. These studies support the efficacy and safety of continuing trastuzumab-based therapy beyond disease progression. Therefore, further investigations in patients who receive a substantial clinical benefit from continuation of trastuzumab-based therapy are required.

Some HER2-positive breast cancers demonstrate primary (de novo or intrinsic) resistance to trastuzumab, and even more cancers show acquired resistance. A number of resistance mechanisms have been described, including p95HER2 expression [9], PTEN deficiency and PI3 K/Akt activation [10], IGF-IR overexpression [11], and cyclin E overexpression [19]. Unfortunately, there are few verified resistance markers to use in clinical practice at present, so that defining the treatment efficacy of continuing trastuzumab after first-line therapy could be useful. Thus, we propose that 1st TTP serves as a surrogate marker for trastuzumab primary resistance but not response rate.

Using the median TTP of 8.6 months calculated from our data, we separated patients who substantially benefited from continuing trastuzumab from those who did not. We determined that this period was a sufficient marker for comparison because the Hermine study also reported a median 1st TTP of 8.6 months at initiation of trastuzumab-based therapy among all patients, including subgroups who received trastuzumab as first-, second-, and third-line treatment or beyond [18]. Additionally, the increase of TTP by trastuzumab in combination with chemotherapy has also been seen in several studies: current study, TTP 9.4 vs. 6.3 months, P = 0.026); paclitaxel with or without trastuzumab as first-line therapy (Slamon et al.), TTP 6.9 vs. 3.0 months, P < 0.001 [4], docetaxel with or without trastuzumab as first-line therapy (Marty et al.), TTP 11.7 vs. 5.7 months, P = 0.0001 [3], capecitabine with or without trastuzumab as second-line or subsequent therapy (von Minckwitz et al.), TTP 8.2 vs. 5.6 months, P = 0.033 [7], and trastuzumab first-line monotherapy (Vogel et al.), TTP 3.5 months [20]. Even in consideration of these data, the cutoff of 8.6 months would be considered acceptable. It is reasonable to use the median value as the cutoff when evaluating a patient among subgroups. For clinical practice, to decide the universal cutoff point, further examination is required.

The current data showed that long 1st TTP was associated with subsequent long survival, so we extracted 1st TTP as the predictive factor for the continuation of trastuzumab-based therapy. Our rationale was that continuing trastuzumab is important for the patients with HER2-positive breast cancer after progression of trastuzumab containing therapy. Therefore, even though we did not compare the trastuzumab-based therapy with no trastuzumab-based therapy, it does not necessarily mean that patients with short 1st TTP would not benefit from continuing trastuzumab. In addition, we also must consider that the survival of patients with metastatic breast cancer might be affected by the intensity of chemotherapy. The patients with longer 1st TTP were treated with more intensive chemotherapy than those with shorter 1st TTP at the first trastuzumab-based therapy (refer to Table 1), although there was no significant difference between the groups. It might be possible that the same result was expected among the patients after their first disease progression.

Meanwhile, we found no significant correlation between patient survival and commonly used biological markers such as ER, PgR, and Ki-67 status; p53 overexpression was only a prognostic factor in patients who continued trastuzumab-based therapy in this analysis. The overexpression of p53 is a predictive factor for poor response to conventional systemic therapy because of the failure of apoptosis in breast cancer [14, 21]. Interestingly, there was one report that trastuzumab increased apoptosis by inhibiting the PI3K/Akt pathway, even in neoadjuvant trastuzumab monotherapy induction [22]. This finding indicated that p53 expression status is also a predictive factor for response to trastuzumab-based therapy.

In conclusion, TTP at the initiation of trastuzumab-based therapy serves as a prognostic marker of benefit, but not response rate, in patients treated with continuing trastuzumab. We suggest that the 1st TTP be a surrogate marker of primary resistance to trastuzumab-based therapy. In clinical practice, a decision on whether to continue trastuzumab-based therapy or change to another anti-HER2 therapy after disease progression could be undertaken by referring to the 1st TTP. A prospective study is required for validating the results of continuing or discontinuing trastuzumab based on 1st TTP.

Notes

Acknowledgments

We thank the staff of the Department of Clinical Pathology at Kumamoto City Hospital for their technical assistance.

Conflict of interest

H. Iwase received honoraria from Pfizer and research funding from Chugai-Roche and Novartis. The other authors report no conflict of interest.

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Copyright information

© Japan Society of Clinical Oncology 2011

Authors and Affiliations

  • Mitsuhiro Hayashi
    • 1
    • 2
  • Yasuhiro Okumura
    • 2
  • Tomofumi Osako
    • 2
  • Yasuo Toyozumi
    • 3
  • Nobuyuki Arima
    • 3
  • Hirotaka Iwase
    • 1
  • Reiki Nishimura
    • 2
  1. 1.Department of Breast and Endocrine Surgery, Faculty of Life SciencesKumamoto University Graduate School of Medical SciencesKumamotoJapan
  2. 2.Department of Breast and Endocrine SurgeryKumamoto City HospitalKumamotoJapan
  3. 3.Department of Clinical PathologyKumamoto City HospitalKumamoto-cityJapan

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