Prognostic Value Of Circulating Tumor Cells In Metastatic Breast Cancer

Only three studies have correlated the presence of immunopurified CTCs with clinical outcome. The first by Gaforio et al. (30) evaluated a heterogeneous population of patients spanning the clinical contexts of neoadjuvant therapy, adjuvant therapy, and metastatic disease. Utilizing Kaplan-Meier analysis for progressionfree survival (PFS) and overall survival (OS), they found that patients with elevated CTCs prior to therapy had worse PFS (P = 0.058) and OS (P = 0.003). However, they did not stratify for disease stage, and at the time of publication neither of the medians for PFS or OS had been reached, making interpretation of the data difficult. The second study by Bauernhofer et al. (27) evaluated CTCs in 32 patients with metastatic breast cancer. They found that patients with detectable CTCs had a significantly shorter median OS of four months, compared with 13 months for patients without CTCs (P < 0.001). These authors did not specify the timing of the blood draws, and they did not compare CTCs to other prognostic factors such as line of therapy, hormone receptor status, sites of disease, or performance status. Thus, it is also difficult to fully interpret the results from this second trial.

A third trial reported by Cristofanilli et al. (25,31) utilized the CellSearch methodology and demonstrated that CTCs are highly prognostic in the setting of metastatic breast cancer. In a prospective, double-blind, multi-centre trial, 177 patients with metastatic breast cancer who were beginning a new therapy were evaluated. Patients could be initiating any line of hormonal therapy or chemotherapy, and CTCs were drawn at baseline, first follow-up, and at each subsequent visit until clinical progression. Using a training set of 102 patient samples, a level of >5 CTC per 7.5 mL of whole blood was identified as the threshold that best distinguished PFS between the two groups. This threshold and its prognostic value were then confirmed in an independent, prospectively collected set of 75 patient samples. Elevated CTCs at baseline predicted extremely

FIGURE 1 Kaplan-Meier curves demonstrating differences in progression-free survival (PFS) (A and C) and overall survival (OS) (B and D) based upon high- and low-risk circulating tumor cell (CTC) classifications. Patients with elevated CTCs at baseline (A and B) and at first follow-up after one cycle of therapy (C and D) have significantly worse median PFS and OS compared with the corresponding patients with low CTCs. Source: Adapted from Ref. 25.

FIGURE 1 Kaplan-Meier curves demonstrating differences in progression-free survival (PFS) (A and C) and overall survival (OS) (B and D) based upon high- and low-risk circulating tumor cell (CTC) classifications. Patients with elevated CTCs at baseline (A and B) and at first follow-up after one cycle of therapy (C and D) have significantly worse median PFS and OS compared with the corresponding patients with low CTCs. Source: Adapted from Ref. 25.

short median PFS and OS of 3 and 10 months, respectively. This is in comparison with patients with low/negative CTCs in whom PFS and OS were 7 and 22 months, respectively (Fig. 1). Thus, elevated CTCs at baseline identify a group of high-risk patients. Even more interesting, CTC values obtained after one cycle of therapy predicted which patients were likely on ineffective therapy. Patients with elevated CTCs after one cycle of therapy had median PFS and OS of approximately 2.1 and 8.2 months, respectively, when measured from baseline (Fig. 1). In contrast, patients with low CTCs had median PFS and OS of 7.0 and 22 months, respectively. These differences in PFS and OS were all highly statistically significant (P < 0.001) for patients receiving chemotherapy. For patients initiating hormonal therapy, baseline CTCs were not prognostic, but CTCs evaluated at first follow-up after initiating hormonal therapy did result in substantial differences in median PFS (2.3 vs. 8.3 months, P = 0.15) and median OS (10.9 vs. >18 months, P = 0.002). Although the PFS comparison was not statistically significant, it suggests that CTCs may be able to distinguish patients who are on ineffective hormonal therapy. The subset of patients starting hormonal therapy was smaller (n = 53) than the group starting chemotherapy (n = 109). So, the analysis in hormonal therapy patients was likely underpowered and requires further investigation. Because of the lack of strong statistical significance in the hormonal therapy group, the FDA cleared indication for the CTC assay is currently limited to women undergoing chemotherapy for metastatic breast cancer.

Further analysis of this data suggests that the prognostic value is independent of the line of chemotherapy. The original publication (25) presented combined data for all patients receiving any line of therapy. Approximately half of these patients were receiving first-line therapy, and a subsequent publication demonstrated that the prognostic information was the same in patients receiving first-line therapy (Table l) (31,32). In this report, 59 patients were initiating first-line chemotherapy. Using the cut-off of >5 CTCs, patients with elevated CTCs at baseline had significantly worse PFS (2.3 vs. 7.2 months, P = 0.046) and worse median OS (14.2 vs. >18 months, P = 0.024). Of these, 44 patients had CTC data from the first follow-up visit (three to four weeks) after initiating chemotherapy. The first follow-up CTC results were highly prognostic of PFS (2.0 vs. 8.2 months, P = 0.008) and OS (9.2 vs. >18 months, P = 0.0006), suggesting that patients who have elevated CTCs after one cycle of first line chemotherapy are on ineffective therapy.

It is particularly difficult to determine progression in women with non-measurable forms of metastatic breast cancer, such as bone-only disease. Preliminary data suggest that CTCs may also provide prognostic information in this population (33) (Table 1). To evaluate this population, 46 patients with non-measurable metastatic breast cancer underwent CTC evaluation at baseline and at first follow-up after initiating a new therapy. Patients with elevated CTCs > 5 CTC) at baseline had trends toward worse median PFS at 4.4 versus 9.5 months, although this did not reach statistical significance (P = 0.44). Analysis of CTCs at first follow-up demonstrated an even wider difference in median PFS (3.5 vs. 14.4 months, P = 0.032), which was statistically significant. Median OS had not been reached for either group at the time of presentation. Again, this suggests that patients with non-measurable disease who have elevated CTCs at first follow-up are likely on ineffective therapy.

TABLE 1 Patients with Elevated Circulating Tumor Cells Have Significantly Worse Outcomes as Measured by Progression-Free Survival and Overall Survival

Median PFS Median OS

TABLE 1 Patients with Elevated Circulating Tumor Cells Have Significantly Worse Outcomes as Measured by Progression-Free Survival and Overall Survival

Median PFS Median OS

CTC

count

CTC

count

n

>5

<5

P

>5

<5

P

CTCs at baseline

All patients (25,31)

177

2.7

7.0

<0.001

10.9

21.9

<0.001

Chemotherapy

54

2.3

6.8

<0.001

8.3

>18

<0.001

Hormonal therapy

118

8.1

8.3

0.44

>18

>18

0.09

First line therapy (32)

83

11.3

>18

<0.001

>18

>18

<0.001

Chemotherapy

23

2.3

7.2

0.0464

14.3

>18

0.235

Hormonal therapy

59

11.3

>18

0.148

>18

>18

0.576

Non-measurable disease (33)

46

4.4

9.5

0.44

19

>20

0.25

CTCs at first follow-up

All patients (25)

163

2.1

7

<0.001

8.2

22

<0.0001

Chemotherapy

53

2.3

6.8

0.002

8.3

>18

<0.001

Hormonal therapy

109

2.3

8.3

0.15

10.9

>18

0.002

First line therapy (32)

60

2.1

9.5

0.006

11.1

>18

0.001

Chemotherapy

15

2.0

8.2

0.008

9.2

>18

0.001

Hormonal therapy

44

11.3

>18

0.289

>18

>18

0.670

Non-measurable disease (33)

40

3.5

14.4

0.032

NR

NR

NR

Abbreviations: CTC, circulating tumor cell; NR, not reported; PFS, progression-free survival; OS, overall survival.

Abbreviations: CTC, circulating tumor cell; NR, not reported; PFS, progression-free survival; OS, overall survival.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment