Management and Outcome of HER2-Positive Early Breast Cancer Treated With or Without Trastuzumab in the Adjuvant Trastuzumab Era

Original Study

Management and Outcome of HER2-Positive Early Breast Cancer Treated With or Without Trastuzumab in the Adjuvant Trastuzumab Era Carlo Palmieri,1 Deep Shah,1 Jonathan Krell,1 Ondrej Gojis,1 Katy Hogben,2 Pippa Riddle,1 Riz Ahmad,1 Tri Tat,3 Kevin Fox,4 Andrew Porter,4 Sarah Mahmoud,5 Stephanie Kirschke,5 Sami Shousha,6 Mihir Gudi,6 R. Charles Coombes,1 Robert Leonard,1 Susan Cleator7 Abstract Background: Adjuvant trastuzumab (AT) is known to significantly improve survival of women with HER2⫹ early breast cancer. This study explores the use and nonuse of AT in early breast cancer, as well as the efficacy in a neoadjuvant and adjuvant population, within a routine clinical setting. Patients and Methods: Histopathology reports of invasive breast cancer resected at Imperial College Healthcare NHS Trust (ICHT) between January 2006 and December 2008 were reviewed. HER2⫹ patients were identified and their case notes reviewed. In addition, patients who received AT at our center but underwent surgery elsewhere were included in the efficacy and safety analyses. Results: The local HER2⫹ rate was 13.1%, with 54.5% of these patients receiving AT. A total of 128 patients received AT (85 local and 43 referrals from elsewhere). Neoadjuvant chemotherapy (CT) followed by postoperative AT was associated with a significantly increased risk of recurrence compared with adjuvant CT and then AT (hazard ratio [HR] 18.6 [95% CI, 1.8 –152.2]; P ⫽ .013). The proportion of patients who were disease free at 3 years from primary therapy was 96.4% (95% CI, 89.8%–100%) for adjuvant therapy, compared with 72.0% (95% CI, 56.5%–91.6%) for neoadjuvant therapy. AT was omitted in 49 HER2⫹ patients; the main reason for AT omission was clinical judgment that the breast cancer was low risk. Patients treated with AT had a significantly decreased risk of recurrence (HR 0.27 [95% CI, 0.08 – 0.97]; P ⫽ .04) compared with the untreated patients. The majority of untreated relapses were in patients in whom there was an original intent to use AT. The proportion alive at 3 years for adjuvant CT, neoadjuvant CT, and untreated AT was 100%, 74.5%, and 92.7% respectively. Conclusion: The overall efficacy and safety of AT in our routine clinical setting is comparable to the large randomized trials. HER2⫹ patients who underwent neoadjuvant CT had a significantly increased risk of disease recurrence compared with patients treated with adjuvant CT followed by trastuzumab. Untreated patients had an increased risk of recurrence. Clinical Breast Cancer, Vol. 11, No. 2, 93-102 © 2011 Elsevier Inc. All rights reserved. Keywords: Breast, Trastuzumab, Untreated, Neoadjuvant, Adjuvant

Introduction Breast cancer is the most common female malignancy in the developed world and is known to be a heterogeneous disease.1 Overex1

Cancer Research UK Laboratories, Division of Cancer, Imperial College London, UK Department of Surgery, Imperial College Healthcare NHS Trust, London, UK 3 Statistical Advisory Service, Imperial College London, London, UK 4 Department of Cardiology, Imperial College Healthcare NHS Trust, London, UK 5 Pharmacy Department, Imperial College Healthcare NHS Trust, London, UK 6 Department of Pathology, Imperial College Healthcare NHS Trust, London, UK 7 Breast Unit, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 2

Submitted: Jun 20, 2010; Revised: Sep 21, 2010; Accepted: Sep 24, 2010 Address for correspondence: Carlo Palmieri, MD, Cancer Research UK Laboratories, Division of Cancer, Imperial College London, Du Cane Road, London W12 0NN, UK Fax: ⫹44 20 8383 5830; e-mail contact: [email protected]

1526-8209/$ - see frontmatter © 2011 Elsevier Inc. All rights reserved. doi: 10.1016/j.clbc.2011.03.001

pression of HER2 accounts for 15% to 30% of breast cancers2,3 and is generally associated with a poor prognosis.2,4-7 The pivotal phase III trial demonstrated that addition of HER2 blockade with trastuzumab to standard CT regimens significantly increased time to disease progression and overall survival in women with metastatic breast cancer.3 Subsequent adjuvant phase III trials with trastuzumab therapy administered concomitant with or sequential to CT in HER2⫹ early breast cancer showed improvements in disease-free and overall survival and established adjuvant trastuzumab (AT) as a standard of care for HER2⫹ breast cancers that require CT;8-11 1 study has been reported to be negative.7 Controversy remains about the utility of trastuzumab in low-risk disease,12-17 and there are no published data regarding its use without CT in the adjuvant setting. In the phase III

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Management and Outcome of HER2-Positive Early Breast Cancer Table 1 Local HER2 Positive Rate for Charing Cross and St Mary’s Hospital for Early Invasive Breast Cancer for 2006-2008

but received adjuvant treatment at ICHT were included in the efficacy and safety analyses but were excluded from the HER2⫹ analysis.

Data Collection and Analysis Positivity Rate Year

Charing Cross Hospital

St. Mary’s Hospital

HER2 Patients/ Total Patients

%

HER2ⴙ Patients/ Total Patients

%

2006

39/296

13.2

14/123

11.4

2007

39/280

13.9

18/117

15.4

2008

33/280

11.8

13/95

13.7

111/856

13.2

45/335

13.4

Total

ⴙ

Combined positivity rate: 156/1192 ⫽13.1%

trials, AT was well tolerated. The main documented adverse effect was cardiac toxicity, with decreases in left ventricular ejection fraction (LVEF) and other cardiac events (including rare occurrences of symptomatic heart failure) reported in 2.2% to 14% of patients randomized to trastuzumab, although the definition of a cardiac event varied among studies.7,8,10,12,18,19 To date, all the published experience of AT has come from wellcontrolled and well-funded clinical trials. No data have yet been published on its routine use, and no information is available on HER2⫹ cohorts in whom a decision to omit AT has been made since publication of the pivotal phase III trials. To investigate the use, omission, efficacy, sequencing, and safety of adjuvant trastuzumab in a routine clinical setting, we reviewed all HER2⫹ early breast cancers diagnosed and managed in the Imperial College Healthcare NHS Trust Breast Unit. In addition, we investigated the reasons that untreated HER2⫹ patients did not receive AT and their outcomes.

Patients and Methods Identification of HER 2-positive Patients All histopathology reports of invasive breast cancer resected between January 2006 and December 2008 at Imperial College Healthcare NHS Trust (ICHT) (Charing Cross and St Mary’s Hospital) were reviewed. The total numbers of breast cancers were recorded, and patients presenting with metastatic disease were excluded. All HER2⫹ cancers were identified and included in the study. HER2 was determined by immunohistochemistry (IHC) at ICHT and scored from 0 to 3⫹. Scoring of 2⫹ was assigned when there was weak to moderate complete membrane staining in ⬎ 10% of tumor cells, whereas scoring of 3⫹ consisted of uniform intense membrane staining of ⬎ 10% of invasive tumor cells. Silver in situ hybridization (SISH) or fluorescence in situ hybridization (FISH) analyses were carried out for all HER2 IHC 2⫹ samples. HER2 was considered amplified if the ratio of HER2 gene– chromosome 17 was ⱖ 2.0. SISH and FISH analyses were conducted at the Charing Cross Hospital and University College Hospital, respectively.

Identification of Additional Patients for Efficacy and Safety Analyses ICHT also acts as a treatment center for other West London centers. Patients who received surgical treatment at these other centers

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Data collected for HER2⫹ patients included patient age, date and type of surgery, grade and size of tumor, lymph node involvement, and estrogen and progesterone receptor status. For patients undergoing neoadjuvant CT, tumor size was based on pretreatment measurements; radiologic (mammography/ultrasonography) measurements were recorded when possible and clinical measurements were used when radiologic measurements were not available. Clinical notes were reviewed to obtain details on CT and radiotherapy (RT) treatment and the temporal relationship to initiation of trastuzumab. Details of disease-specific relapse and death, as well as non– breast cancer deaths, were also recorded. Patients entered into the ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) trial were excluded from the efficacy analysis. In the efficacy analysis of disease-free survival (DFS), an event was defined as new primary breast cancer, local recurrence, or distant relapse. The radiologic date of diagnostic confirmation of recurrent disease was used as the date of relapse. DFS was calculated from the date of initial primary therapy (surgery for untreated patients or those receiving adjuvant therapy or initiation of CT for patients receiving neoadjuvant therapy) for both groups, as well as from the time of first infusion of trastuzumab to an event for the treated cohort. Patients without recurrence at the date of last follow-up or treatment were censored. Data were censored on November 15, 2009.

Cardiac Monitoring Patients were assessed using a Philips iE33 ultrasound scanner (Philips, Andover, MA) using second harmonic imaging with a 1–5 MHz phased array transducer. Ejection fraction was determined from the apical 4- and 2-chamber views using the modified Simpson’s biplane method of summation of discs. In some cases ejection fractions were estimated following multiple gated acquisition scans. Cardiotoxicity was defined as a decrease in LVEF of ⱖ 10% from baseline or a decrease to an LVEF ⬍ 50% at any time.

Statistical Analyses Association of baseline characteristics with subsequent treatment pathways was tested using a ␹2 test with Yates’ continuity correction. Wald confidence intervals were calculated for unadjusted death rates. Survivor functions were calculated using the Kaplan-Meier method and tested using a log-rank test. Adjusted estimates of hazard ratios (HRs) were calculated using Cox proportional hazards regression and tested using the Wald method. Confidence intervals (CIs) for estimates were calculated throughout.

Results HER2-positivity Rate Between 2006 and 2008, a total of 1,192 invasive early breast cancers were diagnosed at ICHT (Charing Cross and St Mary’s Hospital). There were 156 cases of HER2⫹ breast cancer over this period, giving a positivity rate of 13.1%. Over this 3-year period, the positivity rate varied from 11.4% to 15.4% (Table 1).

Carlo Palmieri et al Table 2 Clinicopathologic Features of HER2ⴙ Patients Adjuvant (N ⴝ 87) Age: Years, Median (Range)

Neodjuvant (N ⴝ 41) 52.3 (31.1–80.7)

64.3 (36.8–90.3)

⬍ 35 years, n (%)

2 (1.6)

0

35–49 years, n (%)

52 (40.6)

5 (10.2)

50–59 years, n (%)

44 (34.4)

16 (32.7)

⬎ 60 years, n (%)

30 (23.4)

28 (57.1)

Histologic Type: n (%) Invasive ductal carcinoma

85 (97.7)

39 (95.1)

48 (98.0)

Invasive mucinous carcinoma

1 (1.1)

0

1 (2.0)

Micropapillary carcinoma

1 (1.1)

1 (2.4)

0

Invasive lobular carcinoma

0

1 (2.4)

0

Tumor Size: n (%) ⬍ 20 mm

34 (39.1)

2 (4.9)

24 (49.0)

20–49 mm

47 (54.0)

23 (56.1)

16 (32.6)

ⱖ 50 mm

5 (5.8)

16 (39.0)

7 (14.3)

Not available

1 (1.1)

0

2 (4.1)

Grade I

1 (1.1)

1 (2.4)

3 (6.1)

Grade II

32 (36.8)

13 (31.7)

14 (28.6)

Grade III

54 (62.1)

27 (65.9)

32 (65.3)

Positive

45 (51.7)

25 (61.0)

14 (28.6)

Negative

42 (48.3)

15 (36.6)

33 (67.3)

0

1 (2.4)

2 (4.1)

ER -ve and PR -ve

38 (43.7)

17 (41.5)

20 (40.8)

ER -ve and PR ⫹ve

3 (3.5)

0

0

0

1 (2.4)

0

ER ⫹ve and PR ⫹ve

32 (36.8)

17 (41.5)

17 (34.7)

ER ⫹ve and PR -ve

13 (14.9)

5 (12.2)

10 (20.4)

Tumor Grade: n (%)

Nodal Status: n (%)

Not available Hormone Receptor Status: n (%)

ER -ve and PR unknown

ER ⫹ve and PR unknown

0

0

2 (4.1)

1 (1.1)

1 (2.4)

0

Breast-conserving procedure

40 (46.0)

13 (31.7)

19 (38.8)

Mastectomy

45 (51.7)

28 (68.3)

30 (61.2)

Unavailable

2 (2.3)

0

0

Missing Surgery: n (%)

pCR: n (%)

9/44 (20.4)*

Chemotherapy Regimen: n (%) CMF

1 (1.1)

AC

3 (3.4)

FEC

40 (46.0)

17 (41.4)

4 (8.2)

FEC-D

24 (27.6)

13 (31.7)

2 (4.1)

1 (1.1)

1 (2.4)

Taxane alone

2 (4.1)

Capecitabine alone

1 (2.0)

Neo-tAnGo A1 (EC ¡ T)

0

2 (4.9)

Neo-tAnGo A2 (T ¡ EC)

0

1 (2.4)

1 (2.0)

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Management and Outcome of HER2-Positive Early Breast Cancer Table 2 Continued

Neo-tAnGo B1 (EC ¡ GT)

Adjuvant (N ⴝ 87)

Neodjuvant (N ⴝ 41)

0

1 (2.4) 5 (12.2)

Neo-tAnGo B2 (GT ¡ EC)

0

TACT 2 arm 1 (E ¡CMF)

8 (9.2)

TACT 2 arm 2 (EAC ¡ CMF)

4 (4.6)

TACT 2 arm 4 (EAC ¡ X)

3 (3.3)

No chemotherapy

1 (1.1)

Unavailable

2 (2.3)

1 (2.4)

Endocrine Therapy: n (%) Tamoxifen

48 (68.6)

9 (31.0)

Aromatase inhibitor

8 (11.4)

1 (3.4)

Tamoxifen then aromatase inhibitor

11 (15.7)

9 (31.0)

Ovarian function suppressive therapy

1 (1.4)

1 (3.4)

Unknown

2 (2.9)

9 (31.0)

Abbreviations: AC ⫽ Adriamycin, cyclophosphamide; CMF ⫽ cyclophosphamide, methotrexate, 5-fluorouracil; D ⫽ docetaxel; E ⫽ epirubicin; EAC ⫽ accelerated epirubicin; EC ⫽ epirubicin and cyclophosphamide; ER ⫽ estrogen receptor; FEC ⫽ 5-fluorouracil, epirubicin, and cyclophosphamide; FEC-D ⫽ FEC and docetaxel; GT ⫽ gemcitabine and paclitaxel; pCR ⫽ complete pathological response; PR ⫽ progesterone receptor; T ⫽ paclitaxel; X ⫽ capecitabine. * All patients receiving neoadjuvant therapy treated or untreated with adjuvant trastuzumab.

Management of Early HER2-positive Breast Cancers

Untreated Patients Exposed to Adjuvant Chemotherapy

With regard to the locally diagnosed HER2⫹ patients, 54.5% (85/156) received AT at ICHT; 12.2% (19/156) received treatment elsewhere or were recently diagnosed and no MDT decision made; 1.3% (2/156) were randomized into the ALTTO trial; 1 patient died of pancreatic cancer before commencing any adjuvant therapy for breast cancer; and 31.4% (49/156) did not receive AT. An additional 43 patients were referred to ICHT for systemic therapy that included AT. In total 128 patients received AT with a loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks for 1 year.

Of the AT-untreated group receiving CT (n ⫽ 10), in 7 (70%) patients the reason for omission of AT was a CT-related reduction in LVEF.

Patient Characteristics Patient characteristics for trastuzumab-treated and untreated populations are summarized in Table 2. The median age for the treated and untreated cohorts was 52.3 years (range, 31.1– 80.7 years) and 64.3 years (range, 36.8 –90.3 years), respectively. Compared with the untreated cohort, patients treated with trastuzumab were significantly younger (P ⱕ .001), were more likely to have a tumor ⱖ 20 mm in diameter (P ⫽ .016), and were more likely to be lymph node–positive (P ⫽ .0051) There was no statistical difference between the 2 groups based on grade or estrogen receptor (ER) or progesterone receptor (PR) status (Table 3). Only 20.4% (10/49) of the trastuzumab-untreated patients received systemic CT, compared with all but one of the trastuzumab-treated cases in whom CT could not be given because of preexisting renal failure.

Neoadjuvant Cases The complete pathologic response (pCR) rate in patients receiving neoadjuvant CT was 20.5% (9/44 patients). In only 1 patient was trastuzumab used in combination with neoadjuvant CT; in all other cases AT was given after surgery.

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Reasons for Patients Not Receiving Adjuvant Trastuzumab The predominant reason for women not receiving AT was that they were deemed to be at low risk of recurrence by the treating physician and made up 32.7% (16/49) of untreated cases. Age accounted for 24.5% (12/49) and patients declining adjuvant therapy accounted for a further 22.4% (11/49) of patients not receiving AT. The median age was 82 years (range, 72–90 years) in the group in which age was the determining factor. Cardiac issues in the form of a low baseline ejection fraction accounted for omission of AT in 14.3% (range, 7/49) of patients. This group was composed of patients in whom the ejection fraction dropped as a result of CT. The reasons and clinicopathologic features of these untreated groups are summarized in Table 4.

Time to Initiation of Trastuzumab from Last Definitive Breast Cancer Treatment Of the AT-treated patients, 71% (92/128) also received breast RT. AT was initiated after completion of RT in 43% (40/92) of patients; with a median time of 27.5 days (range, 2–183 days) from completion of RT to initiation of trastuzumab. Fifty-seven percent (52/92) of patients commenced AT during breast RT. In the 31% (40/128) of patients who did not receive RT, the median time from completion of CT (or surgery for patients receiving neoadjuvant treatment) to commencing trastuzumab was 27.5 days (range, 1–123 days).

Carlo Palmieri et al Table 3 Analysis of Risk of Untreated vs. Treated With Trastuzumab Variable

Adjuvant Trastuzumab n (%)

Relative Risk (95% CI)*

Untreated (N ⴝ 49)

Treated (N ⴝ 128)

Untreated

Treated

ⱖ 60 years

28 (48.3)

30 (51.7)

5.70 (2.36, 13.73)

0.57 (0.44, 0.73)

50–59 years

16 (26.7)

44 (73.3)

3.15 (1.23, 8.04)

0.80 (0.68, 0.95)

⬍ 50 years

5 (8.5)

54 (91.5)

1.0

1.0

7 (25.0)

21 (75.0)

0.63 (0.31, 1.27)

1.25 (0.92, 1.68)

⬎ 20–50 mm

16 (18.6)

70 (81.3)

0.47 (0.27, 0.80)

1.36 (1.08, 1.71)

ⱕ 20 mm

24 (40.0)

36 (60.0)

1.0

1.0

3

32 (28.3)

81 (71.7)

1.07 (0.65, 1.76)

0.98 (0.81, 1.18)

1 or 2

17 (26.6)

47 (73.4)

1.0

1.0

Age

P 9.2e-6

Size ⬎ 50 mm

Test*

0.016

Grade

0.94

Nodal Status

0.0051

Positive

14 (16.7)

70 (83.3)

0.45 (0.26, 0.79)

1.32 (1.09, 1.58)

Negative

33 (36.7)

57 (63.3)

1.0

1.0

Positive

29 (30.2)

67 (69.8)

1.19 (0.73, 1.94)

0.93 (0.78, 1.12)

Negative

20 (25.3)

59 (74.7)

1.0

1.0

ER Status

0.58

PR Status

0.64

Positive

17 (24.6)

52 (75.4)

0.85 (0.51, 1.41)

1.06 (0.89, 1.28)

Negative

30 (29.1)

73 (70.9)

1.0

1.0

Abbreviations: ER ⫽ estrogen receptor; PR ⫽ progesterone receptor. * Adjusted estimates of hazard rate ratios were calculated using Cox proportional hazards regression and tested using the Wald test.

Outcome: Treated Cohort The length of follow-up after primary therapy of the 128 treated patients ranged from 5.3 to 45.7 months (median, 25.1 months). During follow-up, 10 breast cancer events occurred in the AT cohort, with 87.5% (95% CI, 79.6%-96.1%) of patients disease free at 3 years after primary therapy (Figure 1A). Of note, 90% (9/10) of the disease-free events were in patients treated neoadjuvantly despite the total person-time follow-up being half that of the adjuvant group. Therefore 22% (9/41) of patients in the neoadjuvant CT group had relapsed compared with 1.1% (1/87) of the adjuvant CT group. The pCR rate was 11% (1/9 patients) in those who relapsed after neoadjuvant CT. In these treated patients 3 years after primary therapy, 96.4% (95% CI, 89.8%–100%) of AT-treated patients were disease free compared with 72.0% (95% CI, 56.5%–91.6%) of the patients receiving neoadjuvant treatment (Figure 1B). The median time to disease recurrence from first infusion of trastuzumab was 8.5 months (range, 2.2–25.8 months). Three years after the first infusion of trastuzumab, 97% (95% CI, 91.3%–100%) of patients treated adjuvantly were disease free compared with 67% (95% CI, 49%–91.7%) of those treated neoadjuvantly (Figure 1C). Taking into account group differences in person-time denominators, age at primary therapy, tumor size, nuclear grade, nodal and ER status, patients who had neoadjuvant CT had a significantly increased risk of recurrence (HR 18.6; [95% CI, 1.8 –152.2]; P ⫽

.013) compared with those who received adjuvant CT. Five breast cancer–specific deaths were recorded, with no deaths from other causes. The cancer-specific overall survival was 89.6% (95% CI, 79.8%–100%) at 3 years, with all deaths recorded to date in the neoadjuvant group. The 3-year survival was 100% for patients treated adjuvantly compared with 74.5% (95% CI, 55.2%– 100%) for the neoadjuvant group (Figure 1D). Although all 5 deaths in the treated cohort occurred in patients treated neoadjuvantly, no reliable estimate of difference from patients treated adjuvantly could be obtained.

Outcome: Untreated Cohort For the 49 untreated HER2⫹ patients, the length of follow-up after primary therapy ranged from 0.4 to 43.6 months (median, 18.2 months). During follow-up, 5 breast cancer events occurred, with 86.7% (95% CI, 76.2%–98.6%) of patients still disease free at 3 years after primary therapy (Figure 1A). After adjustment for age at primary therapy, tumor size, nuclear grade, nodal and ER status, patients who were treated with AT (adjuvant and neoadjuvant CT) had a significantly decreased risk of recurrence (HR 0.27 [95% CI, 0.08 – 0.97]; P ⫽ .04) compared with those who were untreated. However 80% (4/5) of relapses occurred in patients in whom there was an original intent to treat with AT but factors subsequently intervened that prevented such treatment. With regard to overall survival, the proportion still alive at 3 years was similar, with 92.7%

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Management and Outcome of HER2-Positive Early Breast Cancer Table 4 Reasons for Early Breast Cancer Patients Not Receiving Adjuvant Trastuzumab Therapy Reason

Number n (%) N ⴝ 49

Clinicopathologic Details

Breast cancer considered low risk by treating physician

16 (32.7)

Median age 64.3 years (range, 36.8–74.6) Intermediate grade DCIS ⫹ microinvasion: 1 High-grade DCIS ⫹ microinvasion: 5 Median tumor size (excl microinvasive disease): 3.5 mm (range, 1–20) Lymph node positive: 0* Grade 1: 1 Grade 2: 5 Grade 3: 10

Age

12 (24.5)

Median age: 82.0 years (range, 71.9–90.3) Median tumor size: 24 mm (range, 9.3–65) Lymph node positive: 58% (7/12)* Grade 2: 2 Grade 3: 10

Patient declined treatment

11 (22.4)

Median age: 56.4 years (range, 48.2–68.1) Median tumor size: 16.5 mm (range, 7–39) Lymph node positive: 18% (2/11) Grade 1: 1 Grade 2: 5 Grade 3: 5

Low ejection fraction/ cardiac

7 (14.3)

Median age: 58.2 years (range, 50.9–81.6) Median tumor size: 25 mm (range, 15–86) Lymph node positive: 29% (2/7) Grade 1: 1 Grade 2: 2 Grade 3: 4

Traveled to country with no access to drug

1 (2.0)

Age 55.2 years, 50 mm, grade 3, node positive

Incorrect histopathologic data recorded

1 (2.0)

Age 71.9 years, 59 mm, grade 3, node positive

No reason documented

1 (2.0)

Age 55.8 years, 31 mm, grade 3, node-positive

Abbreviation: DCIS ⫽ ductal carcinoma in situ. * Lymph node status unknown in 1 case.

(95% CI, 85.1%–100%) AT-untreated patients and 89.6% (95% CI, 79.8%–100%) AT-treated alive patients (Figure 1E).

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Cardiac Safety During Trastuzumab Therapy The overall range of changes seen in LVEF across all echocardiograms obtained during the study was –39% to ⫹18%. Cardiotoxicity was observed in 8.6% (11/128) of treated patients: 81% (9/11) of these patients were asymptomatic and cardiotoxicity was detected by echocardiography. However 19% (2/11) of cases of cardiotoxicity were symptomatic with congestive heart failure (1.6% of all treated patients). In the patients with cardiotoxicity, the absolute drop in LVEF ranged from –39% to –10%. Cardiotoxicity was detected at a median of 9 cycles (range, 3–16 cycles). Trastuzumab treatment was completed in 36.4% (4/11) of patients. One patient who discontinued trastuzumab treatment subsequently had relapse of disease.

Discussion This is the first report of the use or omission of AT in an HER2⫹ population in the trastuzumab era with associated outcomes. In addition, efficacy data are presented on the sequence of neoadjuvant CT followed by postoperative AT. Unlike previous data sets, ours is derived from clinical practice in a publically funded hospital. Our local HER2⫹ rate, assessed in 2 separate laboratories, ranged from 11.8% to 15.4% across the 3 years, with an overall rate of 13.1%. This HER2⫹ rate is similar to that reported by others.20,21 The HERA trial was the largest European AT trial and the United Kingdom was a major participant. Thus after publication of HERA,9 guidance in the UK was for AT to be used per the HERA design (ie, on completion of all adjuvant therapies). In the HERA trial, randomization was required within 7 weeks of the last CT treatment or 6 weeks from the end of RT or definitive surgery, whichever occurred later. In our cohort, the median time to starting AT was 27.5 to 28 days from the last definitive therapy. No previous data have been published on time to initiation of AT, and these data indicate that in a routine clinical setting, sequential trastuzumab is commenced promptly and falls within the time frame used in the HERA trial. Of note, 53% of patients commenced AT while receiving RT. The reason for this is unclear but may reflect a feeling that given the targeted nature of the agent and the poor prognosis of this patient group or specific features of particular patients, initiation of AT before completion of RT was warranted. In the AT-treated cohort at a median follow-up of 25.1 months (range, 5.3– 45.7 months), 87.5% of patients were disease free at 3 years and the cancer-specific overall survival rate was 89.6%. This outcome is similar to the HERA study 3-year disease-free and overall survival rates of 80.6% and 92.4%, respectively.9,19 Within our CT-treated cohort, 30% of patients received neoadjuvant therapy compared with 10.5% of the study population in the HERA trial.9 It is this neoadjuvant group that accounts for 90% (9/10) of the recorded DFS events and for all the deaths recorded to date. Patients treated neoadjuvantly had a significantly higher HR for disease recurrence compared with the adjuvant group, with 96.4% of patients receiving adjuvant treatment disease free compared with 72.0% of the patients receiving neoadjuvant treatment 3 years after primary therapy. The pCR in the neoadjuvant group was similar to that in the CT-only arm in published neoadjuvant trastuzumab studies.22,23 No efficacy data are available on the sequence of neoadjuvant CT

Carlo Palmieri et al FIGURE 1 (A) Disease-free Survival (DFS) From Initiation of Primary Therapy In Untreated Vs. Treated Patients. (B) DFS From Initiation of Primary Therapy In Untreated Vs. Adjuvant Vs. Neoadjuvant Treatment. (C) DFS From Initiation of Trastuzumab Adjuvant Vs. Neoadjuvant Treatment. (D) Overall Survival From Initiation of Primary Therapy In Untreated Vs. Neoadjuvant Vs. Adjuvant Chemotherapy (CT). (E) Overall Survival From Initiation of Primary Therapy In Untreated Versus Treated Patients

1.0 |||

A

||||| | ||||

|||||||

|||

||||||||||

|||| |||||

0.9

|||||||||||||| | ||||||||||||||

||||||||||| |||||

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|||| ||||| |||||| ||||||||||

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|||

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0.8

Proportion Disease Free

0.7 0.6 0.5 3-year proportion disease free (%) U 86.7% (76.2 to 98.6%) T 87.5% (79.6 to 96.1%)

1-year proportion disease free (%) U 93.1% (85.8 to 100%) T 98.3% (96.1 to 100%)

0.4 0.3

Group proportion with subject censoring mark

0.2 0.1

|

Untreated (U)

|

Trastuzumab (T)

0.0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

46

Follow up time since primary therapy (Months) Group

Patients at risk

Untreated:

49

47

46

40

34

29

24

19

17

10

5

4

1

1

1

0

Trastuzumab:

128

128

127

125

114

106

95

77

63

52

38

25

17

10

4

0

B

1.0 | |

||

| || |||| | | | || | | || | |

| | |

0.9

| | | | | ||| |||| | |||| | || || | | | || | | || | | | | || | | | | | | ||| | | | | ||| | | | ||| | | | | |

|| | | || |

|| | | | |||| |

|||

|

| ||

|

||

0.8

Proportion Disease Free

||

|| ||

|| |

||

| ||

0.7

|

|

|

|

|

|

||

|

0.6 0.5

1-year proportion alive (%) U 93.1% (85.8 to 100%) N 95.1% (88.8 to 100%) A 100%

0.4

3-year proportion alive (%) U 86.7% (76.2 to 98.6%) N 72.0% (56.5 to 91.6%) A 96.4% (89.8 to 100%)

0.3

Group proportion with subject censoring mark

0.2

| | |

0.1

Untreated (U) Neoadjuvant (N) Adjuvant (A)

0.0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

46

Follow up time since primary therapy (Months) Group

Patients at risk

Untreated:

49

47

46

40

34

29

24

19

17

10

5

4

1

1

1

0

Neoadjvant:

41

41

41

41

38

34

31

26

18

16

12

9

7

5

3

0

Adjuvant:

87

87

86

84

67

72

64

51

45

36

26

16

10

5

1

0

followed by postoperative AT; given that AT was not the standard of care when these randomized studies of neoadjuvant trastuzumab were conducted, the vast majority randomized to CT only in these

studies did not receive postoperative AT.22,23 An indirect comparison suggests that neoadjuvant CT followed by postoperative AT is inferior to concurrent CT and trastuzumab.22,23 This is plausible

Clinical Breast Cancer April 2011

99

Management and Outcome of HER2-Positive Early Breast Cancer FIGURE 1 (continued)

1.0 |

C

| || |

||||

|| ||

|| ||| | | |||| ||||

| | | | ||

| | | | || | || || || |

|

0.9

||| |||||

| ||

| |

|

|

|

| |

|| | || | | |

0.8

| |

Proportion Disease Free

| | | || |

|| |

|

0.7

|

|

| |

|

0.6 0.5

3-year proportion disease free A 97.0% (91.3 to 100%) N 67.0% (49.0 to 91.7%)

1-year proportion disease free (%) A 100% N 84.7% (74.1 to 96.8%)

0.4 0.3

Group proportion with subject censoring mark | Adjuvant (A)

0.2 0.1

|

Neoadjuvant (N)

0.0 0 Group Untreated: Trastuzumab:

3

6

9

12

15

21

24

27

30

33

36

40

Patients at risk 87 81 76 41 37 36

72 33

58 28

48 22

33 14

19 11

14 7

6 5

2 3

1 1

0 0

1.0 | |

D

| | ||||

| |||||| | || | || | ||

|

| | ||

0.9

| | || | ||| |||| | |||| | || || | | | || | | || | | | | || | | | | | | | || || | | |||| | | | | | | |||

|| | || | || | | ||| ||

|| | | | |||| | | ||| |

|||

|| ||

| || || |

| |

0.8 |

|

|

|

|

| ||

|

Proportion Alive

0.7 0.6 0.5

18 3-year proportion alive (%) 1-year proportion alive (%) 92.7% (85.1 to 100%) (85.1 to U 92.7% Follow up100%) time since start of trastuzumabU (Months) N 74.5% (55.2 to 100%) N 100% A 100% A 100%

0.4 0.3

40 18

Group proportion with subject censoring mark | Untreated (U)

0.2 0.1

|

Neoadjuvant (N)

|

Adjuvant (A)

0.0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

46

Follow up time (Months) Group

Patients at risk

Untreated:

49

47

46

40

34

30

25

20

17

10

5

4

1

1

1

0

Neoadjvant: Adjuvant:

41 87

41 87

41 86

41 84

40 76

37 72

34 64

30 51

22 45

18 36

14 27

12 17

8 11

6 5

4 1

0 0

given that breast cancers treated neoadjuvantly are high risk and the addition of a further known predictor of poor outcome would compound this already poor prognosis. Therefore the prompt com-

100

Clinical Breast Cancer April 2011

mencement of a targeted treatment soon after diagnosis would be expected to have a greater impact on outcome in addition to any potential synergy that may occur with CT.

Carlo Palmieri et al FIGURE 1 (continued)

1.0

E

| |

| | ||||

| || |||| | ||

||

|| | || | | ||

0.9

| | | | | | ||||||| | ||| | | | | ||| | ||| | || | | | | ||| | | | | || | | | | |||| | || | | | | || || | | ||| || | | | |||| | ||| | || | | | |||| || | | |

| | | || | || ||

|

0.8

Proportion Alive

0.7 0.6 0.5

3-year proportion alive (%) U 92.7% (85.1 to 100%) T 89.6% (79.8 to 100%)

1-year proportion alive (%) U 92.7% (85.1 to 100%) T 100%

0.4 0.3

Group proportion with subject censoring mark | Untreated (U) | Trastuzumab (T)

0.2 0.1 0.0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

46

Follow up time (Months) Group Untreated: Trastuzumab:

Patients at risk 30

25

20

17

10

5

4

1

1

1

0

128 128 127 125 116 109

49

47

46

40

34

98

81

67

54

41

29

19

11

5

0

The omission of AT in ‘low-risk’ HER2⫹ disease remains controversial, and disparate results have been reported. HER2 status has been reported to be an independent poor predictor of outcome in a number of retrospective studies of patients treated in the preadjuvant trastuzumab era.13,14,24,25 However others failed to find such correlations.12,15,16 Within our untreated cohort, low clinical risk or age were the predominant reasons for omitting AT. The decisions to omit AT in these patients, unlike previously published historical HER2 cohorts, were made with full knowledge about the design and results of the pivotal phase III data, with all decisions being made in a multidisciplinary team setting. The AT-treated cohort had a significantly decreased risk of recurrence compared with the untreated cohort. However, 80% (4/5) of the relapses in the untreated cohort to date were in patients in whom a decision had been made to give AT, but it was not given as a result of the patient moving to a health care system that did not provide it, a drop in LVEF after CT, or the patient declining therapy. Only 1 relapse has occurred in which a prospective decision was made to withhold AT. We acknowledge that this untreated cohort is small and the median follow-up is relatively short. This cohort is still being followed to assess their longterm outcomes. The rate of cardiotoxicity and the discontinuation rate were similar to those observed in the HERA study.18,19 No short-term cardiotoxicity was observed in patients who received concomitant RT,

as has been reported by others.26 Long-term follow-up of this cohort is required to assess any possible long-term cardiac toxicity.

Conclusions HER2⫹ rates were within the expected range, and the efficacy and toxicity of AT were comparable to those in the pivotal studies. Of note, the overwhelming majority of AT relapsers were patients receiving neoadjuvant treatment, and they had a significantly higher risk of recurrence. Based on these data and the published randomized neoadjuvant data, consideration should be given to the routine incorporation of neoadjuvant trastuzumab into clinical practice. ATtreated patients had a significantly decreased risk of relapse, although there was no difference in overall survival when compared with untreated cases.

Acknowledgments C.P. and R.C.C. wish to acknowledge the grant support they received from Cancer Research UK (Grant numbers: C20208/ A8667). O.G. wishes to acknowledge grant support from the European Society of Medical Oncology and the Ministry of Education of the Czech Republic (Project “Oncology” MSM 0021620808). The Department of Oncology at Imperial College London/Imperial College HealthCare NHS Trust is an Experimental Cancer Medicine Centre (ECMC), which is supported by funds from Cancer Research UK and the Department of Health.

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101

Management and Outcome of HER2-Positive Early Breast Cancer The authors’ contributions were as follows: C.P. and S.C. conceived the study and participated in its design and coordination; they were involved in data analysis and drafted the manuscript. D.S., J.K., and O.G. carried out the data collection and data analysis. C.P., S.C., K.H., P.R., R.A., S.S., M.G., R.C.C., R.L., K.F., and A.P. provided patient data for the study. S.M. and S.K. provided data relating to trastuzumab treatment. T.T. undertook the statistical analysis. All authors read and approved the final manuscript.

Disclosures This work was supported by an unrestricted educational grant from Roche. There is no conflict of interest to declare.

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