Trastuzumab in breast cancer metastatic setting: a retrospective study of clinical predictors of exceptional responders

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Örebro University

School of Medical Sciences Degree project, 15 ECTS June 2019

Trastuzumab in breast cancer metastatic setting: a retrospective study of

clinical predictors of exceptional responders

Author: Emilia Thunborg Supervisor: Assoc Prof Antonis Valachis, MD, PhD

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Abstract

Background Currently, human epidermal growth factor 2 (HER2)- positive, metastatic breast

cancer is considered an incurable disease; however, a small group can remain in long-term remission with the use of anti-HER2 treatment. This small group of exceptional responders may be clinically cured.

Aim In this retrospective cohort study, the aim was to identify the rate of exceptional

responders to trastuzumab-based therapy and potential clinical predictive factors in a consecutive cohort of patients with HER2 metastatic breast cancer.

Methods Electronic medical records from 148 patients with HER2-positive metastatic breast

cancer that had received trastuzumab as a first line treatment were retrospectively evaluated. The patients included had been treated at three different hospitals in Sweden between 2010-2018.

Results In total, 24 patients (16.2%; 95% Confidence Interval (CI): 10.9 – 23.4%) were

classified as exceptional responders to trastuzumab-based therapy. Two clinical factors were potentially associated to exceptional responses: complete remission as best response in 1st line treatment was associated to higher probability (Odds Ratio (OR): 7.67; 95% CI: 2.63 - 22.33); presence of lymph node metastases with lower probability for exceptional response (OR: 0.35; 95% CI: 0.11 - 1.09)

Conclusion- A meaningful number of patients with HER2-positive metastatic breast cancer

are expected to be exceptional responders to trastuzumab-based therapy. The achievement of CR is an important predictive factor for exceptional responses. Additional studies preferably with a uniform and widely accepted definition of exceptional responses are warranted to confirm our findings and further investigate potential clinical and molecular predictors.

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Abbreviations

ALND- Axillary lymph node dissection BCS- Breast conserving surgery

CI- Confidence interval CR- Complete response CT- Chemotherapy ER-Estrogen receptor ET- Endocrine therapy

HER2- human epidermal growth factor receptor 2 KI-67- Cell cycle and tumour growth marker OR- Odds ratio

PAD- Pathological anatomical diagnosis PD- Progressive disease

PgR- Progesterone receptor PR-Partial response

PS- Performance status

PS at M1- Performance status at metastasis SD- Stable disease

SLNB- Sentinel lymph node biopsy TKR-Tyrosine kinase receptor

TNM- Classification of malignant tumours

Trastuzumab- a monoclonal antibody against HER2 WHO- World Health Organisation

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Introduction

Breast cancer is one of the most common types of cancer in Sweden [1,2], falling second only to prostate cancer[3,4]. In Sweden, 7800 women were diagnosed and 1400 women died in breast cancer as an underlying cause of death during 2017[3]. Of the 7800 women diagnosed in Sweden[3], 12% are estimated to be human epidermal growth factor 2 (HER2) – positive. HER2 also called ERBb2 or proto-oncogene Neu [5], is a four transmembrane receptor tyrosine kinase that mediates cell survival, cell growth and differentiation [6]. Its

overexpression and activation has traditionally been associated with poorer outcome, tumour growth and progression[5,7]. However, the natural history of HER2-positive breast cancer was altered by the implementation of trastuzumab, a humanised monoclonal antibody against HER2.

Trastuzumab revolutionised HER2- positive breast cancer treatment, increasing survival rates and decreasing 10 year mortality [8] leading to a survival that is not only comparable but even higher compared to HER2-negative metastatic disease [9,10].

Trastuzumab is frequently used concurrently with chemotherapy, because this combination has shown synergistic effect [8,9]. Most of the patients develop resistance to trastuzumab with a median time to disease progression of 12 months [11,12]. However, some patients have a long-term response to trastuzumab that exceeds by far the median time to disease progression [13,14]. These exceptional responders or long-term survivors could represent a subgroup of patients with metastatic breast cancer who might be cured by trastuzumab-based therapy. The true rate of exceptional responders to trastuzumab remains unknown. Furthermore, no clinical predictive factors for exceptional response have been identified [15].

Anti-HER2 treatment using the combination of chemotherapy and trastuzumab is a treatment associated with side effects [16,17] such as diarrhoea, nausea, fatigue and neurological symptoms [18]. Trastuzumab is generally well tolerated but one rare side effect is cardiotoxicity, ranging between asymptomatic left ventricular dysfunction to severe symptomatic cardiac failure [10,19]. Identifying patients with exceptional response to

trastuzumab-based therapy would enable a more individualised treatment approach that could limit the toxicity associated with these treatment strategies. The aim of this study was to analyse the rate of exceptional responders to trastuzumab in a consecutive cohort of patients with HER2-positive metastatic breast cancer and identify potential clinical predictive factors for exceptional response.

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Method

Study design

A retrospective cohort study was performed

Study cohort

The eligible patients were identified using an electronic database for oncologic treatment. All patients treated with trastuzumab as a first line of treatment due to HER2-positive metastatic breast cancer between 2010 – 2017 at Örebro University Hospital and between 2010-2018 at Uppsala University Hospital and Eskilstuna County Hospital were identified using an

electronic database for oncologic treatment. Inclusion criteria were: (1) patients with HER2-positive metastatic breast cancer that had received trastuzumab as a first line of treatment, (2) at least one trastuzumab dose should have been administered.

Patients were excluded if they received trastuzumab with curative intention, or if information was too scarce to be analysed. Male patients were excluded.

Data collection

The following data were collected from electronic medical records: age at diagnosis,

comorbidities according to Charlson Comorbidity index[20], diabetes mellitus, hypertensive disease, heart disease, TNM stage at primary diagnosis (stage 1 to 4), Elston tumour grade at diagnosis (grade 1 to 3) [21], primary treatment, ER-status, PgR-status, HER2-status, KI-67 status, PAD, date of recurrence, site of recurrence, number of metastatic location, change in PAD if any, length, weight, World Health Organisation (WHO) performance status (PS) at recurrence and during subsequent lines of treatment, therapy in subsequent lines of treatment, best tumour response, date of progression, date of treatment discontinuation, reason for discontinuation, trastuzumab related toxicity, death, date of death, cause of death.

Definitions and outcomes

Recently, the National Cancer Institute (NCI) proposed a definition of exceptional responders in oncology using 3 criteria: (1) patients that received a treatment in which < 10% of patients had a complete response (CR) or a durable (lasting at least 6 months) partial response (PR) based on clinical trial data; (2) patient that achieved either CR or PR with duration of at least 6 months; or (3) patients with sustained CR or PR for at least three times longer than the median duration of response from literature resources for that treatment [22]. For the definition of exceptional responders in the study, the proposed NCI criteria with 2

modifications based on the retrospective nature of the study and the type of cancer were used. Therefore, the 1st criterion was excluded as the study was a retrospective study and not a

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clinical trial, and the 2nd criterion was modified using a longer duration of response (12 months instead of 6 months) and only when CR was achieved considering the expected treatment outcome in breast cancer patients. The later modifications of the 2nd criterion are in accordance with the definition used in the AURORA trial which is dedicated to breast cancer patients [23]. For the 3rd criterion, a 12-month median duration of response in patients treated with trastuzumab-combined therapy was assumed.

Thus patients were defined as exceptional responders if they had CR for at least 1 year

(corresponding to the modified 2nd NCI criterion) or PR for at least 3 years (3rd NCI criterion after assumptions).

The primary outcome of interest was to analyse the rate of exceptional responders. Secondary outcomes were to identify clinical predictive factors in exceptional responders and to analyse the treatment pattern in each treatment line in the study cohort.

Statistical analysis

The data were analysed using SPSS version 25 (Statistical Packages for Social Sciences IBM, Chicago, II, USA). P-value < 0.05 was the cut-off for statistical significance.

Categorical variables were summarised using frequency and percentage, and continuous variables using median and range.

The association between patients or tumour characteristics and exceptional response was analysed using univariate logistic regression analysis. Odds ratios (ORs) and 95% Confidence Intervals (CIs) were obtained from logistic regression models.

Kaplan-Meier analyses of overall survival after the diagnosis of metastatic disease were performed for the whole cohort and divided in groups regarding complete remission on 1st line treatment or not, the latter complemented by logrank test.

Ethical considerations

Anonymized data were used for the analyses. The study has been approved by the Swedish Ethical Review Authority. (Reference numbers 2018/191-31/2 and 2019-01591). The ethical dilemma was the intrusion into electronic patients records. Careful consideration was taken to only include variables important to the study. All patient social security numbers were

anonymised and given ID-numbers. All patient data was presented on group level and therefore difficult to trace back to a specific individual.

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Results

Study cohort

The characteristics of the study population are shown in Table 1. In total, 148 patients were included in the study cohort. The median age at the time of metastasis was 54 years (range: 21-83 years). The most common metastatic site was bone (76 patients; 51.4%), followed by liver (50 patients; 33.8%).

Table 1 Characteristics of the study population(n=148).

Variables N (%) Site Örebro Uppsala Eskilstuna Missing 33(22.3) 61(41.2) 54(36.5) 0(0.0)

Age at dx, median (range) 54.00(21-83)

Charlson Comorbidity Index, median (range) 1(0-6)

Diabetes Mellitus No

Yes, without complications Missing 131(88.5) 10(6.8) 7(4.7) Hypertension No

Yes, without complications Yes, with complications Missing 109(73.6) 31(20.9) 1(0.7) 7(4.7) Heart disease Arrhythmia Angina Pectoris

Prior myocardial infarction Valve disease Heart failure Missing 6(4.1) 5(3.4) 2(1.4) 2(1.4) 1(0.7) 35(20.9) Histology Ductal Lobular Other Missing 122(82.4) 8(5.4) 7(4.7) 11(7.4) Type of surgery Mastectomy BCS No surgery Missing 93(62.8) 37(25.0) 16(10.8) 2(1.4) Type of axillary surgery

ALND SLNB None 98(66.2) 26(17.6) 20(13.5)

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8 Missing 4(2.8) pT (TNM, tumour size) 0 1 2 3 4 Missing 3(2.0) 31(20.9) 69(46.6) 17(11.5) 4(2.7) 24(16.2) Stage at Dx 1 2 3 4 Missing 21(14.2) 18(12.2) 64(43.2) 41(27.7) 4(2.7) ER-status Positive Negative Missing 86(58.1) 57(38.5) 5 (3.4) PgR-status Negative Positive Missing 89(60.1) 50(33.6) 9(6.1)

Age at metastasis, median (range) 58.50(24-89)

Time from diagnosis to recurrence in months, median (range) 22(0-366) WHO Performance status at metastasis

0-1 2-4 Missing 113(76.4) 18(12.2) 17(11.5) Elston grade 1-2 3 Missing 41(27.7) 82(55.4) 25(16.9) Metastatic site Visceral Skeletal Multiorgan Liver Lymph node Lung Other Skeletal only CNS Skin Missing 81(54.7) 76(51.4) 56(37.8) 50(33.8) 49(33.1) 46(31.1) 26(17.6) 22(14.9) 16(10.8) 7(4.7) 0(0.0)

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Abbreviations: BCS, Breast Conserving Surgery; ALND, Axillary Lymph Node Dissection;

SLND, Sentinel Lymph Node Dissection; ER-status, estrogen-receptor status; PgR-status, Progesterone-receptor status; CNS, Central Nervous System

Treatment pattern and response

The treatment pattern based on line of treatment is summarised in Table 2. Anti-HER2 treatment was combined with chemotherapy in 124 patients (83.8%) whereas 24 patients (16.2%) received endocrine therapy in 1st_{line. The rates of patients who received 2}nd_{, 3}rd_{, 4}th_,

and 5th lines of treatment were 75%, 57.4%, 39.9%, and 27%, respectively.

Table 2 Treatment pattern based on treatment line

Line of therapy N (%)

First line (all included patients received trastuzumab) Chemotherapy Docetaxel Vinorelbine Paclitaxel Other Combination Endocrine therapy Aromatase inhibitor Tamoxifen Fulvestran Total 124(83.8) 51(41.1) 41(33.1) 23(18.5) 6(4.8) 3(2.4) 24(16.2) 17(70.8) 5(20.8) 2(8.3) 148(99.9) Second line (n=111; 75.0%) Trastuzumab + vinorelbine Trastuzumab-emtansin Lapatinib + capecitabine

Trastuzumab + chemotherapy other than vinorelbine and capecitabine

Trastuzumab + endocrine therapy Trastuzumab + capecitabin Total 38(34.2) 19(17.1) 18(16.2) 16(14.4) 12(10.8) 8(7.2) 111(99.9) Third line (n=85; 57.4%)

Trastuzumab+ chemotherapy other than vinorelbine and capecitabin

Trastuzumab + endocrine therapy Trastuzumab + vinorelbine Trastuzumab + capecitabine Lapatinib + capecitabine Trastuzumab + emtansin 23(27.1) 14(16.5) 12(14.1) 11(12.9) 11(12.9) 10(11.8)

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10 Lapatinib + Endocrine therapy Trastuzumab + lapatinib Total 2(3.5) 1(1.2) 85(100.0) Fourth line (n=59; 39.9%)

Trastuzumab + chemotherapy other than vinorelbine and capecitabin Trastuzumab + Vinorelbine Trastuzumab + chemotherapy Lapatinib + Capecitabine Trastuzumab + capecitabine Trastuzumab + emtansin Trastuzumab + lapatinib Lapatinib + Endocrine therapy Total 15(25.4) 13(22.0) 11(18.6) 9(15.3) 5(8.5) 3(5.1) 2(3.4) 1(1.7) 59(100.0) Fifth line (n=40; 27.0%)

Trastuzumab + chemotherapy other than vinorelbine and capecitabine

Trastuzumab + emtansin

Trastuzumab + endocrine therapy Lapatinib + capecitabine

Trastuzumab + Vinorelbine Trastuzumab + capecitabine Lapatinib + Endocrine therapy Total 15(37.5) 5(12.5) 4(10.0) 4(10.0) 4(10.0) 3(7.5) 3(7.5) 2(5.0) 40(100.0)

In Figure 1, the response rates according to different lines of treatment in the metastatic setting are presented. Type of response is shown in different colours. Rates of CR and PR were higher in first line of treatment than during any other line of treatment. Rates of PD were higher during fourth and fifth lines of treatment. Rates of PR and SD were between 25 and 35% in later lines of treatment.

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Figure 1 Response rates according to different lines of treatment in metastatic setting Abbreviations: CR, Complete response; PR, Partial response; SD, Stable disease; PD,

Progressive disease

Clinical predictors of exceptional responses

Out of 148 patients in this cohort 24 (16,2%; 95% CI: 10.9 – 23.4%) obtained long-term remission.

Results of univariate analyses of clinical variables regarding potential associations to achievement of exceptional responses are seen in Table 3. CR as best response in 1st line treatment for metastatic disease was strongly associated to higher probability of exceptional response (OR: 7.67; 95% CI: 2.63-22.33). Presence of lymph node metastases was associated with lower probability of exceptional response (OR: 0.35; 95% CI: 0.11-1.09) although this difference did not reach statistical significance.

Table 3 Univariate analyses of variables in relation to Exceptional responses

Variable Exceptional responders (n = 24) Non-exceptional responders (n = 124) OR (95% CI) P-value

Age at Dx, median (range) 59.5 (24-78) 58.5 (29-89) 0.99 (0.96-1.02) 0.509 Charlson Comorbidity Index,

median (range)

0.50 (0-5) 1.00 (0.6) 0.77 (0.55-1.09) 0.139 Diabetes Mellitus 1 (4.5) 9 (7.6) 0.58 (0.07-4.84) 0.612 De novo metastatic disease 7 (29.2) 37 (29.8) 0.97 (0.37-2.53) 0.947 Histology 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% 45,0% 50,0% 0 1 2 3 4 5 6 p e rc e n t o f p ati e n ts

Line of treatment in metastatic setting

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12 Ductal Lobular Other 17 (81.0) 3 (14.3) 1 (4.8) 105 (90.5) 5 (4.3) 6 (5.2) 1 3.71 (0.81-16.95) 1.03 (0.12-9.09) 0.091 0.979 ER-status Yes No 15 (68.2) 8 (34.8) 71 (59.2) 49 (40.8) 1 0.77 (0.30-1.96) 0.588 PgR-status Yes No 7 (31.8) 15 (68.2) 43 (36.8) 74 (63.2) 1 1.25 (0.47-3.29) 0.658 WHO Performance status at

metastasis 0-1 2-4 21 (100.0) 0 (0.0) 92 (83.6) 18 (16.4) 8.6 (0.5-148.37) 1 0.138 Elston grade 1-2 3 7 (41.2) 10 (58.8) 34 (32.1) 72 (67.9) 1 0.68 (0.24-1.93) 0.460 Time from diagnosis to

recurrence, in months 14.5 (0-207) 22.5 (0-366) 1.00 (0.99-1.01) 0.518 Metastatic site Visceral Skeletal Liver Lung Skeletal only Multiorgan Other Lymph node CNS Skin 14 (58.3) 14 (58.3) 8 (33.3) 8 (33.3) 6 (25.0) 6 (25.0) 4 (16.7) 2 (8.3) 2 (8.3) 0 (0.0) 67 (54.0) 62 (50.0) 42 (33.9) 38 (30.6) 16 (12.9) 50 (40.3) 24 (19.4) 45 (36.3) 14 (11.3) 7 (5.6) 1.19 (0.49-2.89) 1.40 (0.58-3.39) 0.98 (0.39-2.47) 1.13 (0.45-2.87) 2.25 (0.78-6-51) 0.49 (0.18-1.33) 0.38 (0.08-1.72) 0.35 (0.11-1.09) 0.71 (0.15-3.37) 0.32 (0.02-5.79) 0.698 0.455 0.959 0.795 0.135 0.162 0.209 0.071 0.671 0.440 Complete remission 9 (37.5) 9 (7.3) 7.67 (2.63-22.33) < 0.001

Abbreviations: Age at Dx, Age at diagnosis; ER- status, Estrogen- receptor status; PgR-status,

Progesterone-receptor-status; WHO, World Health Organisation: CNS, Central Nervous System

Survival of the study cohort

The median follow-up duration of the whole study cohort was 32 months, and their median predicted overall survival was 44 months (Figure 2). The predicted 5-year overall survival was 36% (95% CI: 31-41%) and the predicted 10-year 14% (95% CI: 10-18%).

Patients with complete remission on 1st_{line therapy had a statistically significant improved}

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Figure 2 Kaplan-Meier curve on overall survival after diagnosis of metastatic disease, for the entire study cohort.

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Figure 3 Kaplan-Meier showing overall survival after diagnosis of metastatic disease for the entire study cohort depending on treatment response on 1st_{line therapy. Green for complete}

remission; red for other response than complete remission.

Discussion

In our study cohort of 148 patients with metastatic breast cancer from three hospitals, 16.2% of the patients could be defined as exceptional responders to trastuzumab treatment. Two potential relevant clinical predictors for exceptional response could be identified in univariate analysis (p-value < 0.1): achievement of CR at 1st_{line treatment and the absence of lymph}

node metastases.

Few prior studies have investigated the rate of exceptional responders to trastuzumab and their results are limited due to the inadequate definition of exceptional response. In fact, Witzel et al. retrospectively analysed a cohort of 268 patients and showed that 47.1% of patients remained in remission for more than 5 years after trastuzumab initiation [24]. On the

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contrary, Gullo et al. used a more strict definition of exceptional complete response and found that 8 out of the 85 patients included in study cohort had exceptional complete response [25]. The strength of our study is the fact that we are using a definition for exceptional responders that is in accordance with the National Cancer Institute´s (NCI) definition for exceptional response with some modifications that reflect the retrospective nature of our study and the inclusion of only breast cancer patients. The lack of uniform definition of exceptional

response among current studies makes the comparison of their results difficult. Future studies should adopt an acceptable definition for exceptional response, preferably the NCI-based definition that we used in our study.

Another strength of the present study was the consecutive cohort of patients and the inclusion of patients from several hospitals; as a result, the study cohort reflects a real-world clinical setting rather than a selected cohort or a single-center treatment practice.

The presence of complete response at 1st_{line treatment as a predictor of exceptional response}

is in accordance with previous studies [24] and represents an observation with biological rationale. However, the trend that the absence of lymph node metastasis could be a potential predictive factor for exceptional response is a novel observation that deserves further

investigation. Although it is possible that this observation could be a result of chance due to the limited number of patients, a biological explanation cannot be excluded. In fact, a recent study of patients with de novo metastatic breast cancer found that the presence of lymph node metastasis (N3 according to the TNM classification system) was associated with poorer prognosis compared to N0 [26]. Two possible biological explanations for this observation could be the potential higher risk for treatment-resistance in cancer cells that show

organotropism to lymph nodes and the risk that lymphoid tissue might be a pharmacologic sanctuary from systemic oncological therapy.

Our study has several limitations that need to be discussed. First, the retrospective nature of the study is prone to well-described biases such as recall bias. Second, we were unable to obtain complete data from all patients regarding some clinical variables of potential interest such as performance status. In addition, the study cohort is relatively small and the statistical validity of our results can be questioned. Furthermore, the follow-up time was relatively short and as a result, the long-term prognosis of patients with exceptional response could not be analysed. Finally, a molecular characterization of exceptional responders could add valuable

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information to the potential clinical predictors; a molecular sub-study of the present study cohort is planned.

Identifying variables to predict exceptional responders would be of great importance considering the risk for toxicity due to trastuzumab-based therapies. If predictive variables could beforehand identify patients with high possibility of exceptional responses, a de-escalating treatment strategy could be possible.

Conclusion

A meaningful number of patients with HER2-positive metastatic breast cancer become

exceptional responders to trastuzumab-based therapy. The achievement of complete remission during 1st line therapy is closely associated with exceptional response. Additional studies, preferably with utilisation of uniform response criteria, are warranted to validate our findings and to investigate potential further clinical and molecular predictors of desirable long-term responses.

Acknowledgement

I would like to thank Antonis Valachis for being an excellent supervisor during this project. He has continuously given me feedback, helped me understand the statistical analysis and showed patience and understanding with all my questions.

I would also like to thank the Oncology clinic at Örebro University Hospital for lending me space and giving me access to the electronic patient records.

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Trastuzumab in breast cancer metastatic setting: a retrospective study of clinical predictors of exceptional responders