Keywords
Human epidermal growth factor receptor 2 positive - India - metastatic breast cancer
- targeted therapy
Introduction
An estimated 15%–20% of women with breast cancer overexpress human epidermal growth
factor receptor 2 (HER2).[1],[2] Ghosh et al. reported that 16.7% and 8.1% of patients (n = 2001) with breast cancer presenting at their referral cancer center in Mumbai had
HER2 immunochemistry (IHC) scores of 3+ and 2+, respectively,[3] while Doval et al. found that 23% of a cohort of 1284 breast cancer patients from their institution
in New Delhi were HER2 positive.[4] More recently, Chatterjee et al.[5] and Agrawal et al.[6] have reported HER2-positive rates in locally advanced breast cancers to be as high
as 38%–40% based on the use of quality-assured automated IHC and fluorescence in situ hybridization tests.
HER2-positive subtype of breast cancer has historically been associated with poor
clinical outcomes.[7] The disease course is typically aggressive with a high propensity for early metastases,
relapse, and shorter survival than other subtypes. In this backdrop, the use of several
HER2-directed therapies [Table 1] has substantially improved the outcomes in this population.[8],[9],[10],[11] These anti-HER2 therapies are available in India.
Table 1
US Food and Drug Administration-approved anti-human epidermal growth factor receptor
2 agents for breast cancer
|
Anti-HER2 agent
|
Indication
|
Year of approval by the US FDA
|
|
FDA – Food and Drug Administration; HER2 – Human epidermal growth factor receptor
2; mBC – Metastatic breast cancer; T-DM1 – Trastuzumab emtansine
|
|
Trastuzumab
|
Trastuzumab (Herceptin™) combined with paclitaxel in patients with mBC whose tumors
overexpress HER2 protein and who have not received chemotherapy for their metastatic
disease
|
1998
|
|
Lapatinib
|
Lapatinib (Tykerb®) for use in combination with capecitabine for treatment of patients
with advanced breast cancer or mBC whose tumors overexpress HER2 (ErbB2), and who
have received prior therapy including anthracycline, taxane, and trastuzumab
|
2007
|
|
Pertuzumab
|
Pertuzumab (Perjeta™) for use in combination with trastuzumab and docetaxel for the
treatment of HER2-positive mBC who have not received prior anti-HER2 therapy or chemotherapy
for metastatic disease
|
2012
|
|
T-DM1
|
Trastuzumab
|
|
emtansine (Kadcyla™) for use as a single agent for the treatment of patients with
HER2-positive mBC, who had previously received treatment with trastuzumab and taxane,
either separately or in combination
|
2013
|
However, in certain clinical scenarios, the treatment decision-making becomes arduous
due to limited availability of evidence. Moreover, the interpretation and applicability
of Western data in Indian population could be challenging given the diverse socio-cultural-economic
environment. This article discusses some representative scenarios commonly seen in
India, examines the available high-level evidence relevant to such scenarios, and
provides treatment recommendations based on the consensus of a panel of experts. However,
the panel acknowledges that for any given patient, the clinical judgment of the treating
physician, considering all factors, should take precedence over expert recommendations.
Methods
Based on a survey [Figure 1], a panel of nine medical and clinical oncologists with expertise in the treatment
of breast cancer developed representative clinical scenarios commonly seen in practice
in India. This was followed by two face-to-face meetings, the first at New Delhi on
April 08, 2016 (attended by ten medical and clinical oncologists, including the nine
who developed the scenarios) and the second at Mumbai on January 22, 2017 (attended
by 14 medical and clinical oncologists).
Figure 1: Profile of patients with human epidermal growth factor receptor 2‑positive
metastatic breast cancer, based on a survey of expert panel of nine medical oncologists
across India. (Note: The graph represents responses received from the experts, and
the total may not exactly equal 100%). HER2 – Human epidermal growth factor receptor
2
The panel discussed the choice of treatment for each clinical scenario based on the
available evidence from relevant Phase 3 randomized controlled trials. The final treatment
recommendation was reached by consensus or vote. Panelists were asked to indicate
their choices on the assumption that the patients had access to all approved anti-HER2
drugs and were able to afford treatment or were adequately covered by insurance.
Clinical Scenario 1: first-Line Treatment for Human Epidermal Growth Factor Receptor
2-Positive Metastatic Breast Cancer
Clinical Scenario 1: first-Line Treatment for Human Epidermal Growth Factor Receptor
2-Positive Metastatic Breast Cancer
A 56-year-old woman with HER2-positive, hormone receptor-negative breast cancer underwent
surgery for a 25-mm, Grade 3 invasive duct cancer. Postoperatively, she was started
on doxorubicin and cyclophosphamide, followed by paclitaxel and trastuzumab (ACσ TH
regimen), followed by continuation of adjuvant trastuzumab, for a total anti-HER2
therapy duration of 1 year. Two years after completion of adjuvant trastuzumab therapy,
she developed biopsy-confirmed HER2-positive, hormone receptor-negative metastatic
disease in the liver.
In addition, two subscenarios in the first-line metastatic breast cancer (mBC) setting
were also considered. In the first subscenario, the same representative patient as
above had received a similar treatment with the exception that she did not receive
adjuvant trastuzumab (i.e., she was trastuzumab naïve at the time of developing metastases).
In the second subscenario, the same patient as above presents with de novo HER2-positive
mBC at the time of initial diagnosis.
The following therapeutic options were discussed for this scenario and subscenarios:
-
Combination of trastuzumab and taxane
-
Combination of lapatinib and taxane
-
Combination of pertuzumab, trastuzumab, and docetaxel
-
Combination of trastuzumab, paclitaxel, and everolimus
-
Trastuzumab emtansine (T-DM1).
Literature analysis
The Herceptin trial (H0648 g) conducted by Slamon et al.[8] was the first large Phase 3 trial to demonstrate that targeting a specific dysfunctional
genetic alteration in a human solid tumor was feasible and could lead to clinical
benefits. This pivotal study included 450 women with HER2-positive mBC who had not
previously received chemotherapy for metastatic disease, but could have received anthracycline
in the (neo) adjuvant setting (were treated with trastuzumab and paclitaxel).[12] Clinical outcomes in the trastuzumab plus chemotherapy arm were significantly superior
to those in the chemotherapy-alone arm [Table 2], although concurrent anthracycline and trastuzumab had increased the risk of cardiac
dysfunction and led to the approval of Herceptin with paclitaxel in HER2-positive
mBC by the US-Food and Drug Administration. The MA 31 trial was an interesting comparison
between different approaches to HER2 blockade in mBC – oral small molecule versus
intravenous antibody. It compared the efficacy of lapatinib versus trastuzumab in
combination with taxanes as first-line treatment for HER2-positive mBC. After 24 weeks
of chemotherapy plus HER2-directed therapy, the respective anti-HER2 monotherapy was
continued until disease progression. In both arms, 18% patients had received prior
(neo) adjuvant trastuzumab therapy and 42% of patients had de novo mBC at primary diagnosis.
The results showed that patients in the trastuzumab arm had longer progression-free
survival (PFS) than those in the lapatinib arm [Table 2]; however, there was no significant difference in overall survival (OS) between the
two arms.[13] Patients treated with lapatinib displayed characteristic adverse effects, especially
gastrointestinal and skin toxicity.
Table 2
Drugs used in various treatment protocols used to treat acute lymphoblastic leukemia
|
Trial
|
Treatment arms
|
Treatment-specific criteria
|
Results
|
|
*Chemotherapy consisted of an anthracycline plus cyclophosphamide for patients who
had never before received anthracycline or paclitaxel for patients who had received
adjuvant (postoperative) anthracycline. HER2+ – Human epidermal growth factor receptor
2 positive; LABC – Locally advanced breast cancer; MBC – Metastatic breast cancer;
OS – Overall survival; PFS – Progression-free survival; TTP – Time to progression;
T-DM1 – Trastuzumab emtansine; RR – Relative risk; HR – Hazard ratio; NA – Not available;
BC – Breast Cancer
|
|
H0648g[8]
|
Chemotherapy* + trastuzumab (n=235) versus chemotherapy (n=234)
|
HER2-positive mBC; no previous chemotherapy for metastatic disease
|
Trastuzumab + chemotherapy versus chemotherapy Median TTP: 7.4 months versus 4.6 months
(RR: 0.51; P<0.001) Median OS: 25.1 months versus 20.3 months (RR: 0.80; P=0.046)
Trastuzumab + paclitaxel (n=92) versus paclitaxel (n=96) Median TTP: 6.9 months versus 3.0 months (RR: 0.38; P<0.001) Median OS 22.1 months
versus 18.4 months (RR: 0.80; P=0.17)
|
|
MA.31[13]
|
Lapatinib + taxane (n=326) versus trastuzumab + taxane (n=326)
|
HER2-positive mBC; prior (neo) adjuvant trastuzumab and/or taxane therapy allowed provided last dose ≥1 year
before randomization (18% patients)
|
Lapatinib + taxane versus trastuzumab + taxane Median PFS: 9 months versus 11.3 months
(HR: 1.37; P=0.001) Median OS: Median not observed (HR: 1.28; P=0.11)
|
|
CLEOPATRA[10]
[14]
[15]
|
Trastuzumab + docetaxel + pertuzumab (n=402) versus trastuzumab + docetaxel + placebo (n=406)
|
Locally recurrent, unresectable, or metastatic HER2+ve BC; Prior (neo) adjuvant chemotherapy including trastuzumab and/or taxane allowed if ≥1 year has
elapsed between treatment completion and detection of mBC
|
Trastuzumab + docetaxel + pertuzumab versus trastuzumab + docetaxel + placebo Overall
population Median PFS: 18.5 months versus 12.4 months (HR: 0.62; P<0.001) Median OS:
56.5 months versus 40.8 months (HR: 0.68; P<0.001) Prior (neo) adjuvant trastuzumab-treated patients (12%, n=88) Median PFS: 16.9 months versus
10.4 months (HR: 0.62) Median OS: 53.8 months versus 46.2 months (HR: 0.68)
|
|
BOLERO-1[16]
|
Trastuzumab + paclitaxel + everolimus (n=480) versus trastuzumab + paclitaxel + placebo (n=239)
|
Locally recurrent, unresectable, or metastatic HER2+ve BC; no prior anthracycline/taxane
in the metastatic setting; previous (neo) adjuvant trastuzumab and chemotherapy allowed, if >12 months elapsed at the date
of randomization (11% patients)
|
Trastuzumab + everolimus versus trastuzumab + placebo Median PFS: 14.95 months versus:
14.49 months (HR: 0.89; P=0.1166)
|
|
MARIANNE1171
|
T-DM1 (n=367) versus T-DM1 + pertuzumab (n=363) versus trastuzumab + taxane (n=365)
|
Unresectable- progressive- or recurrent locally advanced, or previouslyuntreated MBC;
prior (neo) adjuvant chemotherapy with vinca alkaloid or taxane allowed if >6 months since
diagnosis of advanced BC
|
T-DM1 versus trastuzumab + taxane Overall patient population Median PFS: 14.1 months
versus 13.7 months (HR: 0.91; P=0.31) Prior (neo) adjuvant trastuzumab-/lapatinib-treated patients (31%, n=226) Median PFS: 15.2
months versus 10.3 months (HR: 0.75) T-DM1 + pertuzumab versus trastuzumab + taxane
Overall population Median PFS: 15.2 months versus 13.7 months (HR: 0.87; P=0.14) Median
OS was not reached in any treatment group
|
|
EMILIA [11]
[18]
|
T-DM1 (n=495) versus lapatinib + capecitabine (n=496)
|
Unresectable locally advanced or metastatic HER2+ve BC: Prior taxane and trastuzumab;
progression during treatment for metastasis, or progression within 6 months of adjuvant
treatment (early relapse
|
T-DM1versus lapatinib plus T-DM1versus lapatinib plus capecitabine Overall population
Median PFS: 9.6 months versus 6.4 months (HR: 0.65; P<0.001) Median OS: 30.9 months
versus 25.1 months (HR: 0.68; P<0.001) Patients with early relapse (16%, n=118) Median
PFS: 10.8 months versus 5.7 months (HR: 0.51) OS: Median not reached versus 27.9 months
(HR: 0.61)
|
The CLEOPATRA trial investigated single-versus-dual HER2 blockade (trastuzumab plus
placebo versus trastuzumab plus pertuzumab, a HER2 dimerization inhibitor), in combination
with a taxane, in HER2-positive mBC.[10],[14] In this trial, approximately 50% of patients were treatment naïve and only 10% of
patients had received trastuzumab in the (neo) adjuvant setting, as recruitment began <2 years after the initial approval of
adjuvant trastuzumab.[19] Median PFS in the pertuzumab arm was significantly longer than that in the comparator
arm [Table 2]; the between-group difference was statistically significant across all subgroups.
In the subgroup of patients who had received adjuvant or neoadjuvant therapy with
trastuzumab, the median PFS was increased by 6.5 months in the pertuzumab arm (hazard
ratio [HR], 0.62; 95% confidence interval, 0.35–1.07).[15] Despite the presence of visceral metastasis in 78% of the patients, the median survival
approached 5 years in the pertuzumab arm. Indeed, at the time of reporting, patients
had spent more time off pertuzumab than on it (18 months of PFS followed by approximately
38 months of post-PFS).[14] Similar to the “carryover” effect observed after cessation of tamoxifen,[20] the survival curves continued to diverge; this phenomenon is usually not seen with
other oncology drugs. Post the trial treatment, nearly 72% of the patients received
additional HER2-directed treatment and this proportion was comparable in both the
study arms. There was a 10-month difference in the post-PFS between the pertuzumab
and the control arm,[14] although the OS was comparable in patients with and without prior trastuzumab exposure.[15] The adverse events reported in the study included neutropenia, which was primarily
attributed to concomitant treatment with docetaxel.[21] It may be noted that in the safety analysis of the ongoing PERUSE study (n = 1436), the preliminary toxicity profile of first-line pertuzumab, trastuzumab,
and the investigator's choice of taxane regimen was generally consistent with the
previous clinical experience of pertuzumab and the known taxane safety profile.[22]
A real-world, retrospective noninterventional study [23] assessed the clinical outcomes of patients treated with pertuzumab containing therapy
as first-line treatment in US community oncology practices. Most patients (93.6%)
were treated with a combination of pertuzumab, trastuzumab, and a taxane (docetaxel
or paclitaxel or nab-paclitaxel). In line with the current practice, 61.5% of patients
received (neo) adjuvant trastuzumab. The median PFS (16.9 months) and toxicity profile were similar
to that observed in the CLEOPATRA trial.
Blockade of the HER2 receptor may trigger signaling via alternate pathways.[24] Thus, it may be hypothesized that dual blockade (of the HER2 receptor and of a component
of the downstream PI3K/AKT/mammalian target of rapamycin [mTOR] canonical pathway)
could potentially lead to more effective outcomes than those achieved with HER2 targeting
alone. However, in the BOLERO-1 trial that tested dual blockade of HER2 and mTOR in
early mBC, there was no significant difference in PFS between the trastuzumab plus
everolimus and the trastuzumab plus placebo arms in the overall population [Table 2], although there was a potential signal of benefit in patients with hormone receptor-negative
disease.[16]
The noninferiority MARIANNE trial compared T-DM1 with or without pertuzumab against
trastuzumab and docetaxel. A more resistant population was also enrolled in this trial
(>6 months of prior [neo] adjuvant vinca alkaloid or taxane chemotherapy). Thirty
percent of the patients in both arms had received prior (neo) adjuvant HER2-targeted (trastuzumab/lapatinib) therapy. No significant between-group
difference in outcomes was observed in this trial [Table 2].[17] Of note, the combination of trastuzumab, pertuzumab, and taxane was not approved
at the time of this trial and was, therefore, not tested.
A prospective observational study (registHER) by Yardley et al.[25] revealed significantly better outcomes in patients with de novo HER2-positive mBC as compared to those with recurrent HER2-positive mBC (OS: 41.7
vs. 32.8 months, respectively; HR: 0.766). Prior adjuvant chemotherapy perhaps renders
the mBC more refractory to treatment because of the selection of resistant or aggressive
clones of HER2-positive cells.
In the EMILIA study, a Phase 3 trial, patients treated with the antibody drug conjugate
T-DM1 had significantly longer PFS and OS than those treated with a combination of
lapatinib and capecitabine [11]
[Table 2]. T-DM1 significantly improved PFS and OS among patients with HER2-positive mBC with
a disease-free interval of <6 months after completion of trastuzumab-based therapy
in the adjuvant or neoadjuvant setting.[18]
Economic impact of various human epidermal growth factor receptor 2-directed treatments
In this context, some Indian centers have reported that there is limited access to
HER2-targeted therapies for their patients,[3],[6] although this situation is now improving (Sudeep Gupta, personal communication).
Anti-HER2 therapy has substantial cost implications, especially for low- and middle-income
countries.[26] Durkee et al. assessed the cost-effectiveness of pertuzumab therapy in HER2-positive mBC based
on modeling the survival from the raw data of the CLEOPATRA study and also took into
account other associated costs (cost of other drugs, hospitalization, toxicity, and
subsequent treatments). They concluded that the addition of pertuzumab to trastuzumab
and taxane was unlikely to be cost-effective in the United States.[27]
In India, the cost of pertuzumab is currently capped under a patient assistance program.
A patient pays for 13 vials over 36 weeks (9 months), and drugs for subsequent treatment
cycles are supplied free until the progression of disease. Therefore, the incremental
cost-effectiveness ratio may be more favorable in the Indian context under this assistance
program.
Panel recommendation
Pertuzumab in combination with trastuzumab and taxane is recommended as the first-line
therapy for HER2-positive patients, including patients with or without prior (neo) adjuvant trastuzumab (relapsed >12 months after [neo] adjuvant use), as well as
those with de novo mBC.
For patients who have relapsed within 6 months of adjuvant trastuzumab, T-DM1 can
be considered as a preferred therapeutic option. The panel acknowledges that there
is insufficient level-one data to make recommendations for the group that relapse
between 6 and 12 months from the end of adjuvant therapy. The use of pertuzumab-trastuzumab-taxane,
T-DM1, or other anti-HER2 combinations can be considered by treating physicians in
this scenario.
Clinical Scenario 2: Second-Line Treatment for Human Epidermal Growth Factor Receptor
2-Positive Metastatic Breast Cancer, Progressed on Trastuzumab
Clinical Scenario 2: Second-Line Treatment for Human Epidermal Growth Factor Receptor
2-Positive Metastatic Breast Cancer, Progressed on Trastuzumab
A 45-year-old woman was diagnosed 6 years ago with HER2-positive and hormone receptor
negative breast cancer (T2N1M0; 20 mm in size, Grade 2). Following a mastectomy and
axillary dissection, she underwent adjuvant treatment with doxorubicin and cyclophosphamide
(AC; 4 cycles), weekly paclitaxel (12 cycles), and trastuzumab for a total duration
of 1 year. She developed HER2-positive, hormone receptor-negative hepatic metastases
5 years later and was treated with weekly paclitaxel in combination with trastuzumab.
After 6 months of trastuzumab monotherapy, a new lesion was found in the liver.
The following treatment regimens were considered for discussion in this scenario:
-
Lapatinib in combination with capecitabine
-
T-DM1
-
Vinorelbine in combination with trastuzumab and everolimus
-
Vinorelbine in combination with afatinib.
Literature analysis
The EGF100151 study included patients with HER2-positive mBC who progressed after
treatment with regimens containing anthracyclines, taxanes, and trastuzumab. A significant
improvement in median TTP and overall response rate was observed with lapatinib combined
with capecitabine versus. monotherapy;[28] however, there was no significant difference in median OS [29] between the two treatment arms.
In the EMILIA trial, patients with HER2-positive mBC previously treated with trastuzumab
in combination with a taxane were randomized to either lapatinib plus capecitabine
or T-DM1. PFS and OS in the T-DM1 arm were superior than that in the lapatinib plus
capacitabine arm [Table 3].[11] In a subgroup of patients (n = 118) who had relapsed within 6 months of completion of adjuvant treatment, PFS
with T-DM1 (10.8 months) was significantly longer than that with the combination of
lapatinib and capecitabine (5.7 months).[18] The commonly reported adverse effects of T-DM1 were elevation of liver enzymes and
thrombocytopenia and both these adverse effects were manageable.[11]
Table 3
Overview of trials in patients with human epidermal growth factor receptor 2-positive
metastatic breast
cancer who progressed on trastuzumab therapy
|
Trials
|
Treatment arms
|
Treatment‑specific criteria
|
Results
|
|
HER2 – Human epidermal growth factor receptor 2; LABC – Locally advanced breast cancer;
mBC – Metastatic breast cancer;
OS – Overall survival; PFS – Progression‑free survival; T‑DM1 – Trastuzumab emtansine;
TTP – Time to progression; HR – Hazard ratio;
NR=Statistical significance for OS cannot be claimed because of the hierarchical testing
of OS after the primary PFS end point
|
|
EGF100151[9]
[28]
[29]
|
Capecitabine + lapatinib (n=198) versus capecitabine (n=201)
|
HER2-positive LABC or mBC that progressed after prior treatment with anthracycline,
taxane, and trastuzumab
|
Capecitabine + lapatinib versus capecitabineMedian TTP: 6.2 months versus 4.3 months
(HR: 0.57; P=<0.001) Median OS: 75 weeks versus 64.7 weeks (HR: 0.87; P=0.210)
|
|
EMILIA[11]
|
T-DM1 (n=495) versus lapatinib + capecitabine (n=496)
|
Unresectable locally advanced or metastatic HER2+ve BC: Prior taxane and trastuzumab;
progression during treatment for metastasis, or progression within 6 months of adjuvant
treatment
|
T-DM1 versus lapatinib + capecitabineMedian PFS: 9.6 months versus 6.4 months (HR:
0.65; P<0.001) Median OS: 30.9 months versus 25.1 months (HR: 0.68; P<0.001)
|
|
BOLERO-3[30]
|
Trastuzumab + vinorelbine + everolimus (n=284) versus trastuzumab + vinorelbine + placebo (n=285)
|
LABC or metastatic HER2-positive breast cancer: Recurrence during or <12 months of
adjuvant treatment or progression during or <4 weeks of treatment for advanced disease
|
Trastuzumab + vinorelbine + everolimus versus trastuzumab + vinorelbineMedian PFS:
7 months versus 5.8 months (HR: 0.78; P=0.0067)
|
|
LUX breast-1[31]
|
Vinorelbine + afatinib (n=339) versus vinorelbine + trastuzumab (n=169)
|
HER2-positive mBC who had progressed on or <12 months following adjuvant trastuzumab
or first-line treatment of metastatic disease with trastuzumab
|
Vinorelbine + afatinib versus vinorelbine + trastuzumab Median PFS: 5.5 months versus
months (HR: 1.10; P=0.043) Median OS: 20.5 months versus 28.6 months (HR: 1.48; P=0.048)
|
|
PHEREXA[32]
[33]
|
Pertuzumab + trastuzumab + capecitabine (n=228) versus trastuzumab + capecitabine (n=224)
|
HER2-positive mBC: Experienced disease progression during or after trastuzumab-based
therapy; received a prior taxane
|
Pertuzumab + trastuzumab + capecitabine versus trastuzumab + capecitabineMedian PFS
11.1 months versus 9 months (HR: 0.82; P=0.0731) Median OS 36.1 months versus 28.1
months (HR: 0.68; P=NR)
|
The BOLERO 3 study was conducted to assess whether the addition of the mTOR inhibitor
everolimus to trastuzumab would restore sensitivity to trastuzumab. In patients with
HER2-positive, trastuzumab-resistant advanced breast carcinoma, there was a significant
improvement in the median PFS in favor of everolimus versus the placebo group [Table 3]; however, 42% of patients in the everolimus arm experienced a serious adverse event.[30]
In the LUX Breast-1 study, patients who progressed on trastuzumab fared better on
further trastuzumab than on the pan-HER2 inhibitor afatinib [Table 3]. The reason could be related to the differing mechanisms of antibody versus small
molecule, as well as to the immunological effects. However, the treatment was associated
with an unfavorable benefit/risk ratio.[31]
The results of PHEREXA trial presented at the ASCO 2016 showed that addition of pertuzumab
to trastuzumab plus capecitabine as the second-line treatment of patients with mBC
did not significantly improve PFS.[32],[33]
Panel recommendation
On a review of all trials in the context of patients who progressed on trastuzumab,
a survival advantage was evident only in the EMILIA trial in those treated with T-DM1.
In the absence of cost constraints, T-DM1 would be the preferred choice in this setting.
The panel also recommends that in patients with HER2-positive mBC who show indolent
progression on a trastuzumab-based regimen, a change of the chemotherapy partner or
re-introduction of chemotherapy, with continuation of trastuzumab, could also be a
viable option.
Clinical Scenario 3: Central Nervous System Metastases in Human Epidermal Growth Factor
Receptor 2-Positive Breast Cancer
Clinical Scenario 3: Central Nervous System Metastases in Human Epidermal Growth Factor
Receptor 2-Positive Breast Cancer
A 52-year-old woman presented with HER2-positive, hormone receptor-positive, invasive
ductal carcinoma of the breast (T2N1M0; 32 mm, Grade 3 with 5 of 14 lymph nodes involved).
She received adjuvant chemotherapy with docetaxel in combination with carboplatin
and trastuzumab (TCH) and continued on trastuzumab monotherapy (to complete 1 year)
with aromatase inhibitor. One year later, she developed biopsy-confirmed HER2-positive
and hormone receptor-positive metastases in liver. She received six cycles of paclitaxel
with trastuzumab. After 6 months on trastuzumab monotherapy, she developed multiple
unresectable central nervous system (CNS) metastasis.
For this scenario, the following treatment regimens were considered for the discussion:
-
Continue trastuzumab with locoregional treatment of CNS metastasis
-
Change to a combination of lapatinib and capecitabine
-
Locoregional treatment of CNS metastasis followed by T-DM1.
Literature analysis
There is some evidence, although not from randomized trials, that use of chemotherapy
and HER2-targeted therapy in addition to brain radiation might improve OS in patients
with CNS metastasis.[34]
Human epidermal growth factor receptor 2-positive metastatic breast cancer without
central nervous system metastasis at baseline
A retrospective study by Park et al. showed that addition of trastuzumab to chemotherapy increased the time to onset
of CNS metastasis (15 months vs. 10 months, P = 0.035) and time to death from CNS metastases (14.9 months vs. 4.0 months, P = 0.0005) in patients with HER2-positive mBC. However, among patients with HER2-positive
disease, the incidence of CNS metastasis in those treated with trastuzumab (37.8%)
was higher than that in patients who were not treated with trastuzumab (25.0%; P = 0.028).[35] It is worth noting that following radiation therapy, the concentration of trastuzumab
in the cerebrospinal fluid tends to increase.[36]
In the CEREBEL trial, no significant difference was observed between the lapatinib
plus capecitabine and the trastuzumab plus capecitabine arms with respect to time
to metastasis and development of new CNS metastasis [5.7 and 4.4 months, respectively;
[Table 4]. Further, there was low overall incidence of CNS progression at any time (7% and
6%, respectively).[37]
Table 4
Overview of trials involving human epidermal growth factor receptor 2-positive patient
population with and without central nervous system metastasis at baseline
|
Trials
|
Treatment arms
|
Treatment-specific criteria
|
Results
|
|
@Exploratory analysis; *Post hoc analysis; $ ≥50% volumetric reduction of CNS lesions
in the absence of increased steroid use, progressive neurological symptoms and progressive
extra-CNS disease; #Patients with asymptomatic CNS metastases previously treated with
radiotherapy were eligible to enroll 14 days after last radiotherapy treatment. CNS
– Central nervous system; HER2 – Human epidermal growth factor receptor 2; LABC –
Locally advanced breast cancer; mBC – Metastatic breast cancer; MRI – Magnetic resonance
imaging; HR – Hazard ratio; OS – Overall survival; PFS – Progression-free survival;
T-DM1 – Trastuzumab emtansine; TTP – Time to progression
|
|
HER2-positive mBC without CNS metastasis at baseline
|
|
CEREBEL[37]
|
Capecitabine + lapatinib (n=271) versus capecitabine + trastuzumab (n=269)
|
HER2-positive mBC without CNS metastasis at baseline
|
Capecitabine + lapatinib versus capecitabine + trastuzumab Incidence of CNS metastasis
as first site of relapse: 3% versus 5% (HR: 0.65; P=0.36) Median PFS: 6.6 months versus 8.1 months; (HR: 1.30; P=0.021) Median OS: 22.7 months versus 27.3 months; (HR: 1.34; P=0.095)
|
|
CLEOPATRA@[38]
|
Trastuzumab + docetaxel + pertuzumab (n=55) versus trastuzumab + docetaxel + placebo (n=51)
|
Patients without CNS metastasis at baseline
|
Pertuzumab arm versus placebo arm Median TTP in CNS: 15 months versus 11.9 months
(HR: 0.59; P=0.0049) Median OS in patients with CNS progression 34.4 months versus 26.3 months
(HR: 0.66; P=0.1139)
|
|
HER2-positive mBC with CNS metastasis at baseline
|
|
LANDSCAPE[39]
|
Lapatinib + capecitabine (n=45)
|
HER2-positive mBC: At least one measurable CNS lesion of ≥10 mm in diameter on MRI
|
Objective CNS response$: 65.9%
|
|
EMILIA*[40]
|
T-DM1 (N=45) versus lapatinib + capecitabine (n=50)
|
HER2-positive mBC patients who had stable CNS disease at baseline#
|
T-DM1 versus lapatinib+capecitabine Median PFS: 5.9 months versus 5.7 months (HR:
1; P=1.000) Median OS: 26.8 m vs. 12.9 m (HR: 0.38; P=0.0081)
|
|
LUX breast-3[41]
|
Vinorelbine + afatinib (n=38) versus Afatinib (n=40) versus investigator’s choice
|
HER2-positive breast cancer with documented CNS recurrence/ progression (on imaging)
during or after trastuzumab and/or lapatinib-based therapy
|
Patient benefit at 12 weeks (absence of CNS or extra‑CNS disease progression, no tumor-related
worsening of neurological signs or symptoms, and no increase in corticosteroid dose)
Vinorelbine + afatinib, 34·2% Afatinib, 30·0% Investigator’s choice: 41·9%
|
|
KAMILLA[42]
|
T-DM1 (n=399)
|
Subgroup of HER2-positive breast cancer received prior HER2-targeted therapy and chemotherapy
with CNS metastasis at baseline
|
Partial response: 44%
Clinical benefit rate: 59% Median PFS: 6.1 months
|
In the CLEOPATRA study, the combination of pertuzumab, trastuzumab, and docetaxel
was superior to that of placebo, trastuzumab, and docetaxel in delaying the onset
of CNS disease [Table 4], an effect that is likely attributable to the superior systemic disease control
achieved with pertuzumab-based treatment.[38]
Human epidermal growth factor receptor 2-positive metastatic breast cancer with central
nervous system metastasis at baseline
In a pivotal study that led to the approval of lapatinib in HER2-positive mBC, the
incidence of CNS disease in the lapatinib plus capecitabine arm was lower than that
in the capecitabine alone arm; however, the difference was not statistically significant.[9] The LANDSCAPE study was an exploratory single-arm, Phase 2, open-label, multicenter
study, which evaluated the combination of lapatinib and capecitabine for the treatment
of previously untreated CNS metastases from HER2-positive breast cancer. Partial response
was evident in all patients, and objective CNS response was observed in nearly 70%
of the patients [Table 4].[39]
In the EMILIA study, some patients (95 out of 991) had CNS metastasis at baseline,
a majority of whom had received whole-brain radiotherapy. The patients were asymptomatic
at baseline. Post hoc analysis showed significant survival benefits following treatment
with T-DM1 as compared to that with lapatinib and capecitabine combination [Table 4].[40]
In the LUX Breast 3 study (afatinib alone vs. afatinib plus vinorelbine vs. investigators'
choice), there was no significant difference in the PFS and OS or patient benefits
between the three treatment arms [Table 3]; however, patients treated with afatinib experienced more frequent adverse events.[41]
A more recent presentation on a large cohort of patients (n = 399) with CNS metastasis suggested a clinical benefit rate of 43% with T-DM1 in
those with measureable CNS disease.[42]
Panel recommendation
Owing to lack of robust evidence in this specific group of patients, deciding on systemic
anti-HER2 therapy is challenging. Based on the indirect evidence generated by the
EMILIA study, T-DM1 can be considered as an option in patients with HER2-positive
CNS metastasis who have received radiotherapy. The survival benefit in patients with
asymptomatic metastasis could be attributed to control extracranial disease rather
than to the effect of the drug on CNS metastasis. However, other options including
trastuzumab or lapatinib can also be considered based on the characteristics of individual
patients. It is important to note that the outcome of patients with HER2-positive
CNS metastasis may be better than those with triple-negative breast cancer.
The panel recommends initial locoregional treatment of CNS metastasis, followed by
T-DM1 as a preferred option in this scenario, although trastuzumab- or lapatinib-based
combination therapy could also be considered.
Clinical Scenario 4: Her2-Positive Metastatic Breast Cancer Progressing on Two Prior
Anti-Her2 Agents
Clinical Scenario 4: Her2-Positive Metastatic Breast Cancer Progressing on Two Prior
Anti-Her2 Agents
A 60-year-old woman presented to the emergency department with persistent cough and
dyspnea on exertion. Five years ago, she was diagnosed with Stage II, HER2-positive
and hormone receptor-positive breast cancer. Postsurgery, she received AC-TH followed
by tamoxifen for 4 years. Six months ago, the cancer recurred as a solitary pulmonary
lesion, and she was treated with trastuzumab and anastrozole. After 2 months, the
patient developed increased cough and difficulty in breathing. She was then treated
with lapatinib and capecitabine. Currently, she exhibits signs of progression with
appearance of liver metastasis and enlargement of the pulmonary lesion.
The following treatment regimens were considered for discussion in this scenario of
a HER2-positive mBC patient who progresses on two anti-HER2 agents:
-
Continue trastuzumab but change chemotherapy partner
-
Continue with lapatinib and capecitabine
-
T-DM1
-
Lapatinib and trastuzumabChemotherapy alone.
Literature analysis
In the TH3RESA trial, the median number of previous regimens for advanced breast cancer
was 4 or 5. The PFS and OS in patients treated with T-DM1 were significantly better
than those associated with treatment of physicians' choice [Table 5], which was mainly trastuzumab-containing combinations (80% patients).[43],[44]
Table 5
Overview of clinical trials on patients with human epidermal growth factor receptor
2-positive metastatic breast cancer progressed on two anti-human epidermal growth
factor receptor 2 agents
|
Trial
|
Treatment arms
|
Treatment-specific criteria
|
Results
|
|
HER2 – Human epidermal growth factor receptor 2; LABC – Locally advanced breast cancer;
mBC – Metastatic breast cancer; MRI – Magnetic resonance imaging; HR – Hazard ratio;
OS – Overall survival; PFS – Progression‑free survival; T-DM1 – Trastuzumab emtansine
|
|
TH3RESA[43]
[44]
|
T-DM1 (n=404) versus treatment of physician’s choice (n=198)
|
HER2-positive advanced breast cancer: ≥2 prior HER2-directed therapies for advanced
breast cancer; prior treatment with trastuzumab, lapatinib, taxane
|
T-DM1 versus treatment of physician’s choice Median PFS: 6.2 months versus 3.3 months
(HR: 0.53; P<0.0001) Median OS: 22.7 months versus 15.6 months (HR: 0.58; P=0.0002)
|
|
EGF104900[45]
[46]
|
Lapatinib (n=146) with trastuzumab versus lapatinib alone (n=145)
|
HER2-positive mBC: Prior taxane, anthracycline, and trastuzumab; prior HER2-directed
therapies for advanced breast cancer; Progression on trastuzumab within most recent
regimen for mBC
|
Lapatinib with trastuzumab versus lapatinib alone Median PFS: 12.0 weeks versus 8.1
weeks, (HR: 0.73; P=0.008) Median OS: 14 months versus 9.5 months, (HR: 0.74; P=0.026)
|
In the EGF104900 trial, the median number of prior anti-HER2 therapies for mBC was
3. PFS and OS in the lapatinib plus trastuzumab arm were significantly longer than
that with lapatinib alone [Table 5]. Improvement in absolute OS rate at 6 and 12 months was 10% and 15%, respectively,
in the combination arm compared with the monotherapy arm.[45],[46]
Panel recommendations
For patients with HER2-positive mBC who progress on anti-HER2 agents (trastuzumab
and lapatinib), T-DM1 should be the treatment of choice. An alternative option may
be chemotherapy in combination with trastuzumab. For heavily pretreated patients who
have received multiple lines of treatment, a dual HER2-targeted regimen (i.e., trastuzumab
and lapatinib) may be considered.
Conclusion
Based on evidence from multiple well-conducted clinical trials, anti-HER2 therapy
has become a central element in the therapeutic strategy for HER2-positive mBC leading
to a paradigm shift in the management of HER2-positive breast cancer. In the Indian
scenario, in addition to available evidence, socioeconomic variables would need to
be considered by treating physicians. The panel of experts has summarized the evidence
and made recommendations pertaining to commonly encountered clinical scenarios in
HER2-positive mBC that may potentially improve patient outcomes.
Acknowledgment
The authors would like to acknowledge medical writing and editing support provided
by A Dharman, S Verma, and KS Saini of Quantum Health Analytics SPRL, Belgium.
