Abstract
HER2-positive breast cancer has a distinctive biology, wherein amplification of the HER2 oncogene leads to a cascade of downstream effects. While in the past this distinctive biology was associated with a higher risk of recurrence and impaired long-term outcome, our current understanding of this breast cancer subtype has led to important advances in both the metastatic and adjuvant disease settings. Monoclonal antibodies directed against the extracellular membrane domain of the HER2 receptor tyrosine kinase protein (e.g., trastuzumab, pertuzumab, and T-DM1) represent the mainstays of therapy for this disease, and their use has both improved the survival of metastatic patients and increased the disease-free and overall survival of early stage disease. These benefits require the collaboration of the pathologist with the medical oncologist. Further advances in treatment will increasingly rely on an improved understanding of HER2 biology.
Keywords
HER2, trastuzumab, pertuzumab, T-DM1, ASCO/CAP guidelines, receptor tyrosine kinase
HER2-positive breast cancer, in the course of a decade and a half, has gone from being the most feared to perhaps the most treatable of breast cancers. This sea change resulted from the recognition in the late 1980s that HER2 represented a potent driver of a small (15%–20%) fraction of breast cancers and the subsequent development of molecularly targeted therapies for HER2. The progressive application of these agents, first in the metastatic setting but subsequently in the adjuvant setting, has transformed the disease. Emerging therapies, currently under study in the adjuvant setting, have the potential to largely eliminate HER2 metastatic breast cancer as a public health threat.
This chapter reviews the biology of HER2, followed by a discussion of HER2 as a subject of pathologic analysis. It then discusses the role of HER2-targeted therapies in the adjuvant and metastatic settings and future prospects for HER2-targetd therapies.
HER2 Biology
HER2 (also known as c-erbB2 or neu ) is an oncogenic driver of breast cancer growth, survival, invasion, and metastasis. A member of the Epidermal Growth Factor Receptor (EGFR) family of transmembrane receptor tyrosine kinases, it differs from other members of the family in that it lacks a functioning ligand-binding domain. The HER2 kinase is primarily activated by dimerization with other members of the HER family, with HER3 representing the preferential dimerization partner, although when HER2 is present in excess quantities, it may dimerize with other HER2 molecules. The tyrosine kinase portion of HER3 is defective, but HER3 is able to bind ligands of the neuregulin family and to transactivate other members of the family. HER2, in contrast, is incapable of ligand binding.
After dimerization, kinase activation occurs and results in numerous downstream effects. These effects include activation of both proliferation and survival pathways, mediated via the PI3K/Akt/mTOR intracellular pathway and the mitogen-activated protein kinase (MAPK) pathway.
In human breast cancer, HER2 pathogenesis occurs preferentially as a result of an amplification of a genomic region containing the HER2 gene on chromosome 17q12. HER2 is a constitutive protein present in organs throughout the body, but in HER2-positive tumors the amplification event results in significantly increased numbers of the HER2 molecule on the cancer cell surface. HER2-positive tumors can be either estrogen positive or estrogen negative, in roughly equal proportions. One consequence of HER2 activation is the downregulation of the estrogen receptor (ER) via crosstalk with that receptor, and HER2-positivity and ER expression are therefore inversely correlated, rendering HER2-positive tumors relatively less sensitive to estrogen blockade.
Although the vast majority of HER2-driven tumors occur as a result of an amplification event, recent analysis of deep-sequenced primary breast cancers has suggested that a small fraction of these tumors harbor activating somatic mutations in HER2, perhaps in the 1% to 2% range. These tumors are not positive through standard immunohistochemical or in situ hybridization testing, nor do they appear sensitive to standard monoclonal antibody therapies or to lapatinib, although preclinical trials suggest they may be sensitive to other investigational agents (e.g., neratinib), and there are at least anecdotal cases of response in this population.
HER2 Pathology
HER2 amplification can be tested for in several ways. The HER2 cell surface protein may be evaluated by immunohistochemistry (IHC; using a 0, 1+, 2+, 3+ scoring system) or HER2 DNA copy number may be evaluated by fluorescence in situ hybridization (FISH). The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have published a joint guideline for the evaluation of HER2 that represent the current standard of care. These guidelines (modified from Wolff and colleagues ) are shown in Box 56.1 .
Key Recommendations for Oncologists
- •
Must request HER2 testing on every primary invasive breast cancer (and on metastatic site, if stage IV and if specimen available) from a patient with breast cancer to guide decision to pursue HER2-targeted therapy. This should be especially considered for a patient who previously tested HER2 negative in a primary tumor and presents with disease recurrence with clinical behavior suggestive of HER2-positive or triple-negative disease.
- •
Should recommend HER2-targeted therapy if HER2 test result is positive, if there is no apparent histopathologic discordance with HER2 testing, and if clinically appropriate. If the pathologist or oncologist observes an apparent histopathologic discordance after HER2 testing, the need for additional HER2 testing should be discussed.
- •
Must delay decision to recommend HER2-targeted therapy if initial HER2 test result is equivocal. Reflex testing should be performed on the same specimen using the alternative test if initial HER2 test result is equivocal or on an alternative specimen.
- •
Must not recommend HER2-targeted therapy if HER2 test result is negative and if there is no apparent histopathologic discordance with HER2 testing. If the pathologist or oncologist observes an apparent histopathologic discordance after HER2 testing, the need for additional HER2 testing should be discussed.
- •
Should delay decision to recommend HER2-targeted therapy if HER2 status cannot be confirmed as positive or negative after separate HER2 tests (HER2 test result or results equivocal). The oncologist should confer with the pathologist regarding the need for additional HER2 testing on the same or another tumor specimen.
- •
If the HER2 test result is ultimately deemed to be equivocal, even after reflex testing with an alternative assay (i.e., if neither test is unequivocally positive), the oncologist may consider HER2-targeted therapy. The oncologist should also consider the feasibility of testing another tumor specimen to attempt to definitely establish the tumor HER2 status and guide therapeutic decisions. A clinical decision to ultimately consider HER2-targeted therapy in such cases should be individualized on the basis of patient status (comorbidities, prognosis, and so on) and patient preferences after discussing available clinical evidence.
Key Recommendations for Pathologists
- •
Must ensure that at least one tumor sample from all patients with breast cancer (early-stage or metastatic disease) is tested for either HER2 protein expression (IHC assay) or HER2 gene expression (ISH assay) using a validated HER2 test.
- •
In the United States, the American Society of Clinical Oncology/College of American Pathologists Guideline Update Committee preferentially recommends the use of an assay that has received Food and Drug Administration approval, although a CLIA-certified laboratory may choose instead to use a laboratory-developed test.
- •
Must report HER2 test result as positive if (a) IHC 3+ positive or (b) ISH positive using either a single-probe ISH or dual-probe ISH. This assumes that there is no apparent histopathologic discordance observed by the pathologist.
- •
Must report HER2 test result as equivocal and order reflex test on the same specimen (unless the pathologist has concerns about the specimen) using the alternative test if (a) IHC 2+ equivocal or (b) ISH equivocal using single-probe ISH or dual-probe ISH. This assumes that there is no apparent histopathologic discordance observed by the pathologist.
- •
Must report HER2 test result as indeterminate if technical issues prevent one or both tests (IHC and ISH) performed in a tumor specimen from being reported as positive, negative, or equivocal. This may occur if specimen handling was inadequate, if artifacts (crush or edge artifacts) make interpretation difficult, or if the analytic testing failed. Another specimen should be requested for testing, if possible, and a comment should be included in the pathology report documenting intended action.
- •
Must ensure that interpretation and reporting guidelines for HER2 testing are followed.
- •
Should interpret bright-field ISH on the basis of a comparison between patterns in normal breast and tumor cells, because artifactual patterns may be seen that are difficult to interpret. If tumor cell pattern is neither normal nor clearly amplified, test should be submitted for expert opinion.
- •
Should ensure that any specimen used for HER2 testing (cytologic specimens, needle biopsies, or resection specimens) begins the fixation process quickly (time to fixative within 1 hour) and is fixed in 10% neutral buffered formalin for 6 to 72 hours and that routine processing, as well as staining or probing, is performed according to standardized analytically validated protocols.
- •
Should ensure that the laboratory conforms to standards set for CAP accreditation or an equivalent accreditation authority, including initial test validation, ongoing internal quality assurance, ongoing external proficiency testing, and routine periodic performance monitoring.
- •
If an apparent histopathologic discordance is observed in any HER2 testing situation, the pathologist should consider ordering additional HER2 testing, conferring with the oncologist, and should document the decision-making process and results in the pathology report. As part of the HER2 testing process, the pathologist may pursue additional HER2 testing without conferring with the oncologist.
- •
Must report HER2 test result as negative if a single test (or all tests) performed in a tumor specimen show (a) IHC 1+ negative or IHC 0 negative or (b) ISH negative using single-probe ISH or dual-probe ISH.
CLIA, Clinical Laboratory Improvement Amendments; IHC, immunohistochemistry; ISH, in situ hybridization.
Immunohistochemical testing of HER2 has suggested the presence of heterogeneity in anywhere from less than 1% to 30% of tumors, although a carefully performed recent analysis suggests a rate of 5% for FISH. For HER2 testing by in situ hybridization, amplified cells can be present diffusely (the standard pattern) or as a minor population in either intermixed or clustered patterns. Although there are limited data to suggest significant differences in outcomes between clustered and intermixed minority HER2 amplified cells, current CAP/ASCO HER2 testing guidelines recommend counting clustered cell populations separately.
A common early problem with HER2 testing involved the lack of concordance seen between local and central laboratories, which occurs even in the hands of expert pathologists. An analysis of samples from three large adjuvant trastuzumab trials revealed 92% concordance among three expert pathologists for both IHC and FISH. It is likely that results are worse in labs that do not routinely test for HER2 or have a pathologist that does not regularly evaluate HER2.
HER2-Targeted Therapy
The realization that HER2 represents an important part of breast cancer biology led to the development of specific HER2-targeted therapies. Currently four US Food and Drug Administration–approved agents are in clinical practice in the neoadjuvant, adjuvant, and metastatic settings, and many other agents are currently in development. A listing of current FDA-approved HER2-targeting agents is provided in Table 56.1 .
| Drug | Indication(s) |
|---|---|
| Trastuzumab | Adjuvant (with or after chemotherapy) |
| Neoadjuvant (in combination with trastuzumab and docetaxel) | |
| Metastatic (first-line with a taxane; monotherapy after one or more chemotherapy regimens) | |
| Pertuzumab | Neoadjuvant (in combination with trastuzumab and docetaxel) |
| Metastatic (in combination with trastuzumab and docetaxel for frontline therapy) | |
| Ado-trastuzumab emtansine | Metastatic (after prior trastuzumab and a taxane) |
| Lapatinib | Metastatic (in combination with (1) capecitabine, after prior therapy including an anthracycline, a taxane, and trastuzumab; or (2) letrozole in hormone receptor–positive, HER2-positive postmenopausal women |
HER2 Metastatic Therapy
HER2-targeted therapy entered the therapeutic armamentarium in 1998 with the results of the pivotal Slamon trial. This trial randomized women with metastatic, previously untreated disease to either chemotherapy alone or chemotherapy plus trastuzumab. When the trial was initiated in the 1990s, doxorubicin represented the standard of care frontline metastatic chemotherapeutic agent. As the trial progressed, however, the increasing use of anthracyclines in the adjuvant setting, and the advent of taxanes in the metastatic setting, limited accrual of patients receiving frontline metastatic doxorubicin, leading to the amendment of the trial to allow the use of paclitaxel as the chemotherapeutic backbone.
This proved to be exceptionally fortunate, and not merely because of the increasing use of metastatic taxane therapy. Unbeknownst to the trial’s investigators, the combination of doxorubicin and trastuzumab resulted in a large cardiotoxicity signal, with a significant increase in congestive heart failure. Subsequent work suggested that HER2 represents an important prosurvival/antiapoptosis signaling mechanism for cardiac myocytes, and interrupting that signaling in the setting of cardiac stress results in myocyte death and clinical congestive heart failure. This is not, fortunately, an issue of similar concern when combined with taxanes.
Subsequent to the initial approval of trastuzumab for metastatic breast cancer, investigators spent much of the next decade studying secondary questions, including optimal therapeutic partners, treatment past first progression, and the role of HER2-targeted therapy in classically HER2-negative tumors.
To summarize what is now a relatively immense literature, trastuzumab may be combined safely with virtually every nonanthracycline chemotherapeutic agent used for the treatment of breast cancer. There is no convincing evidence that any particular chemotherapeutic “dance partner” is superior to any other, although phase III trials comparing chemotherapy/trastuzumab combinations are notable for their absence from the medical literature. An important exception involves paclitaxel itself, where weekly paclitaxel is superior to the initial every 3-week paclitaxel regimen when combined with trastuzumab.
Roughly half of all HER2-positive patients are also ER positive, leading to the reasonable question of whether HER2-targeted therapy should be combined with ER-targeted therapy in the metastatic setting. This question has been asked in phase III trials with both trastuzumab and lapatinib. For both HER2-targeting agents, phase III trial data suggest that overall response rate and progression-free survival are improved by the addition of HER2-targeted therapy to ER-targeted therapy with an aromatase inhibitor. These trials, however, do not address an important question: is the combination of HER2-targeted therapy with ER-targeted therapy as good as the combination of chemotherapy and HER2-targeted therapy? Although we do not have an answer to this question, for the many patients who are intolerant of or unwilling to accept chemotherapy, the combination of HER2-targeted therapy plus an aromatase inhibitor represents a reasonable therapeutic option.
The question of treatment past first progression long vexed medical oncologists. Given the relative safety of trastuzumab in the metastatic setting, and the continuing presence of HER2 on the cell surface of tumors growing through trastuzumab-based therapy, many inclined to continue trastuzumab-based therapy. The question was not, however, successfully answered in the metastatic setting until von Minckwitz and colleagues compared capecitabine to the combination of capecitabine plus trastuzumab in patients progressing on frontline trastuzumab. The combination was statistically superior to capecitabine monotherapy with regard to response rate and progression-free survival and numerically (although not statistically) superior for overall survival.
Trastuzumab was also evaluated in classically HER2-negative metastatic breast cancer. What to call “positive” for HER2 has represented a continuing source of disagreement among medical oncologists and pathologists. If one uses too strict criteria for HER2 positivity, one might well undertreat patients who would benefit from HER2 targeted therapy; in contrast, too loose criteria would result in overtreatment with an expensive (albeit relatively nontoxic) agent. However, in classically HER2-negative metastatic breast cancer, the addition of trastuzumab to paclitaxel failed to improve progression-free or overall survival in a phase III trial. Whether this lesson also holds in the adjuvant setting is currently being studied in a phase III trial being conducted by the NRG cooperative oncology group.
Subsequent to the approval of trastuzumab for patients with metastatic breast cancer, three other HER2-targeting agents have entered routine clinical practice. These include a small molecule receptor tyrosine kinase inhibitor (lapatinib) and two novel HER2-targeting monoclonal antibodies (pertuzumab and T-DM1).
Lapatinib is a small molecule receptor tyrosine kinase inhibitor of HER1 and HER2. Preclinically the combination of lapatinib with trastuzumab was synergistic. Early metastatic trials suggested significant single-agent activity similar to that seen with trastuzumab, as well as the suggestion of a combinatorial benefit. A large phase III trial in patients progressing on trastuzumab compared the use of capecitabine alone with the combination of capecitabine and lapatinib in HER2-positive patients and demonstrated a significant improvement in progression-free survival, although ultimately no improvement in overall survival was seen. This result led to the FDA’s approval of lapatinib in combination with capecitabine in patients whose tumors had progressed while on trastuzumab-based therapy for metastatic disease. More recently, lapatinib was compared with trastuzumab in a large phase III randomized controlled trial as frontline therapy in the metastatic setting, where it demonstrated therapeutic inferiority.
Pertuzumab is a monoclonal antibody that binds to the external membrane domain of HER2, where it interferes with HER2 dimerization and subsequent activation. Although not exceptionally effective as monotherapy in patients previously treated with trastuzumab, the combination of trastuzumab and pertuzumab showed significant combinatorial activity, and little added toxicity, in the metastatic setting. Early phase I/II trial results led to a large phase III randomized controlled trial (the CLEOPATRA—Clinical Evaluation of Pertuzumab and Trastuzumab trial).
CLEOPATRA randomized patients with frontline metastatic breast cancer to receive docetaxel plus trastuzumab or docetaxel plus trastuzumab plus pertuzumab. Patients were eligible if they had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease. The addition of pertuzumab to trastuzumab in this setting was associated with an impressive increase in both progression-free and overall survival. Updated data from this trial suggest that median overall survival was improved from 40.5 months in the control arm to 56.8 months in the combination arm, an impressive increase with important implications for adjuvant trial design.
Although relatively devoid of clinical additive toxicity (in particular, there is no increased rate of congestive heart failure), the combination has significant financial toxicity. A recent cost-benefit analysis of the winning CLEOPATRA regimen suggested that the addition of pertuzumab cost $713,000 per quality-adjusted life year gained, an impressive and discouraging number that puts the combination in the unenviable position of being unaffordable over most of the planet.
T-DM1 represents the other recently FDA-approved agent for metastatic HER2-positive breast cancer. T-DM1/ado-emtansine represents the linkage of trastuzumab to a maytansinoid plant poison, the latter working through its potent antimicrotubule effects. Trastuzumab carries the DM1 to the HER2-positive breast cancer cell, where the linkage is broken intracellularly through lysosomal action. The DM1 is then freed to damage the cancer cell’s microtubules.
After initial phase I and II trials demonstrated relative safety and activity in previously treated patients, the agent was tested in a phase III randomized controlled trial comparing the agent to the existing standard of capecitabine plus lapatinib. The trial demonstrated that T-DM1 was more active than the combination of capecitabine plus lapatinib, with a median overall of 30.9 months versus 25.1 months. This benefit also combined with significantly less toxicity, leading to the FDA approval of T-DM1 and its rapid incorporation into standard practice in previously treated patients.
Subsequently, the combination of T-DM1 with pertuzumab has been compared with the combination of a taxanes plus trastuzumab for first-line metastatic breast cancer (the MARIANNE study; A Study of Trastuzumab Emtansine [T-DM1] Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer). Regrettably, this combination did not prove superior to the standard taxanes + trastuzumab combination.
Taken together, these trials suggest a strategy in the metastatic HER2-POSITIVE-positive stating in which patients initial receive the combination of a taxane with pertuzumab and trastuzumab (per the CLEOPATRA trial) followed by T-DM1. After T-DM1, things become murkier, with options including the lapatinib/capecitabine combination, the combination of a taxane with a nontaxane chemotherapeutic, or the combination of lapatinib and trastuzumab. No sufficiently well-sized studies exist to demonstrate the best path forward in such relatively refractory populations nor whether such combinations prolong survival in patients who have received prior pertuzumab or T-DM1.
Of note, it is worth mentioning that patients should be retested for HER2 expression at the time of development of metastatic disease. As reviewed by Penault-Llorca and coworkers, discordance for HER2 is approximately 8% to 10%, with HER2 gain (as measured by FISH) being more common than HER2 loss.
Recent work in the clinic has focused on mechanisms of resistance to HER2 and their possible therapeutic implications. Preclinical data suggested that aberrant activation of the PI3K/Akt/mTOR intracellular signaling pathway (through loss of PTEN or mutations in PIK3CA, the catalytic subunit of PI3K) resulted in resistance to trastuzumab. This recognition led to the use of mTOR inhibitors as a therapeutic strategy. Everolimus, previously approved for use in ER-positive breast cancer, was examined in two separate phase III trials (BOLERO-1 and BOLERO-3, Breast Cancer Trials of OraL EveROlimus). In the former, patients were randomized to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab as frontline therapy. For the overall group, progression-free survival was not significantly improved, although in the hormone receptor–negative, HER2-positive subpopulation, progression-free survival was improved by 7 months, a finding that should be considered exploratory and hypothesis generating. In the latter trial, patients with prior trastuzumab exposure were randomized to receive daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m 2 ) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles. Median PFS was 7 months with everolimus and 5.78 months with placebo (hazard ratio 0.78, p = .0067). In both studies, everolimus produced side effects similar to those seen in patients treated in the ER-positive setting.
HER2 Adjuvant Therapy
After the initial results of randomized controlled trials of HER2-targeted therapies, trials aimed at the treatment of micrometastatic disease were initiated. Several of these trials came to completion in 2005 and transformed the care of patients with early-stage HER2-positive disease.
Four large (and several smaller) adjuvant trials represented the first wave of therapy for micrometastatic disease. Collectively these trials approached the large question of whether HER2-targeted therapy improved overall therapeutic outcome in early-stage HER2-positive disease, although each trial asked this question in different ways, offering us a mosaic of findings.
With regard to the important question of whether HER2-targeted therapy improved outcome in HER2-targeted disease, the unequivocal answer was a resounding “yes.” In each of the large trials, trastuzumab-based adjuvant chemotherapy significantly, even dramatically, improved disease-free survival, and subsequent follow-up from these trials has demonstrated an improvement in overall survival. Long-term follow-up of the joint analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and North Central Cancer Treatment Group (NCCTG) trials has demonstrated that the initial benefit seen with adjuvant trastuzumab persists for at least a decade, with an improvement in 10-year overall survival from 75.2% to 84%.
These benefits were seen whether trastuzumab was given in combination with chemotherapy (as was performed in the NSABP, NCCTG, and Breast Cancer International Research Group (BCIRG) trials or when given subsequent to adjuvant chemotherapy, as was performed in the HERA trial. Whether trastuzumab is best given in combination with or after chemotherapy remains an open question. The NCCTG adjuvant trial performed a randomization of combination versus sequence as part of the larger trial, and although underpowered, the results suggest that combination may be superior to sequence.
Similarly, the BCIRG-006 trial examined the role of anthracycline-based versus platinum-based chemotherapy. With regard to efficacy, both trials were compared with a nontrastuzumab-based control group, and the results are underpowered to demonstrate a difference, although the anthracycline-based arm is numerically but not statistically better. From a toxicity standpoint, the anthracycline-based arm has a slightly larger number of cardiac events (primarily congestive heart failure and ejection fraction decline), as would be suspected, although this did not translate to an increase in cardiac deaths. Both approaches have impassioned supporters.
Collectively the first generation of large adjuvant trials demonstrated that adjuvant trastuzumab could be given safely and could improve both disease-free and overall survival. Based on these results, adjuvant trastuzumab rapidly entered the oncologist’s therapeutic portfolio and represents the appropriate standard of care on a global basis for patients with early-stage HER2-positive breast cancer.
Although this was accepted early on by physicians and regulatory authorities, several remaining questions were not answered by the initial suite of studies and, in some cases, remain unanswered today. These are discussed in the following sections.
Duration of Adjuvant Trastuzumab
The four large randomized trials all used a year’s worth of trastuzumab, for totally arbitrary reasons. At the same time, the smaller Finland Herceptin (FinnHER) trial suggested that a relatively short course of adjuvant trastuzumab could be as beneficial as a year of therapy. Subsequent adjuvant trials, and longer follow-up of the initial HERceptin Adjuvant (HERA) trial, have compared the 1-year standard to either shorter (6 months) or longer (2 years) periods of therapy with adjuvant trastuzumab. Analysis of these trials suggests that 6 months is inferior to, and 2 years no different from, a year of adjuvant trastuzumab, which remains the standard of care.
Predictors of Response to Adjuvant Trastuzumab
Because the initial large randomized trials all collected tissue specimens for subsequent analysis, several studies have been performed evaluating prediction of benefit or—the other side of the coin—resistance. In general, these analyses have proven frustrating or inconclusive, often due to lack of statistical power and other methodologic issues.
Recent data have suggested that the immune system may play an important role in trastuzumab’s adjuvant efficacy. An analysis of tumor specimens collected in the NCCTG-9832 trial demonstrated that patients whose cancers expressed an immune signature were significantly more likely to receive adjuvant benefit.
Although this marker of benefit is extremely interesting and may explain the lesser benefit of small molecule receptor tyrosine kinase inhibitors seen in the metastatic and adjuvant settings, it is not sufficiently advanced in development to recommend its routine use as a therapeutic biomarker.
Role of HER2 Variants
Although the initial suite of trials all required that patients be called HER2-positive (by either IHC or FISH), testing was performed both locally and centrally, allowing for exploration of several different issues. Again, in all of these analyses, the statistical powering was poor, leading to legitimate concerns over the results. Some breast cancers demonstrate heterogeneity for HER2 expression, and analyses of these tumors suggested that tumors with foci of HER2-positive cells received adjuvant benefit similar to that seen with tumors that were relatively more homogenous.
Similarly, in cases where a tumor was called positive for HER2 based on local analysis but where subsequent central analysis suggested that the patient was not HER2-positive by standard criteria (e.g., a FISH ratio <2), patients still appeared to receive benefit from adjuvant trastuzumab. Although one possible explanation for these results is simple pathologic misclassification due to sampling error or misreading, the interest in and potential importance of this question led to the development of a large adjuvant trastuzumab trial (NSABP B-47) in patients with lesser HER2 expression (IHC 1–2+).
Role of Adjuvant Trastuzumab in Small, Lymph Node–Negative Tumors
The initial HER2 adjuvant trials were largely performed in patients with either larger or lymph node-positive tumors. As such, they left unanswered an important question: how low should one go with HER2-targetd adjuvant therapy? Numerous retrospective analyses have suggested that HER2 positivity increases risk of recurrence in smaller node-negative tumors. Given the relative safety of HER2-targeted therapy, should patients with smaller (<2 cm), lymph node–negative patients receive adjuvant trastuzumab?
Although no randomized controlled trials exist to answer this question definitively, Tolaney and colleagues performed a large registration trial in 406 patients with lymph node negative tumors up to 3 cm in size. Patients received weekly treatment with paclitaxel (80 mg per square meter of body surface area) and trastuzumab for 12 weeks, followed by 9 additional months of every-3-week trastuzumab. The 3-year survival free from invasive disease was 98.7%, with only two distant metastases among the 12 recurring tumors. Relatively few (18.9%) patients entered in this trial had T1a (≤0.5 cm) tumors, rendering conclusions about this low-risk group uncertain. Nevertheless, the results reported support the use of adjuvant trastuzumab in combination with paclitaxel in small, node-negative HER2-positive cancers.
Related posts:
Anatomy of the Breast, Axilla, Chest Wall, and Related Metastatic Sites
Mesenchymal Neoplasms and Primary Lymphomas of the Breast
Therapeutic Value of Axillary Node Dissection and Selective Management of the Axilla in Small Breast Cancers
Surgical Management of Early Breast Cancer
Neoadjuvant Chemotherapy and Radiotherapy
Delayed Diagnosis of Symptomatic Breast Cancer
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
