Liquid Biopsy Tracks Herceptin Resistance in HER2+ Gastric Cancer


Liquid biopsy of circulating tumor DNA (ctDNA) is an “efficient” way to monitor resistance to trastuzumab (Herceptin, Genentech) and spot emerging resistance mechanisms in metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, according to a study from China.

Up to 23% of gastric cancers are HER2+, but the response rate of these tumors to trastuzumab is limited, and any resistance to the drug happens rapidly during treatment, De-Shen Wang, MD, PhD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, told Medscape Medical News.

“Currently, the underlying mechanism of trastuzumab resistance remains unclear, and strategies to overcome resistance are urgently needed,” said Wang.

“We found that liquid biopsy-based ctDNA profiling could promisingly predict the tumor shrinkage and progression, and the underlying mechanism for innate resistance and acquired resistance of Herceptin might be different due to the differences of observed HER2 copy numbers,” Wang added.

The study was published online in the journal Gut.

Researchers evaluated the consistency between molecular alterations in solid tumor biopsies and liquid (plasma) biopsies by sequencing a panel of 416 cancer-related genes from 78 patients with gastric cancer (46 HER2+ and 32 HER2–). They also performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track resistance during trastuzumab treatment and validate candidate resistance genes identified.

The molecular alterations detected in plasma provided a “good representation of the status of the tumor tissue, particularly at advanced stages,” the authors report in their article.

HER2 somatic copy number alterations (SCNA) were “highly consistent” with fluorescence in situ hybridization data, and the detected HER2 copy number variation was better than the plasma carcinoembryonic antigen level at predicting tumor shrinkage and progression, they note.

Most patients with innate trastuzumab resistance had high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance, they found.

PIK3CA/R1/C3 or ERBB2/4 mutations contributed “greatly” to resistance and led to worse progression free survival, whereas ERBB4 S774G mutation increased sensitivity to trastuzumab, Wang said.

The researchers also identified and confirmed NF1 as a resistance-related gene and found evidence that the combination of the HER2 inhibitor lapatinib (Tykerb, GlaxoSmithKline) and MEK/ERK inhibitor selumetinib (AstraZeneca) might overcome trastuzumab resistance.

“We propose that ctDNA profiling could provide helpful information to monitor the occurrence, dissect the potential molecular mechanisms, and provide helpful clues to therapy development for Herceptin resistance,” Wang told Medscape Medical News.

However, the technique, and this study, has several limitations, the authors note. First, although the 416-gene panel covered the majority of solid tumor-related genes, patients might have developed a mutation in a gene not covered by the panel. It’s also possible that the function of a protein encoded by a certain gene was regulated at the transcriptional, translational, or even post-translational level, and thus was not detected by DNA sequencing, they explain.

Second, they note that cell-free DNA (cfDNA) from plasma contains both cfDNA released from normal cells and ctDNA from limited tumor cells, leading to a lower tumor DNA content in the whole plasma cfDNA sample in most cases, which generates large amounts of “noise” and limits ctDNA detection sensitivity.

“A higher sequencing coverage depth might improve the detection sensitivity of ctDNA profiling to a certain extent but would not completely solve the problem due to the limited number of original tumor DNA molecules present in the cfDNA sample,” the authors suggest.

Breast cancer study finds ‘astonishing’ drug combination that gives results .


Using Herceptin in combination with another drug can shrink tumours in less than two weeks, study finds.

The findings could potentially lead to fewer women needing chemotherapy, researchers say.

Using Herceptin in combination with another drug before surgery shrinks and may even destroy tumours in women with an aggressive form of breast cancer in less than two weeks, an “astonishing” study suggests.

The results of the Cancer Research UK-funded trial, presented at the 10th European Breast Cancer Conference in Amsterdam, could – if successfully replicated – lead to fewer women needing chemotherapy.

Around a quarter of 66 women with HER2 positive breast cancer treated for 11 days with both trastuzumab (the generic name for Herceptin) and lapatinib saw their tumours rapidly shrink significantly or even disappear.

Prof Nigel Bundred, from the University of Manchester and the University Hospital of South Manchester NHS foundation trust, who presented the data, said: “This has groundbreaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumours disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy.

“This offers the opportunity to tailor treatment for each individual woman.”

Samia al Qadhi, chief executive at Breast Cancer Care, said: “The astonishing findings in this study show that combining these two drugs has the potential to shrink HER2 positive breast cancer in just 11 days.

“For some HER2 positive breast cancer patients the effect of this drug combination will be amazing and mean they can avoid chemotherapy and its gruelling side effects completely. For others, their tumours may not shrink, but doctors will know either way very quickly, giving them the ability to rapidly decide on further treatment.

“Although an early study, this has game changing potential. Yet before this can be made available we need to see more evidence. Particularly because, at present, trastuzumab’s (Herceptin) licensing means it is only available to be used alongside chemotherapy and not alone. All cancer patients deserve access to clinically effective treatments.”

Trial co-leader Prof Judith Bliss, director of the clinical trials and statistics unit at the Institute of Cancer Research, London, said: “It was unexpected to see quite such dramatic responses to the trastuzumab and lapatinib within 11 days.

“Our results are a strong foundation on which to build further trials of combination anti-HER2 therapies prior to surgery – which could reduce the number of women who require subsequent chemotherapy, which is also very effective but can lead to long-term side effects.”

The trial, led by researchers from Manchester University, the University Hospital of South Manchester NHS foundation trust and the Institute of Cancer Research, studied 257 women with HER2 positive breast cancer in the short gap between their initial diagnosis and surgery to remove their tumours.

Initially women were randomised to receive either trastuzamab or lapatinib or no treatment. Halfway through the trial, after evidence from other trials of the effectiveness of the combination, the design was changed so that additional women allocated to the lapatinib group were also prescribed trastuzumab.

Of the women receiving both, 17% had only minimal residual disease – defined as an invasive tumour smaller than 5mm in size – and 11% had no biological sign of invasive tumour in the breast. Of the women treated with trastuzumab only, 3% had residual disease or complete response.

HER2 positive breast cancer is more likely to come back after treatment than some other types of breast cancer. It is generally treated with surgery, chemotherapy, endocrine therapy and targeted anti-HER2 drugs.

Current treatments are effective, and complete response is common after three to four months, but observing a disease response so quickly took the researchers by surprise.

In the UK, around 53,000 women a year are diagnosed with invasive breast cancer, and in 10% to 15% of these cases it is HER2 positive breast cancer. Around 11,500 women die from the disease every year.

Herceptin was approved by the National Institute for Health and Care Excellence (Nice) 10 years ago after pressure from patients. Lapatinib has not been approved and so is not routinely available on the NHS due to its expense.

According to Cancer Research UK, current treatments are effective, and women often experience a complete response after three to four months. Nevertheless, researchers said the 11-day response was very surprising.

Prof Arnie Purushotham, senior clinical adviser at Cancer Research UK, said: “These results are very promising if they stand up in the long run and could be the starting step of finding a new way to treat HER2 positive breast cancers.

“This could mean some women can avoid chemotherapy after their surgery – sparing them the side-effects and giving them a better quality of life.”

Breast cancer drug turned down for NHS use due to high cost


Decision on Herceptin-style drug which costs £90,000 but can prolong lives by nearly six months heavily criticised

Watchdog blocks breast cancer drug

A new drug for breast cancer which extends women’s lives by almost six months is to be blocked from routine NHS access under draft guidance issued by a health watchdog. Photograph: Rui Vieira/PA

A Herceptin-style drug that can offer some women with advanced breast cancer nearly six months of extra life has been turned down for use in the NHS because of its high cost.

In draft guidance now open to consultation, the National Institute for Health and Care Excellence (Nice) blames the manufacturers, Roche, who are asking for more than £90,000 per patient, which is far more than any comparable treatment.

But the decision was criticised by Roche and some breast cancer charities, which say the drug is needed and that Nice has turned down too many breast cancer drugs already.

The drug, called Kadcyla (generic name trastuzumab emtansine), is already being paid for through the dedicated Cancer Drugs Fund set up by the government. A decision was made to fund it so that women with advanced breast cancer could receive it immediately it was available, without waiting for Nice’s assessment.

But the Nice verdict raises questions about the future of such expensive cancer drugs once the fund ceases to exist at the end of March 2016. At that point, a new pricing scheme for the NHS is intended to be in place, but Nice will still assess whether a drug is worth the price the manufacturer wants for it.

Kadcyla is a new kind of medicine, according to Roche, combining Herceptin (trastuzumab) with a chemotherapy agent. It is designed for women with HER2+ cancer which has spread to other parts of the body and is inoperable.

It is not a cure, but in trials it extended life by a median of 5.8 months, compared with the current combination of lapatinib plus capecitabine.

Nice says the drug does not work well enough to justify the price tag and called on Roche to rethink during the consultation period.

“We had hoped that Roche would have recognised the challenge the NHS faces in managing the adoption of expensive new treatments by reducing the cost of Kadcyla to the NHS,” said Nice chief executive Sir Andrew Dillon.

“This drug is already being funded through the special Cancer Drugs Fund. Our job is to recommend whether it should transfer into the NHS budget. We are very aware of the importance that people place on life-extending cancer drugs and a decision not to recommend a cancer treatment for routine NHS funding is never taken lightly.

“We apply as much flexibility as we can in approving new treatments, but the reality is that given its price and what it offers to patients, it will displace more health benefit which the NHS could achieve in other ways, than it will offer to patients with breast cancer.”

The cost of Kadcyla is tens of thousands of pounds more than existing second-line treatments for this cancer, said Nice.

Professor Paul Ellis, a consultant oncologist at King’s College, London, who worked on the drug trials, said in a statement issued by Roche that it “represents a significant advance in HER2-positive breast cancer, so for Nice to issue negative preliminary guidance is a huge blow.

“The drug tackles the disease in a different way to any other breast cancer medicine and provides women with valuable extra time with their families and loved ones – time that you cannot put a price on. Not only this, Kadcyla is also much better tolerated by women than current standard treatment options, causing much less in the way of traditional chemotherapy associated side effects. As such, the quality of life of women taking Kadcyla is significantly improved.The good news is that patients in England will still be able to access this treatment through the Cancer Drugs Fund, but we are keen to find a more permanent way to effectively assess the value of such drugs to ensure those who need them most can benefit from them.”

Jayson Dallas, general manager of Roche Products Limited, said the company was “extremely disappointed that Nice has failed to safeguard the interests of patients with this advanced stage of aggressive disease”.

Emma Pennery, clinical director at Breast Cancer Care, said: “It’s extremely disappointing news for those living with advanced breast cancer and their families that yet another treatment has not been recommended by Nice.”

Another patient group, Breakthrough Breast Cancer said Kadcyla was a very impressive drug but called for changes to the cost of drugs as well as the appraisal process. “We are now looking to the Department of Health and the pharmaceutical industry to find a way to work together to bring the cost of expensive drugs down and put a sustainable system in place by which new treatments can be made available on the NHS on a routine basis,” said senior policy manager, Dr Caitlin Palframan.

About 1,000 women a month die of advanced breast cancer, although not all of them have the HER2+ variety which the drug targets.

A spokesperson for NHS England said: “The Cancer Drugs Fund (CDF) provides an additional £200m each year to enable patients to access drugs that are not routinely funded by the NHS. A number of the drugs available to patients through the CDF have previously been appraised by Nice and are not recommended for routine use. It was for this purpose that the CDF was established.

“A negative Nice appraisal on trastuzumab emtansine will not affect the availability of this drug via the Cancer Drugs Fund.”

6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.


Background

Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.

Methods

We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30—90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901.

Findings

1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1—51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6—94·9) in the 12-month group and 91·1% (89·7—92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05—1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001).

Interpretation

After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care.

Source: Lancet

Trastuzumab for Women with HER2-Low Breast Cancer.


Name of the Trial
Phase III Randomized Study of Adjuvant Chemotherapy with versus without Trastuzumab in Women with Node-Positive or High-Risk Node-Negative HER2-Low Invasive Breast Cancer (NSABP-B-47). See the protocol summary.

Dr. Louis Fehrenbacher

Principal Investigator
Dr. Louis Fehrenbacher, National Surgical Adjuvant Breast and Bowel Project (NSABP)

Why This Trial Is Important
Women with breast cancer that tests positive for HER2 overexpression have benefited greatly from the development of trastuzumab (Herceptin). Trastuzumab binds to HER2, a receptor protein found in abundance on some cancer cells, and either prevents it from transmitting growth signals to the cell nucleus or “tags” the cells for destruction by the immune system.

The Food and Drug Administration has approved trastuzumab for use with or without chemotherapy in women with HER2-positive metastatic breast cancer. The drug has also been approved for use as an adjuvant therapy in combination with chemotherapy for women with HER2-positive operable breast cancer. In several adjuvant therapy trials, adding trastuzumab to standard chemotherapy led to significant improvements in disease-free and overall survival.

When researchers involved in one of the trials (NSABP B-31) reanalyzed the results and re-examined tumor tissue from the participants in a central laboratory after the trial’s conclusion, they found that nearly 10 percent of the women in the study had breast cancer that should have been classified as HER2-negative or low because their tumors expressed less HER2 protein or had lower HER2 gene copy numbers than the threshold set to be classified as HER2 positive. However, women with these “HER2-negative/low” tumors that had previously tested positive seemed to experience the same benefit from trastuzumab as women whose tumors were “correctly” classified as HER2 positive. Subsequent analyses of available tissue confirmed that the tumors did not express high enough levels of HER2 protein or gene copy numbers to be considered positive and, therefore, eligible for trastuzumab therapy.

The HER2 status of tumor tissue is determined by two different methods: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC measures the level (0, 1+, 2+, or 3+) of HER2 protein expression on the surface of cancer cells, whereas FISH indicates whether the HER2 gene is amplified, meaning that the cancer cells have more copies of the gene than is normal. Currently, for breast cancer to be considered HER2 positive (and the patient to be eligible for trastuzumab), the cells must have an IHC expression score of 3+ or gene amplification must be detected.

Nonetheless, many women have breast tumors that are classified as HER2 negative yet still show some level of HER2 overexpression as measured by IHC (scores of 1+ or 2+). Researchers want to find out whether women with these “HER2-low” breast cancers will benefit from adjuvant trastuzumab as women with classically defined HER2-positive tumors do, as the NSABP B-31 study suggested.

In this clinical trial, women who have recently undergone surgical resection for HER2-low breast cancer and are at high risk for recurrence (because of spread of the cancer to the lymph nodes and/or tumor size) will undergo adjuvant chemotherapy and be randomly assigned to 1 year of trastuzumab treatment or no trastuzumab. Doctors will assess participants’ disease-free and overall survival, as well as the toxicity of the treatments.

“In a large breast cancer population, we find that only about 15 percent of patients [have tumors that] are HER2 amplified or 3+, while those [with tumors] that are HER2 1+ or 2+ may be as much as 45 percent to 50 percent of the population,” Dr. Fehrenbacher explained. “So, this is a study that we really should do because of the potential huge impact of a positive result on the breast cancer burden in the United States.”

For More Information
See the lists of entry criteria and trial contact information or call the NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

Further reading: “Looking to Refine HER2-Targeted Therapy

Source:NCI.

 

Trastuzumab-Related Cardiotoxicity Following Anthracycline-Based Adjuvant Chemotherapy: How Worried Should We Be?


Trastuzumab has improved the clinical course of HER2-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings.16 The joint analysis of the National Surgical Adjuvant Breast and Bowel (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials demonstrated that the addition of 1 year of trastuzumab to sequential anthracycline-taxane chemotherapy reduced the risk of recurrence by approximately half (hazard ratio [HR], 0.48; P < .0001) and the risk of death by one third (HR, 0.67; P = .015).5 A similar benefit was seen in the Herceptin Adjuvant (HERA) trial, for patients randomly assigned to 1 year of trastuzumab (or not) given only after the completion of adjuvant chemotherapy.4 In all three of these initial reports, and as predicted by experience in the earlier metastatic disease trials, trastuzumab’s benefits are associated with the potential for increased cardiotoxicity.1 With broad adoption of adjuvant trastuzumab, it is appropriate to ask several related questions on this issue. How frequent and how severe is the toxicity and what modulates the risk?

Because of the cardiac safety signal in the earlier metastatic disease trials,7 the risk of serious and life-threatening cardiotoxicity with the combination of anthracyclines and trastuzumab was a recognized concern when these phase III adjuvant studies of trastuzumab commenced. To mitigate this risk, strict cardiac criteria that excluded patients predicted to have greater likelihood of cardiac toxicity were used. In addition, rigorous, if arbitrary, cardiac monitoring was incorporated to allow early detection of any signals of increased cardiac risk. Not knowing the magnitude of the benefit for trastuzumab, early stopping rules allowed an increase in congestive heart failure (CHF) and cardiac deaths of up to 4% in some studies, a limit that was nearly breached.8,9

Collectively, the available studies demonstrated that the risk of serious cardiotoxicity with adjuvant trastuzumab was lower than the preset threshold for early stopping and that trastuzumab-related cardiotoxicity, in contrast to anthracycline-induced cardiotoxicity, may occur as an early and reversible event. Perhaps because of increased awareness and scrutiny, the most frequent events were asymptomatic declines in left ventricular ejection fraction (LVEF) for which the long-term clinical significance is largely unknown.

In this issue of the Journal of Clinical Oncology, updated cardiac safety data are presented from patients treated with anthracyclines and trastuzumab in three of the previously reported adjuvant trastuzumab trials. First, Russell et al10 retrospectively reviewed patients with CHF in the NSABP B-31 and NCCTG N9831 studies. Patients with possible cardiac events were identified from the trial database and reviewed by a committee of six oncologists and cardiologists. These reviewers were independent of the original study and were blinded to trastuzumab treatment and the investigators’ original cardiac diagnosis. CHF was rigorously defined by symptoms, physical signs, and objective findings and included an LVEF drop of 10% or a drop to an absolute LVEF of < 50% by locally obtained multigated radionuclide angiography or echocardiogram. This independent review confirmed earlier risk estimates by showing that the addition of trastuzumab to anthracycline-based chemotherapy increased the incidence of CHF nearly four-fold, from 0.45% to 2.0%, at a median follow-up of 1.9 and 2.0 years, respectively. Among those assigned to trastuzumab, 133 (7.4%) patients with possible cardiac events were reviewed, yielding 36 that were deemed to have definitely suffered a cardiac event. Again, consistent with earlier reports,11 Russell et al note that a majority of these patients recovered completely (20 [55.5%]) or partially (11 [30.6%]). In addition, the independent review highlighted three cardiac deaths (< 0.2%) among 1,799 patients randomly assigned to trastuzumab. Two of these occurred before the initiation of trastuzumab. In an attempt to develop a risk stratification model for these adverse events, Russell et al identified age older than 50 years (2.84-fold increase v age < 50 years) and low LVEF post anthracycline treatment (P = .0106) as possible risk factors for cardiac events. Patients with baseline hypertension had a 1.89-fold increased risk of a cardiac event, although this result was not statistically significant.

In another article in this issue of JCO, Procter et al12 report a similar analysis from the HERA study. As expected, the most common cardiac event noted was a “significant” LVEF drop, defined as an absolute decline of at least 10 percentage points from baseline to below 50%. This occurred in 164 (9.8%) trastuzumab-treated patients compared with 49 (2.9%) controls. The clinical significance of these LVEF declines is unclear because they may have been spurious, or at least quickly reversible, since fewer than half these patients overall (73 or 4.3% overall) had a confirmed cardiac event (CHF or second confirmed LVEF decline). Indeed, these observed changes in LVEF rarely translated into symptomatic CHF, which occurred in 32 (1.9%) trastuzumab-treated patients versus two (0.1%) controls (difference, 1.8%; 95% CI, 1.1% to 2.5%).

In both of these articles, the increased rate of clinical CHF (1.9% and 2%) at a median follow-up of 3.6 and 2 years should be seen in the context of the absolute improvements in disease-free survival at 3 years (6.3% and 11.7%, respectively) attributable to the addition of adjuvant trastuzumab to anthracycline-based chemotherapy.5,13 Both articles suggest that these events are usually reversible. For example, in the article by Procter et al, 57 (78%) of 73 were deemed to have a favorable outcome. Reversibility is also suggested by the finding that they attributed no cardiac deaths to trastuzumab.13

Each of these two independent reviews of large prospective clinical trials offer evidence that long-term cardiotoxicity with trastuzumab following anthracycline-based chemotherapy for HER2-positive early breast cancer is relatively infrequent and generally associated with a favorable outcome. If this is reassuring, there remain several cautions and considerations. In these two analyses, cases were selected for review on the basis of previously documented cardiotoxicity, and the independent committees did not review original data from all enrolled patients. Although unlikely, it remains possible that other cardiac events may not have been reported. In addition, the independent review committees assessed reversibility on the basis of the weight of available evidence, but a prospective assessment of reversibility would have been preferable, as would incorporation of a standardized management approach for suspected CHF and possibly a quality-of-life measure to determine the true clinical significance of these events. Although the relatively constant rate of cardiac events in NSABP B-31 in years 1 to 3 suggests that longer-term follow-up is unlikely to change the results of any of these studies,14 relatively small numbers of patients have reached 4-year follow-up (> 500 in HERA). Since anthracycline-mediated cardiotoxicity may occur many years after treatment, we could still see unanticipated long-term effects in the future.

The articles by Russell et al10 and Procter et al12 add to the evidence that patients with HER2-positive early breast cancer and normal baseline LVEF can be safely treated with sequential anthracycline-taxane–based chemotherapy incorporating trastuzumab. The question many will ask is whether we should avoid the entire issue by substituting an evidence-based alternative such as docetaxel, carboplatin, and trastuzumab (TCH) from Breast Cancer International Research Group (BCIRG) 006, or even an as yet untested approach like docetaxel plus cyclophosphamide with trastuzumab (or other drugs). The former can be discussed with available phase III data; the latter has not yet been reported. To date, the significant evidence as reviewed above supports the routine use of sequential anthracyclines and trastuzumab with an overall low risk of cardiotoxicity demonstrated in more than 4,500 patients and confirmed on independent cardiac reviews of almost 3,500 of these (Table 1) . TCH is an alternative therapy, albeit one that has been tested only in a single trial where it did not appear to have inferior efficacy to a relatively standard anthracycline/taxane/trastuzumab regimen. For TCH, there are not yet long-term cardiac safety data for the approximately 1,000 treated patients.

An alternative way of framing the issue is to ask whether there is adequate evidence or reason to abandon anthracyclines followed by trastuzumab for HER2-positive breast cancer. Some in our community have already made this decision, but it is worth noting that the advantages of continuing to treat this way are that it offers a more consistently demonstrated overall survival advantage. The cardiac event rate for sequential anthracyclines and trastuzumab is higher than the same treatment without trastuzumab, but still low, and the events are largely reversible. The sequential use of generic anthracyclines and taxanes can possibly be less expensive than agents such as docetaxel; if the dose-dense approach is used, it can be safer and faster.16 In this regard, we note that in contrast to some preconceived expectations, patients with normal baseline LVEF can safely be treated with dose-dense anthracycline-based chemotherapy and trastuzumab with no evidence of an increased risk of short- or long-term cardiotoxicity to date.16,17 Additionally, experience at the M. D. Anderson Cancer Center has demonstrated that trastuzumab can be combined with both anthracyclines and taxanes in the preoperative setting with no increase in cardiac toxicity.18,19 This finding was confirmed in the randomized phase III Neoadjuvant Herceptin (NOAH) study, in which the addition of trastuzumab to preoperative chemotherapy doubled the complete response rate and, despite concurrent anthracycline-trastuzumab therapy, was associated with a similar low risk of cardiotoxicity.20

Yet another way to approach the issue is to ask whether there are patients without overt cardiac dysfunction whom we should select for an available non-anthracycline containing adjuvant regimen with trastuzumab. The current reports add to the growing evidence that older patients with borderline LVEF function and baseline hypertension may be at increased risk of cardiotoxicity, but no study has prospectively compared treatment regimens in this subset, and the alternative (TCH) might or might not be as toxic or more toxic in other ways for this population.15 The risk-benefit calculations for these patients are challenging, and predictive biomarkers to improve risk stratification and to predict for trastuzumab-induced cardiotoxicity are needed. Unfortunately, putative cardiac biomarkers such as troponin I and C-reactive protein have been disappointing, with no validated serum marker for cardiotoxicity emerging to date.21

Although the overwhelming body of evidence from rigorously conducted randomized control studies supports anthracyclines as the mainstay of current adjuvant trastuzumab-based chemotherapy regimens, the potential omission of anthracyclines for appropriately selected patients has become a major research focus. Subgroup tissue analyses from prospective trials attempting to more precisely define the role of anthracyclines have had conflicting results; some studies suggest that only HER2-positive tumors benefit from anthracyclines,22,23 and other data show that HER2-positive tumors do not benefit from the addition of anthracyclines.24 Attempts to omit anthracyclines from trastuzumab-based chemotherapy have focused on possible biomarkers such as the topoisomerase II alpha (TOPO-II) gene, the putative target of the anthracyclines, which is closely related to the HER2 gene on chromosome 17.25 Preliminary data from a subgroup analysis from BCIRG 006 suggested that anthracyclines may not be needed for trastuzumab-treated patients with coamplification of HER2 and TOPO-II. In contrast, recent data from the National Cancer Institute of Canada Clinical Trials Group Mammary.5 (MA5) trial, which randomly assigned patients to CMF or anthracycline-based chemotherapy, suggested that the anthracycline benefit was confined to patients with tumors with TOPO-II gene deletions as well as amplifications.26 Most strikingly, in a multivariate analysis, when adjusted for TOPO-II status, HER2-positive tumors continued to derive a survival benefit from anthracyclines (HR, 0.44; P = .02).26 The reasons for the extensive inconsistencies surrounding the putative predictive effect of TOPO-II are largely unclear. A possible explanation is that many studies have depended on fluorescent in situ hydridization (FISH) to determine TOPO-II status, and the width of commercial FISH probes may limit specificity. High-resolution techniques, such as comparative genomic hybridization or representational oligonucleotide microarray analysis (ROMA), which allow a more precise definition of these genes, have demonstrated that so-called amplification of HER2 and TOPO-II may be far more complex than previously thought.27 In part, the expression of other genes in the same area on chromosome 17 may play an important role in the interaction of HER2 and TOPO-II as detected by FISH.28 Finally, it is important to recall that TOPO-II is only one of several targets of anthracyclines in cancer. Given these uncertainties, TOPO-II status cannot be used to tailor therapy and, as recently noted in JCO, there are currently insufficient data to recommend replacing anthracyclines in general in adjuvant chemotherapy regimens.29 The current studies extend this caution to the HER2-positive setting in which trastuzumab is used.

One more related issue is the definition of the optimum duration of trastuzumab therapy and the potential interaction of duration on cardiac events. In the smaller Finland Herceptin (FinHer) study, the magnitude of benefit for 9 weeks of trastuzumab was similar to that seen in larger studies incorporating 1 year of therapy (Table 1).3 In the combined N9831–B-31 study, 29.5% of patients discontinued trastuzumab before the planned 1-year duration for reasons other than recurrence, compared with only 10.2% in the HERA trial.5,12 Despite this, there is neither a suggestion that the shorter delivered dose of trastuzumab was associated with an inferior outcome nor a change in cardiac risk. Relevant studies are ongoing, such as the French Protocol of Herceptin Adjuvant With Reduced Exposure (PHARE) study, in which patients are randomly assigned to either 6 months or 1 year of adjuvant trastuzumab, and the Synergism Or Long Duration (SOLD) study, in which patients are randomly assigned to 9 weeks or 1 year of trastuzumab in combination with sequential taxane-anthracycline chemotherapy.30,31

The incorporation of trastuzumab into adjuvant chemotherapy regimens for HER2-positive early breast cancer has been a major clinical advance. Long-term data from HERA and N9831–B-31 suggest that the benefits are durable and that cardiotoxicity is uncommon and generally reversible. Confirmation of equivalent efficacy for a non-anthracycline–containing regimen will be important as will the development of biomarkers and predictive models for toxicity.