It will be critically important to await the longer-term DFS and OS results from the neoadjuvant studies, as well as the adjuvant studies evaluating dual HER2 blockade, prior to these approaches truly becoming the standard of care.
This timely and comprehensive review nicely summarizes current data and state-of-the-art therapeutic approaches for patients with HER2-positive (HER2+) early-stage breast cancer. The current literature suggests that HER2 overexpression and/or amplification is found in approximately 15% to 20% of cases of early-stage breast cancer. As thoroughly reviewed by Brown-Glaberman et al, the incorporation of HER2-targeted agents, and particularly trastuzumab, into treatment protocols for early-stage HER2+ breast cancer has led to dramatic improvements in the therapy of this unique molecular subtype of breast cancer.
As the authors note, our combined joint analysis of the North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trials was the first data that demonstrated the striking impact of incorporating trastuzumab into adjuvant therapy for women with early-stage, potentially curable, HER2+ breast cancer. Both of these studies utilized similar anthracycline/taxane regimens and demonstrated a dramatic impact on both disease-free survival (DFS) and overall survival (OS) with the addition of trastuzumab. The Breast Cancer International Research Group (BCIRG) 006 trial was the first phase III adjuvant trial to include a non-anthracycline trastuzumab-containing investigational arm. Results from this important trial have led to debate regarding anthracycline-containing vs non–anthracyline-containing regimens, and this topic remains an area of ongoing discussion in the treatment of HER2+ breast cancer. As described by Brown-Glaberman et al, the 5-year DFS for the investigational arms in BCIRG 006-AC-TH and TCH-was in each case superior to AC-T. However, in addition to the summary presented by Brown-Glaberman et al, further details from this study are important to consider. This trial was only designed and powered to compare each investigational arm to the control arm. Compared with AC-T, the study reported a hazard ratio for AC-TH of 0.64 (P < .001), and a hazard ratio for TCH of 0.75 (P = .04); it was not powered to establish equivalence of TCH to AC-TH. Thus, it is inaccurate to conclude from this study that there is no statistically significant difference between AC-TH and TCH, since the study was not powered to address this question, as was recently thoroughly reviewed by Burstein et al. While BCIRG 006 clearly demonstrates significant superiority of each investigational arm-ie, AC-TH and TCH-compared to AC-T, no conclusion can be drawn suggesting that either DFS or OS for TCH are equivalent, or not, to that of AC-TH. In fact, the data do not rule out the possibility of inferiority of TCH to AC-TH.
The basis for this ongoing controversy is, of course, the incidence of cardiotoxicity associated with anthracyclines. However, we would point out that we, and others, have shown that the overall incidence of severe cardiotoxicity, or grade 3/4 cardiac dysfunction, is consistently low in a number of different anthracycline-based regimens. Again, as thoroughly summarized in this review, the incidence of severe cardiotoxicity in all of these anthracycline-containing arms, and trials, remains in the range of 2% to 3%. Indeed, the consistency of these findings now in multiple different studies provides reassurance as to the accurate incidence of cardiotoxicity with all of these anthracycline regimens.
For these reasons, as well as several others that are beyond the scope of this commentary, we-as do Brown-Glaberman et al-generally favor an anthracycline-containing regimen for most patients with HER2+ disease. Having said this, we would point out that we agree that the non–anthracycline-containing TCH regimen is also a reasonable choice for routine clinical use. In patients with substantial cardiac risk factors, we concur that there is a more compelling justification for considering use of TCH. One additional point we would make is that recent data have suggested that, unlike the cardiac toxicity of anthracyclines, the cardiac toxicity of trastuzumab is reversible in a substantial percentage of the patients in whom it occurs. Thus, we suggest that, in certain patients, if a decrease in left ventricular ejection fraction (LVEF) occurs and has not recovered within 4 weeks of discontinuation of trastuzumab, it is reasonable to reassess the LVEF later-specifically, 8 weeks after trastuzumab discontinuation-and if at this time there has been a substantial recovery of the LVEF, to cautiously re-initiate therapy with trastuzumab. As we have noted, there is no question that, while it is uncommon, doxorubicin is clearly associated with clinically significant cardiotoxicity, as is trastuzumab. Thus, it remains imperative that ultimately less cardiotoxic adjuvant programs, which potentially will not include anthracylines, be proven to be equally curative for early-stage HER2+ breast cancer.
As the authors note, given the enormous therapeutic impact of trastuzumab, it is of critical importance to accurately test for and identify HER2 in both early-stage and advanced breast cancer. Thus, we strongly recommend a low threshold for retesting for HER2 in borderline cases, or cases in which there are other ambiguities-for instance, focal heterogeneity. This theme of supporting a greater role for retesting is an important feature of the new American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, cited above.  An additional important aspect of these new guidelines is the revision of the fluorescence in-situ hybridization (FISH) criteria such that either a ratio ≥ 2.0 or an absolute value of ≥ 6.0 copies/cell of HER2 is now defined as a positive result. We would also point out that there are data suggesting a utility of testing with immunohistochemistry (IHC) in cases in which FISH results are borderline or negative, in addition to the more routinely used practice of testing with FISH in cases in which IHC is borderline (ie, 2+). Indeed, given the critical importance of accurately determining HER2 overexpression and/or amplification, consideration of proceeding with dual testing as a standard, with both IHC and FISH, is being further explored.
Another question of interest is whether patients with breast cancer that has modest or low levels of HER2 overexpression, but that does not meet the current definition of HER2+ breast cancer, may in fact benefit from HER2-targeted therapeutics. The NSABP, we, and others, have in retrospective subset analyses reported data that raise the question of a possible therapeutic benefit from trastuzumab in HER2-negative early-stage and metastatic breast cancer, determined with both IHC and FISH as currently conventionally defined.[8,9] These data, as well as the data cited by Brown-Glaberman et al, have led to the development of NSABP B47, currently in progress, which is evaluating the impact of trastuzumab in HER2 IHC 1+ and 2+, and FISH-, breast cancer.
Another evolving area is that of the optimal treatment of patients with HER2+ breast cancer that is otherwise low risk-specifically, those with smaller HER2+ primary cancers and node-negative disease. The authors nicely summarize recent data addressing this question, and we concur that in women with < 1 cm node-negative breast cancer (particularly T1b cancer), it is reasonable to consider a less toxic, shorter chemotherapy regimen, as recently reported by Tolaney et al. However, we generally recommend a regimen proven in one of the phase III randomized trials for women with HER2+ breast cancer > 1 cm, or if lymph node–positive as well. Indeed, as Brown-Glaberman et al point out, in a recent meta-anaylsis of patients with smaller HER2+ breast cancers, as all of these patients received standard adjuvant regimens, it is not clear in which patients therapy can be more limited. Thus, we disagree with one detail in the algorithm proposed by Brown-Glaberman et al-their specifically recommending the recently reported phase II paclitaxel/trastuzumab regimen as a general approach for patients with primary HER2+ breast cancer < 2 cm. We generally recommend this for those with < 1-cm node-negative disease, or in those with higher-risk disease who have substantial comorbidities and would likely have unusually significant side effects with one of the more commonly used phase III regimens.
Finally, the authors thoroughly review recent data on neoadjuvant therapy for HER2+ disease. As noted, two recent exciting neoadjuvant clinical trials have led to the US Food and Drug Administration’s accelerated approval of pertuzumab, a novel monoclonal antibody that also targets HER2, but at a unique epitope that is distinct from that targeted by trastuzumab. A series of phase II and phase III neoadjuvant studies have now been completed addressing dual HER2 blockade. In two phase II randomized trials, the addition of pertuzumab to current state-of-the-art therapy with any of several cytotoxic regimens in combination with trastuzumab led to a striking increase in the pathologic complete response rate. The consistency of these findings in both studies, and further data beyond the scope of this commentary, suggest that these findings are particularly clinically meaningful. For patients with HER2+ primary breast cancer > 2 cm, we in fact now routinely recommend treatment with pertuzumab in combination with trastuzumab and chemotherapy, as is recommended as the preferred regimen in the algorithm proposed by Brown-Glaberman et al. It is important to point out, however-as these authors do-that this approach does lead to a substantial increase in the costs incurred. For this, and other reasons, we would emphasize that it will be critically important to await the longer-term DFS and OS results from the neoadjuvant studies, as well as the adjuvant studies evaluating dual HER2 blockade, prior to these approaches truly becoming the standard of care.
Financial Disclosure:Dr. Chamberlin and Dr. Kaufman receive research support from and serve as consultants to Roche-Genentech; they also serve on the Steering Committee for Genentech-sponsored clinical trials.
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