What is the best pharmacotherapeutic strategy for HER-2 positive breast cancer?

KEYWORDS:

• HER2
• breast cancer
• adjuvant
• metastatic
• trastuzumab
• pertuzumab
• T-DM1
• lapatinib
• neratinib
• chemotherapy

1. Introduction

Amplification of the human epidermal growth factor receptor 2 (HER2) oncogene occurs in about 15% of newly diagnosed, operable breast cancer, and in about 20% of patients with advanced breast cancer [1]. This genetic abnormality, which results in overexpression of the HER2 receptor, was recognized in the 1980s as a potent cancer driver [2]. Efforts at trying to neutralize this driver by pharmacological approaches have produced three monoclonal antibodies (trastuzumab, pertuzumab, and the antibody-drug conjugated T-DM1) and two tyrosine kinase inhibitors (lapatinib and neratinib) that are available for clinical use [3]. Pharmacological targeting of HER2, with monoclonal antibodies in particular, has dramatically improved the outlook of HER2-positive breast cancer, both in the adjuvant and in the metastatic setting, with notable increases in life expectation (Tables 1 and 2) [4–15].

Table 1. Selection of the most influential randomized clinical trials of anti-HER2-treatments in the metastatic setting.

Author	Setting	Treatment	N of Pts	Median PFS or TTP (months)	Median OS (months)
Slamon [4]	MBC, I line	Chemotherapy (Paclitaxel or cyclophosphamide + an anthracycline) + trastuzumab vs Chemotherapy alone	234	7.4 vs. 4.6 P < 0.001	25.1 vs. 20.3 P = 0.046
Marty [5]	MBC, I line	Trastuzumab + docetaxel vs docetaxel alone	186	11.7 vs. 6.1 P = 0.0001	31.2 vs. 22.7 P = 0.0325
Geyer [6]	MBC, trast. resistant	Lapatinib capecitabine vs capecitabine	399	8.4 vs. 4.4 P < 0.001	18.8 vs. 16.2 P = 0.210
Von Minckwitz [7]	MBC, trast resistant	Trastuzumab capecitabine vs capecitabine	156	8.2 vs. 5.6 P = 0.0338	25.5 vs. 20.4 0.257
Swain [8]	MBC, I line	Docetaxel, trastuzumab and pertuzumab vs Docetaxel and trastuzumab	808	18.7 vs. 12.4 P < 0.001	56.5 vs. 40.8 P < 0.01
Verma [9]	MBC, trast. resistant	T-DM1 vs lapatinib and capecitabine	991	9.6 vs. 6.4 P < 0.001	30.9 vs. 25.1 P < 0.001
Krop [10]	MBC, trast. and lap. resistant	T-DM1 vs TPC	602	6.2 vs. 3.3 P < 0.0001	22.7 vs. 15.8 P < 0007

MBC, metastatic breast cancer; PFS, progression-free survival; TTP, time to progression; OS, overall survival.

Table 2. Summary of the most influencing randomized trials in the adjuvant setting.

Author	Arms	N. patients	Timepoint	(i)DFS (%)	OS (%)
Cameron [11]	Chemotherapy Chemotherapy → 1y T Chemotherapy→ 2y T	5012	10 years	63 69* 69*	73 79* 80*
Perez [12]	AC→P AC→PT→T	4046	10 years	62.2 73.7*	75.2 84.0*
Slamon [13]	AC→D AC→DT→T DCT→T	3222	10 years	67.9 74.6* 73.0*	78.7 85.9* 83.3*
Von Minckwitz [14]	A(E)C→PT→T or DCT Same as above plus Ptz.	4804	3 years	93.1 94.2**	96.7 96.2
Martin [15]	Placebo Neratinib 1 y	2840 completing prior adj. trast.	5 years	87.7 90.2***	N.A.

T, trastuzumab; (i)DFS, disease-free survival or invasive disease-free survival; OS, overall survival; AC, doxorubicin and cyclophosphamide; P, paclitaxel; D, docetaxel, C; carboplatinum; E; epi-doxorubicin; Ptz, pertuzumab; N.A., non available.

*Difference with the comparator, trastuzumab-free arm is statistically significant.

**Difference with the comparator, pertuzumab-free arm is statistically significant.

***Difference over placebo is statistically significant.

2. Metastatic breast cancer

Over two decades, the median survival of patients diagnosed with advanced, HER2 positive breast cancer has improved by about 3 years, with a first notable increase adding trastuzumab to chemotherapy [4], and a second one by adding pertuzumab to trastuzumab and chemotherapy [8]. Furthermore, newer agents to treat trastuzumab-resistant disease have become available, like T-DM1, which has been associated to increased overall survival in patients with trastuzumab-resistant disease, even when used after several lines of treatment [9]. Consequently, a taxane plus trastuzumab and pertuzumab is now recommended as the optimal first-line treatment for patients with trastuzumab sensitive disease [16]. For patients with metastatic disease that have progressed on trastuzumab or shortly after the completion of adjuvant treatment with this monoclonal antibody, T-DM1 is the preferred option, based on its superiority compared to the former standard of treatment for these patients (lapatinib and capecitabine). Notably, improvements in disease outcomes were obtained without significant increases in toxicities or even reduced toxicity, as was the case with T-DM1. Differently, from these two pharmacotherapeutic strategies, the approach to patients with disease that is resistant to both pertuzumab and T-DM1 is not based on randomized trials conducted in this population, but on historical experience. While lapatinib plus capecitabine seems to be a reasonable choice, trastuzumab with other chemotherapy agents or trastuzumab and lapatinib are suggested options (Table 1) [16].

3. Operable breast cancer

The addition of trastuzumab to standard adjuvant chemotherapy has been one of the major achievements in the treatment of breast cancer [17]. In designing the trastuzumab-containing arms of the pivotal adjuvant trials, researchers had to deal with a number of issues related to prior experience in the metastatic setting (Table 2). To exploit its full anticancer activity, trastuzumab had to be administered concurrently with chemotherapy. Unexpectedly, concomitant administration with anthracyclines resulted in prohibitive cardiac toxicity [4]. Since anthracycline is a pivotal component of adjuvant chemotherapy, especially in HER2-positive breast cancer, different approaches were initially studied to avoid concomitance or even exposure to these drugs. The prevailing one is the administration of sequential regimens of anthracycline and taxanes, starting trastuzumab with these latter drugs and prolonging the administration of this monoclonal antibody for a total of one year. Alternatively, researchers of the Breast Cancer International Research Group developed an anthracycline-free adjuvant regimen consisting of docetaxel, carboplatinum, and trastuzumab for 6 months, followed by trastuzumab alone to complete 1 year of treatment. Recently, based on the results of pertuzumab in the metastatic setting, this monoclonal antibody was studied in a large, adjuvant trial [14]. Overall, double HER2 targeting with trastuzumab and pertuzumab added to adjuvant chemotherapy (either anthracycline followed by taxanes or docetaxel and carboplatinum), resulted in a significant, yet clinically marginal increase in 3-year invasive disease-free interval-IDFS (0.9%). Based on a larger 3-year invasive disease-free survival (IDFS) advantage in patients at higher risk of relapse (i.e. axillary lymph-node positive), regulatory authorities approved pertuzumab for these patients. Finally, while extending adjuvant trastuzumab beyond 1 year was not proven effective, adding 1 year of the irreversible HER1/HER2 tyrosine kinase inhibitor neratinib upon completion of trastuzumab was associated with a significant IDFS survival, which was observed mainly in patients with HER2 positive and hormone receptor-positive tumors [15]. These results led to the approval of neratinib in this setting.

4. Open questions

Despite a number of pharmacotherapeutic choices in the treatment of HER2-positive breast cancer are informed by high-quality, randomized trials, the debate on the optimal approach to patients with this disease is still ongoing.

4.1. Depotentiation

The payoff of increased activity shown in the aforementioned trials is increased complexity, costs, and in some cases toxicities and burdens for the patients. Furthermore, in some settings, there is uncertainty regarding the expected magnitude of clinical benefit by further potentiating the currently available pharmacotherapeutic approaches. Therefore, researchers and clinicians are becoming more and more interested in evaluating depotentiated tailored approaches. In the adjuvant setting, two large Phase II trials evaluated a taxane-based, anthracycline-free adjuvant regime for patients at low risk of disease recurrence [18,19]. Although these regimens are now largely used, lack of formal comparisons with conventional regimens restricts their application either to very low-risk patients, or to those that would not tolerate a full course of adjuvant chemotherapy plus HER2 targeting. However, the excellent 7-year survival of the Tolaney trial, recently updated at the 2017 edition of the Annual Meeting of the American Society of Medical Oncology, demonstrates that a large proportion of patients with HER2 positive, early breast cancer are probably not in need of more chemotherapy subsequent to 12 weeks of taxanes plus trastuzumab. Similarly, in the metastatic setting, alternative first-line approaches are generally felt appropriate for unfit patients or for those who refuse chemotherapy [16]. Thus, at the present time, depotentiated pharmacotherapeutic approaches are often felt more like a sort of ‘plan B,’ rather than elective choices in well-defined categories of HER2-positive breast cancer patients.

4.2. Biomarker-based approach

Strictly related to the previous paragraph is the issue of biomarkers to inform therapeutic choices in HER2-positive patients. Intense research conducted over several years has elucidated the complexity and also the spectrum of diversity of HER2-tumors. Yet, despite a number of putative markers of resistance or susceptibility to HER2-targeting drugs, there is no other requisite than HER2 overexpression to establish eligibility to HER2 targeting and no biomarker that can suggest specific pharmacotherapeutic choice on a ‘patient’ level [20]. One example is the fact that the archetype of breast biomarkers, hormone receptor (HR) expression, stratifies HER2-positive tumors into two molecularly and clinically distinct entities (HER2+/HR+ and HER2+/HR−) [21]. Yet, treatment is not diversified according to HR co-expression, with the exception of a few ‘plan B’ situations [16].

4.3. Overcoming resistance

Despite notable achievements, de novo, as well as acquired resistance to HER2-targeted compounds, are still important drivers for pharmacological research [3]. Newer monoclonal antibodies are in development or in clinical testing, which are more effective at triggering antibody-dependent cell cytotoxicity, one of the putative mechanisms of trastuzumab and pertuzumab action. Newer antibody drug conjugates hold the promise of more effective internalization of the toxic compounds and are showing activity also in HER2 non-positive tumors or tumors resistant to T-DM1. A number of tyrosine kinase inhibitors are being tested with promising results especially in difficult-to-treat breast cancer subsets (i.e. central nervous system involvement). Finally, anti-HER2-treatments are being tested in combination with an endless list of newer compounds, cycline-dependent kinase 4/6 inhibitors, immune checkpoint inhibitors, PI3K/Akt/mTOR pathway inhibitors, just to cite a few. Results of ongoing and future randomized trials will probably add further therapeutic choices to our armamentarium.

5. Conclusion

Current evidence is strongly in favour of HER2-targeting with monoclonal antibodies as the cornerstone of the pharmacotherapeutic strategy to treat HER2-positive breast cancer. Trastuzumab plus pertuzumab added to chemotherapy is the preferred firs-line option for patients with newly diagnosed HER2-positive metastatic disease. Pertuzumab extends overall median overall survival by almost 16 months in these patients. Most importantly, extended survival is achieved at the price of little additional toxicity. In the setting of trastuzumab resistant disease, the antibody-drug conjugate T-DM1 overperforms other pharmacotherapeutic strategies, whether they include or not other anti HER2-compounds. Also in this case, overall survival benefits are obtained without an increase of side effects. On the contrary, T-DM1 results in less serious adverse events than comparators in randomized studies. Shifting these drugs in the adjuvant treatment, with evidence of efficacy already available for pertuzumab and possibly available in the next future for T-DM1, will hopefully fully reduce the incidence of metastatic-HER2-positive breast cancer. Yet, resistance to these compounds is a common phenomenon and the search for new drugs and pharmacological strategies to target HER2 positive disease will become even more intense in the next few years. Thus, ‘what is the optimal pharmacotherapeutic strategy to treat HER2 positive breast cancer’ will be a constantly returning question.

6. Expert opinion

In abstract, what is the best pharmacotherapeutic strategy for HER2-positive breast cancer has one simple and one complex answer. The simple answer relies on evidence-based medicine because current recommendations from scientific societies are based on large, well-designed prospective clinical trials enrolling thousands of patients (Tables 1 and 2) [16,17]. The complex one comes, in our opinion, basically from three problems: first, much of the clinical development of anti HER2 pharmacotherapeutic strategies has been incremental, building more effective treatments by adding newer ingredients to active backbones; second, although the molecular biology of HER2-positive tumors has been largely clarified, no biomarkers have been validated which could allow diversified treatment choices or that could inform treatment in resistant cases; third the current methodology of randomized trial might not fit completely the needs of precision medicine. In fact, in simple terms, a positive randomized trial declares that strategy A is superior to strategy B, thus qualifying strategy A as the best pharmacotherapeutic option in a certain setting. Although exploratory subset analyses may suggest different (or absent) magnitudes of benefit in patients with some features, they are hardly suited to inform clinical decisions. As a consequence, evidence-based medicine supports a ‘one treatment fits all patients’ type of approach, while HER2-targeting should offer opportunities to treatment tailoring and diversified pharmacotherapeutic approaches. Under this perspective, we believe the neoadjuvant setting offers unique opportunities for the identification and validation of new biomarkers for treatment tailoring, but we need a paradigm shift in designing and evaluating the results of these trials. Currently, regimens are compared in terms of differences in rates of pathological complete remission (pCR), which represents the maximum degree of sensitivity to pharmacotherapeutic strategies, still with the aim of establishing a winner and a looser. While this is legitimate, we believe that much attention should also be focused on patients who achieve pCR with the ‘looser’ regimen when this is also less toxic and complex than the winner. One notable example is the KRISTINE trial, where six cycles of Docetaxel, trastuzumab, and pertuzumab produced a pCR rate of 55.7%, which was just about 10% more than that observed in the comparison with T-DM1 and pertuzumab (44.4%) [22]. Superiority was confirmed by a significant p-value and chemotherapy plus double HER2 targeting remains the treatment of choice in the neoadjuvant setting. A similar pCR rate obtained with T-DM1 alone in the West German study ADAPT in women with HER2 positive and HR positive breast cancer (41%) [23], strongly suggests that T-DM1 might be a potentially less toxic and less expensive option for selected patients who need neoadjuvant therapy. While newer drugs will be always welcome, not using active drugs that we already have in a more rationale, biomarker-guided way will remain a missed opportunity to optimize the therapeutic strategy in HER2 positive breast cancer.

Declaration of interest

F Montemurro has received speaker honoraria from AstraZeneca, Novartis and Roche and Eli Lilly and Company as well as travel grants from Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee has received consultancy payments from Roche which holds the patents for Herceptin and Perjeta. Another referee has served on advisory boards for Servier, Sanofi, Abbot, Eli Lilly and Company, Novartis and Pfizer Inc and has acted as a consultant for Servier, Sanofi, and Novartis. This referee also declares serving on speaker’s bureaus for Novartis and has received travel expenses from Novartis and Pfizer Inc.

Additional information

Funding

Filippo Montemurro is supported by the Fondazione Piemontese per la Ricerca sul Cancro (FPRC) (onlus) 5 × 1000 fondi Ministero della Salute 2013, and the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2016 (code 19174).