Materials and methods
I investigated 20 clinical trials regarding treatment of HER-2 positive breast cancer, taking in account standard and new therapies available, in consideration of the latest ESMO/NCCN guidelines. Data regarding safety profile are also shown (especially concerning cardiac toxicity). Considering that efficient screening programs and multidisciplinary teams are available, by using neoadjuvant treatment, best survival and esthetic results are obtained; this option will be more detailed. A mention will be made for the surgical interventions needed. Some treatment options are only available in certain countries.
Treatment in Neo/Adjuvant Setting -
NCCN guidelines (reference numbers
not linked to data in text)
Regimens for HER-2-positive disease(6,7,8)
AC followed by T + trastuzumab ± pertuzumab(9) (doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab ± pertuzumab, various schedules)
TCH (docetaxel/carboplatin/ trastuzumab) ± pertuzumab
AC followed by docetaxel + trastuzumab ± pertuzumab(9)
Docetaxel + cyclophosphamide + trastuzumab
FEC followed by docetaxel + trastuzumab ± pertuzumab(9)
FEC followed by paclitaxel+ trastuzumab ± pertuzumab(9)
Paclitaxel + trastuzumab(10)
Pertuzumab+ trastuzumab + docetaxel followed by FEC(9)
Pertuzumab+ trastuzumab + paclitaxel followed by FEC(9).
Treatment in metastatic setting - NCCN guidelines (reference numbers not linked
to data in text)
Preferred first-line agents for HER-2-positive disease:
Pertuzumab+ trastuzumab + docetaxel (category 1)(4)
Pertuzumab+ trastuzumab + paclitaxel(4).
Other first-line agents for HER-2-positive disease:
Trastuzumab alone or with:
Preferred agents for trastuzumab-exposed HER-2-positive disease:
Ado-trastuzumab emtansine (T-DM1).
Other agents for trastuzumab-exposed HER-2-positive disease:
Lapatinib + capecitabine
Trastuzumab+ Lapatinib (without cytotoxic therapy).
Ideal treatment is from the following guidelines : NCCN 2015 version 3.2015 and ESMO v8–v30, 2015(1,2).
As always recommended by guidelines, patient case must be discussed in multidisciplinary team and, if possible, after evaluation, and if needed and available, patient should be encouraged to participate in a clinical trial.
A possible evaluation of the patient before any course of treatment in a multidisciplinary team brings more benefit for the patient.
Taking in account patient preference and stage of disease, a limited resection/breast conserving surgery is a feasible option with important esthetic results while maintaining similar overall outcome as classic approach.
Of course, neoadjuvant treatment is in many cases necessary and a close collaboration with the surgeon, radiotherapist, anatomopathologist, interventional radiologist (if taking in account image guided clip insertion) harvests best results.
For example, for a patient in Romania, recently approved in neoadjuvant setting - trastuzumab + taxane; for ideal situation - 4 X AC (anthracyclin, cyclofosfamide) followed by taxane + trastuzumab + pertuzumab. The combination taxane + trastuzumab will be given for 4 cycles, completed by current standard – trastuzumab till 1 year of treatment(8), although FinHer trial obtained similar results with just 9 weeks of treatment(6)- data still needs validation in a separate trial - the SOLD study (synergy or long duration study)(9).
What is clear is that 2 years of Tratuzumab treatment doesn’t bring further benefit - as shown in the Hera study. The Phare study did not manage to demonstrate the non-inferiority of Trastuzumab administration for 6 month instead of 12 month(8).
“Triple neoadjuvant therapy” (trastuzumab + pertuzumab + taxane) is fully sustained in the last NCCN guide; the ESMO guide (in course of review - awaits final results of the Aphinity study) sustains the combination Trastuzumab + Pertuzumab in high risk patients(IB-IIIC; T>2 cm regardless of lymph node status or >N1 regardless of primary tumor size)(1,2).
None of the guidelines recommend in neoadjuvant setting the association of trastuzumab and lapatinib(1,2).
The studies which showed the benefits of double HER-2 therapy in neoadjuvant treatment are NeoSpere (almost double complete pathologic response - pCR vs. trastuzumab + docetaxel) and Tryphaena (useful to note pCR 81% on estrogen receptor negative arm)(3-5).
Regarding the safety of the combination Trastuzumab + Pertuzumab - both studies (NeoSphere and Tryphaena) show a favorable safety profile, of course with recommended echocardiography (initial and at 6 weeks)(4,5).
Although severe cardiac events (like congestive heart failure) are rare and usually reversible after stopping the treatment, there are studies which try to asses new markers that reflect earlier the dysfunction of left ventricle.
There is still no evidence regarding the safety of concomitant Tratuzumab/Pertuzumab and anthracyclin, so the guidelines suggest avoiding this combination or giving the treatment subsequently(2).
Association of concomitant trastuzumab and taxane is safe and beneficial when compared to subsequent treatment(10).
As expected, after neoadjuvant chemotherapy it is very possible that the tumor would be difficult to be found by the surgeon at the moment of excision. Usual option in this case would be placing, under guided imaging, of clips before chemotherapy treatment, which will facilitate correct conservative removal of tumor afterwards. Also at the moment of surgery, after the removal of the tumor, another set of guidance clips may be placed, which will facilitate the radiotherapy doctor in planning an efficient localized treatment. Furthermore, if at time of surgery tissue margins are invaded (R1), clips/markers will facilitate the re-excision/shaving of needed areas to offer complete invasion free margins.
Pertuzumab is approved in combination with trastuzumab and chemotherapy as a first-line therapy for metastatic HER-2-positive breast cancer patients(11).
For trastuzumab-naive patients, where pertuzumab is not available, “first-line cytotoxic therapy should always be given in combination with trastuzumab”(12,13,14). In patients who have progression after initial therapy, anti-HER-2 therapy should be continued by either switching to TDM-1(preffered) or continuing trastuzumab and changing cytotoxic therapy or switching to lapatinib plus capecitabine(2).
Results of the anticipated phase III MARIANNE trial found that HER-2-positive metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) plus pertuzumab had similar progression-free survival (PFS) compared with those treated with trastuzumab plus a taxane-based chemotherapy(14).
“T-DM1 was approved in 2013 for HER-2-positive patients who had previously been treated with trastuzumab and a taxane chemotherapy based on the results of the phase III EMILIA study. Patients who received T-DM1 treatment lived almost 6 months longer compared with patients receiving lapatinib plus capecitabine, the previous standard of care (median overall survival 30.9 vs. 25.1 months)”(14,15,16). “The agent also demonstrated the ability to prolong PFS in the third-line setting. The phase III TH3RESA trial showed that HER-2-positive patients who had progressed on two or more previous HER-2-directed therapies including trastuzumab and lapatinib, had improved PFS compared with those treated with physician’s choice of chemotherapy”(14,17).
There are ongoing studies investigating TDM-1 in adjuvant setting.
Future prospects - neratinib
“Neratinib is a multikinase inhibitor targeted to epidermal growth factor receptor (EGFR), HER-2, and HER-4. Unlike lapatinib, which is a reversible inhibitor of HER-2 and EGFR, neratinib binds irreversibly to those kinases. Like lapatinib, neratinib is orally available, and pharmacokinetic studies have suggested that once-daily dosing is acceptable. In phase 1 development, common side effects included diarrhea, nausea, and fatigue”(18,19).
Interesting promising data for HER + comes from the “2-year follow-up data from investigators of the ExteNET study(5) which explored the benefit of neratinib after a year of adjuvant therapy with trastuzumab for patients with HER-2-positive disease”(18,19).
“The ExteNET trial enrolled 2821 patients (median age 52 years) with stage 1-3 HER-2-positive breast cancer. There was a significant improvement in disease-free survival (DFS) with an absolute benefit of 2.3% at 2 years for all patients, including a decrease in central nervous system events. Of great interest, patients with HR-positive breast cancer had even greater benefit from neratinib (4.2% absolute benefit). The major toxicity was diarrhea, with 40% of patients experiencing grade 3 diarrhea in the first 30 days of treatment. There was no protocol-mandated antidiarrheal prophylaxis in place. Studies have shown that loperamide prophylaxis ameliorates or prevents this side effect”(18,19,20).
“With a 2-year follow-up, it appears that the late addition of neratinib decreases breast cancer-related events at the expense of considerable diarrhea, and that the latter could be managed by a structured regimen of antidiarrheal prophylaxis”(18,20).
The continuous and complex evolution of targeted therapies for HER-2 overexpression, patient preferences, the importance of consulting the multidisciplinary team (surgeon-radiotherapist-anatomopathologist-oncologist), the possibilities and limits offered by health care in every region and experience of each center must guide our every medical decision to offer the patient the best benefits with highest safety profile.