Introduction

Breast cancer remains one of the leading causes of cancer-related death worldwide [1]. Although chemotherapy has improved outcomes for patients, the marginal benefits achieved with cytotoxic agents seem to have reached a plateau. Fortunately, technological advances have enabled the characterization of the molecular subtypes [2, 3] of breast cancer, which has, in turn, facilitated the development of molecularly targeted therapeutics for this disease. One subtype is distinguished by amplification of the gene encoding human epidermal growth factor receptor 2 (HER2). This subtype accounts for approximately 20–30% of invasive breast cancers, and until the discovery of effective anti-HER2 therapies (the first of which was trastuzumab), was associated with reduced disease-free survival (DFS), increased risk of metastasis and shorter overall survival (OS) [4, 5]. By 2005, the natural history of this breast cancer subtype in the adjuvant setting was forever changed with the release of the findings of first-generation adjuvant trials that combined trastuzumab with chemotherapy, concomitantly or sequentially.

HER2 is a member of the ErbB family of receptor tyrosine kinases (RTKs), which includes HER1 (epidermal growth factor receptor [EGFR]), HER3, and HER4. HER2-mediated signal transduction is believed to depend largely on heterodimerization with other family members [5]. Trastuzumab is a humanized monoclonal antibody that targets the extracellular portion of HER2. This was the first HER2-targeted agent to be approved by the United States Food and Drug Administration (FDA) for the treatment of both early-stage and metastatic HER2-overexpressing (HER2+) breast cancer [6, 7]. Subsequently, lapatinib , an orally bioavailable small-molecule dual HER2- and EGFR/HER1-specific tyrosine kinase inhibitor (TKI), received FDA approval in combination with capecitabine for patients with advanced HER2+ breast cancer [8]. Pertuzumab in 2012 and ado-trastuzumab emtansine in 2013 were subsequently approved in the US and elsewhere based on evidence showing an improvement in survival outcomes in patients with mostly trastuzumab-naïve or trastuzumab-exposed metastatic disease [9, 10]. The clinical benefit demonstrated by those drugs in advanced disease has triggered several adjuvant and neoadjuvant trials testing them in combination with chemotherapy but also without conventional chemotherapy, using single or dual HER2-targeting drugs. In this chapter, we review the current data on the therapeutic management of HER2-positive early-stage breast cancer in the adjuvant and neoadjuvant settings.

Defining HER2-Positive Breast Cancer

A key first step in appropriately deciding on the use of HER2-targeted therapy is the accurate determination of HER2 overexpression either by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) . The 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines define HER2 positivity as 3+ on IHC (defined as uniform intense membrane staining of >10% of invasive tumor cells) or amplified on FISH (a HER2:chromosome enumeration probe [CEP]17 ratio of >2.0, or <2.0 plus average HER2 copy number >6 signals/cell) [11]. Recently updated 2018 ASCO/CAP HER2 testing guidelines addressed specific testing strategies to better define and distinguish HER2 status of tumors. Specifically, the draft update recommends: the addition of IHC testing in the same laboratory or institution performing ISH as part of the evaluation of less common patterns observed with dual-probe ISH testing. In cases where the recommended testing strategy does not resolve the clinical concerns, the draft update currently states that pathologists may obtain second opinions. The draft update no longer recommends alternative probe testing in the guideline algorithm for dual probe ISH testing.

Although a detailed discussion of HER2 testing is beyond the scope of this chapter, we would like to note that if a patient’s HER2 expression is ultimately deemed to be equivocal on both IHC and FISH , the oncologist can still consider HER2-targeted therapy based on the patient’s history, prognosis, and comorbidities.

Anti-HER-2 Therapy for Early-Stage Breast Cancer

In this section, we summarize all the relevant phase III and some phase II clinical trials that constitute the theoretical framework to support our daily practice. We subdivide this section according to the 2 clinical settings: adjuvant and neoadjuvant (Figs. 16.1, 16.2, 16.3, and 16.4).

Fig. 16.1
figure 1

Adjuvant systemic therapy for stage IA (T1N0M0)—hormone receptor-positive and HER2-positive disease. aThere is no absolute age limit. Instead, treatment depends on the disease, the presence of comorbidities, the patient’s life expectancy, and patient preferences. Treatment should be individualized for patients >70 years of age. bChemotherapy and endocrine therapy as adjuvant therapy should be given sequentially, with endocrine therapy following chemotherapy. The available data suggest that sequential or concurrent endocrine therapy with radiation therapy is acceptable. cAssuming that HER2 positivity is determined according to the ASCO/CAP guidelines, most patients with T1b disease and all patients with T1c disease require anti-HER2 therapy. The chemotherapy regimen for these patients may contain anthracyclines. If provided in stage I and if the tumor diameter is <1 to 2 cm, the combination of paclitaxel and trastuzumab is the preferred regimen. Trastuzumab or chemotherapy is not recommended for microinvasive disease (invasive tumor ≤1 mm). dFertility preservation (e.g., by ovarian tissue or oocyte conservation) should be offered to women <40 years of age. eConsider adjuvant bisphosphonate therapy in postmenopausal (natural or induced) patients receiving adjuvant therapy

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Fig. 16.2
figure 2

Adjuvant systemic therapy for stage IA (T1N0M0)—hormone receptor-negative and HER2-positive disease. aThere is no absolute age limit. Instead, treatment depends on the disease, the presence of comorbidities, the patient’s life expectancy, and patient preferences. Treatment should be individualized for patients >70 years of age. bAssuming that HER2 positivity is determined according to the ASCO/CAP guidelines, most patients with T1b disease and all patients with T1c disease require anti-HER2 therapy. The chemotherapy regimen for these patients may contain anthracyclines. If provided in stage I and if the tumor diameter is ≤1 cm, the combination of paclitaxel and trastuzumab is the preferred regimen. For patients in stage I with a tumor diameter >1, anthracyclines followed by taxanes and trastuzumab may be preferred, although paclitaxel-trastuzumab may also be an option in select patients. Trastuzumab or chemotherapy is not recommended for microinvasive disease (invasive tumor ≤1 mm). cFertility preservation (e.g., by ovarian tissue or oocyte conservation) should be offered to women <40 years of age. dConsider adjuvant bisphosphonate therapy in postmenopausal (natural or induced) patients receiving adjuvant therapy

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Fig. 16.3
figure 3

Adjuvant systemic therapy for stage I, II, IIIA—hormone receptor-positive and HER2-positive disease. aThere is no absolute age limit. Rather, treatment depends on the disease, the presence of comorbidities, the patient’s life expectancy, and patient preferences. Treatment should be individualized for patients >70 years of age. bNeoadjuvant therapy is recommended in HER2-positive stage II and III patients. Trastuzumab and pertuzumab are recommended in neoadjuvant therapy. The St Gallen panel did not support dual HER2 blockade with pertuzumab or lapatinib in the postoperative adjuvant treatment. According to the APHINITY study, which published the early results, adjuvant trastuzumab + pertuzumab treatment prolonged disease-free survival in HER2-positive patients. This benefit was particularly evident in high-risk patients who were hormone receptor negative and node positive. According to a randomized controlled trial, 1-year neratinib use after 1-year administration of trastuzumab reduced the recurrence rate. This benefit was especially evident in ER-positive, Her-2-positive disease. However, diarrhea was an important adverse effect. After 1 year of trastuzumab administration in hormone receptor-positive patients, 1 year of neratinib can be used. cIn high-risk premenopausal patients, “LHRH-agonist + aromatase inhibitor” may be the preferred adjuvant endocrine therapy. In postmenopausal patients, aromatase inhibitors may be preferred over tamoxifen. dChemotherapy and endocrine therapy as adjuvant therapy should be given sequentially, with endocrine therapy following chemotherapy. The available data suggest that sequential or concurrent endocrine therapy with radiation therapy is acceptable

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Fig. 16.4
figure 4

Adjuvant systemic therapy for stage IB, II, IIIA—hormone receptor-negative and HER2-positive disease. aThere is no absolute age limit. The choice of treatment choice depends on disease, co-morbidities, life expectancy and patient preferences. Neoadjuvant therapy is recommended in HER2-positive stage II and III patients. Trastuzumab and pertuzumab are recommended in neoadjuvant therapy. For patients >70 years of age, treatment should be individualized. bAC—paclitaxel and trastuzumab (± pertuzumab); TCH ± pertuzumab (pertuzumab given to patients with greater than or equal to T2 or greater than or equal to N1, HER2-positive, early-stage breast cancer) can be recommended. According to the early results of the APHINITY study, the authors concluded that pertuzumab can be considered as adjuvant therapy in patients with node-positive or locally advanced tumors. cIn patients with HER2-positive, stage 2 disease, chemotherapy should always be provided to patients who require anti-HER2 therapy. The chemotherapy regimen for these patients should preferably contain anthracyclines and taxanes. Anti-HER2 therapy should be initiated concurrently with taxane therapy. dConsider adjuvant bisphosphonate therapy in postmenopausal (natural or induced) patients receiving adjuvant therapy

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Adjuvant Setting

Published results from adjuvant trials have described anti-HER2 therapy use in concomitant and sequential combination with anthracycline and non-anthracycline chemotherapy regimens (Table 16.1). The monoclonal antibody trastuzumab is the first and only targeted agent approved for the adjuvant treatment of early-stage HER2-positive breast cancer. Trastuzumab binds to the extracellular domain of HER2, thereby suppressing its signaling activity and inducing antibody-dependent cell-mediated cytotoxicity (ADCC).

Table 16.1 Selected clinical trials in the adjuvant setting for human epidermal growth factor receptor-2-positive breast cancer
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Concomitant Chemotherapy/Trastuzumab

While initially designed as 2 separate trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials were jointly analyzed in 2005 due to their similar eligibility criteria and to allow an earlier evaluation of clinical outcomes. The studies had similar patient populations, although N9831 also included women with high-risk node-negative disease defined as tumors ≥2 cm and positive for hormone receptors or tumors larger than 1 cm with negative hormone receptors. NSABP B-31 compared four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of paclitaxel (AC-T) every 3 weeks to the same regimen plus trastuzumab given for 52 weeks starting concurrently with paclitaxel (AC-TH). NCCTG N9831 randomized patients to receive 4 cycles of AC followed by weekly paclitaxel for 12 cycles with or without trastuzumab administered concurrently or sequentially with paclitaxel for 52 weeks (AC-T-H vs AC-TH). In a joint analysis that included patients similarly treated in the control (AC-T) and concomitant (AC-TH) arms of N9831 and the NSABP B-31 trials, a significant improvement in DFS (HR: 0.52, P < 0.001) and a reduction of death by 39% (OS, HR: 0.61, P < 0.001) were observed with the addition of trastuzumab starting with paclitaxel versus chemotherapy only [12]. The efficacy of concurrent vs sequential administration of trastuzumab showed a trend toward improvement in DFS in the concurrent arm; however, sequential was still better than placebo (P < 0.001).

Sequential Chemotherapy/Trastuzumab

Another pivotal adjuvant trial also first reported at the 2005 Annual Meeting of the American Society of Clinical Oncology was the HERA trial [13], which tested adding 1 or 2 years of trastuzumab after completion of various standard adjuvant chemotherapy regimens. HERA randomly assigned 5102 patients to begin adjuvant trastuzumab versus no adjuvant trastuzumab after chemotherapy (median time from diagnosis, 8 months). Patients with HER2-positive disease were eligible if node-positive or node-negative with tumor >1 cm (T1c). At a median follow-up of 4 years, one year of adjuvant trastuzumab led to a 24% reduction in recurrence (HR: 0.76, P < 0.0001). However, partly due to the significant crossover (65%) from the observation arm to trastuzumab after the first results were released, the OS benefit from trastuzumab in HERA became apparent when evaluated after 4 years (HR: 0.85, P = 0.11) [14]. A recent update after a median follow-up of 8 years confirmed the DFS (HR: 0.76, P < 0.0001) and OS benefit (HR: 0.76, P = 0.0005) from one year of trastuzumab [13]. However, there was no incremental benefit from a longer duration of trastuzumab (2 years), and more cardiac events were observed.

Cardiotoxicity is the most important adverse effect of treatment with trastuzumab and is worsened when combined with anthracyclines. Therefore, there has been a special interest in studying anthracycline-free regimens to minimize the cardiotoxicity risk. The BCIRG 006 [15] study was designed to provide information on this issue. Patients received AC followed by docetaxel (AC → T), AC followed by docetaxel with 1 year of trastuzumab (AC → TH), or docetaxel plus carboplatin and trastuzumab followed by trastuzumab to complete 1 year of therapy (TCH). After 65 months of follow-up, DFS was significantly improved with the addition of trastuzumab to chemotherapy (AC → T: 75%, AC → TH: 84%, and TCH 81%; HR for AC-TH was 0.64 (P < 0.001) and for TCH was 0.75 (P = 0.04) with a significant improvement in OS (AC → T: 87% vs AC → TH: 92%; HR: 0.63, P < 0.001), and TCH 91% (HR: 0.77, P = 0.038). However, despite the apparent numerical advantage of AC → TH over TCH, the study was not designed to directly compare these two arms. To confirm that one regimen is better than the other, further evidence is required. Additionally, the incidence of cardiac toxicity was five times greater with ACTH (2%) compared with TCH (0.4%). Reductions in LVEF of greater than 10% from basal measurements were more frequently associated with AC → TH than with TCH (18.6 vs 9.4%; P < 0.001). In addition, the rate of symptomatic congestive heart failure favored treatment with TCH (P < 0.001).

The only trial that did not show a survival benefit from adjuvant trastuzumab was FNCLCC-PACS-04 [16]. A total of 3010 patients with early-stage breast cancer were randomly assigned to adjuvant treatment with anthracycline-based chemotherapy with or without docetaxel. Patients with HER-2 over-amplified tumors (n = 528) were subsequently randomized to receive trastuzumab sequentially every 3 weeks. The primary endpoint was DFS. Treatment with trastuzumab resulted in a nonsignificant 14% reduction in the risk of relapse (P = 0.41), and there was no difference in OS. However, 10% of the patients assigned to trastuzumab were never treated, and 25% of patients discontinued before the 16th cycle. In addition, sequential use seemed to be inferior to concurrent use of trastuzumab and chemotherapy.

Shorter Duration of Trastuzumab

The duration of adjuvant treatment in HER2-positive breast cancer is a current topic of discussion. Based on the previously analyzed HERA trial, 2 years of treatment with trastuzumab is not superior to 1 year. There is a special interest in investigating whether treatment duration could be shortened due to concerns about cardiotoxicity. In the early 2000s, the Finland Herceptin (FinHER) trial [17] aimed to determine the role of vinorelbine compared to docetaxel in the adjuvant setting in patients with node-positive and high-risk node-negative breast cancer and tested a shorter course of trastuzumab. A total of 1010 patients were randomized to treatment with vinorelbine or docetaxel for 3 cycles followed by three cycles of 5-FU, epirubicin and cyclophosphamide. A group of 232 patients with HER-2-amplified tumors were again randomized to receive nine weekly cycles of trastuzumab concurrently with docetaxel or vinorelbine. The primary endpoint was distant DFS, and with a median follow-up of 62 months, it favored treatment with docetaxel over vinorelbine (P = 0.010). OS also tended to be better in patients treated with docetaxel compared to vinorelbine (39 vs 55 deaths, respectively; P = 0.086). In HER-2-positive patients, the trastuzumab arms had favorable recurrence-free survival irrespective of the chemotherapy regimen (80% vs 73%; P = 0.12). This benefit was maintained when adjusted for nodal involvement and in patients treated with docetaxel over vinorelbine . The main limitation of this trial is the small number of patients with HER-2-positive tumors that were included, which reduced the power of the study to detect a statistically significant benefit with trastuzumab. In addition, even though the results suggested a benefit in patients treated with trastuzumab in combination with chemotherapy, the short course of treatment might have underestimated the real efficacy of the drug in this population.

The PHARE trial [18] is a noninferiority study designed to evaluate adjuvant treatment length with trastuzumab for 6 months compared to 1 year. A total of 1691 patients were treated with trastuzumab for 12 months and 1693 for 6 months after receiving at least 4 cycles of adjuvant chemotherapy . Patients were stratified according to sequential or concurrent treatment and estrogen-receptor (ER) status. The primary endpoint was DFS, and with a median follow-up of 42.5 months, the 2-year DFS was 93.8% for the 12-month group and 91.1% for the 6-month group (HR: 1.28; 95% CI: 1.05–1.56), indicating that 6 months of treatment did not reach the noninferiority criteria. However, cardiac events were more common in the 12-month treatment arm (5.7% vs 1.9%; P < 0.001), and further analysis is still required.

FinHER investigators are now comparing 9 weeks of trastuzumab plus docetaxel and FEC with the same regimen followed by 1 year of trastuzumab therapy in the SOLD study (NCT00593697). SHORT-HER (NCT00629278) is testing 9 weeks versus 12 months of trastuzumab. Two other studies in progress are testing 6 versus 12 months of trastuzumab, including PERSEPHONE (NCT00712140) and a trial by the Hellenic Oncology Research Group (NCT00615602). On the basis of current available evidence, 12 months of adjuvant treatment with trastuzumab remains the standard of care.

Lapatinib

Lapatinib is currently approved for metastatic disease, but its use has also been evaluated in the adjuvant setting due to its oral bioavailability. The TEACH trial [19] studied the efficacy of lapatinib in trastuzumab-naïve patients as adjuvant treatment. A total of 3147 patients were randomized to treatment with lapatinib or placebo for 12 months or until progression. DFS was non-significantly prolonged in patients treated with lapatinib (87% vs 83%; P = 0.09). In patients with centrally confirmed HER-2 status, the HR was 0.92 (P = 0.94). In the ALTTO trial (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) [20], the investigators hypothesized that in the adjuvant setting, two HER2-targeted agents would be superior to trastuzumab alone in preventing breast cancer recurrences. It was the largest-ever adjuvant clinical trial in HER2-positive breast cancer, involving 8381 women from 946 centers in 44 countries. Patients were randomly assigned to 1 year of adjuvant therapy with trastuzumab (T), lapatinib (L), their sequence (T → L), or their combination (L + T). In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. The primary endpoint was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L + T versus T. At a median follow-up of 4.5 years, dual targeting—either concurrently or sequentially—was associated with slight numerical reductions in disease recurrences, but the differences were not statistically significant vs trastuzumab alone. The disease-free survival rates at 4 years were 86% with trastuzumab, 88% with concurrent HER2-directed treatment, and 87% in the sequential T arm (555 DFS events; HR: 0.84; 97.5% CI: 0.70–1.02; P = 0.048). Median overall survival rates were 94%, 95%, and 95%, respectively (HR: 0.96; 97.5% CI: 0.80–1.15; P = 0.61). Updated 10-year results from the phase III ALTTO trial presented at the ASCO 2017 annual meeting showed a stronger benefit of the dual HER2 agents in patients with ER-negative breast cancer. The HRs for this updated analysis were similar to those from the primary analysis, and the event rate remains lower than anticipated (705 vs 850 planned) [21]. This analysis suggests that HER2+/ER− tumors may have a different biology than HER2+/ER+ and may benefit more from dual HER2 blockade. Lapatinib was also associated with significant increases in adverse events—diarrhea, skin rash or erythema, and hepatobiliary problems. In conclusion, lapatinib either as a single agent or in combination with trastuzumab seems to be quite ineffective and more toxic in the adjuvant setting.

Adjuvant Therapy for Tumors Smaller than 1 cm

Data on the role of trastuzumab in small node-negative tumors remain scarce. Retrospective institutional series from MD Anderson Cancer Center (MDACC) [22] and Milan [23] suggest that small HER2-positive tumors prognostically have a poor long-term outcome compared to their HER2-negative counterparts. Subgroup analyses from several randomized trials have shown a benefit of adjuvant trastuzumab irrespective of tumor size [24], though its actual absolute benefit in small stage 1 tumors (such as those with T1a up to 0.5 cm disease) remains unknown. A large, retrospective European study [25] compared the outcomes of patients with T1a/b node-negative tumors who either received adjuvant trastuzumab-based chemotherapy or did not and demonstrated a statistically significant 2–3% improvement in recurrence-free survival in the trastuzumab arm after a multivariate analysis. Hormone receptor (HR) status was also notable, as larger differences were seen in patients with high-risk features such as HR-negative or positive lymphatic vascular invasion. Therefore, it stands to reason that we could treat these tumors with adjuvant trastuzumab, especially if they are T1b or have other poor risk features.

A single-arm multicenter trial [26] included breast cancer patients with node-negative tumors up to 3 cm. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary endpoint was survival free from invasive disease. The 3-year rate of survival free from invasive disease was 98.7% (95% CI: 97.6–99.8). The results suggest a low risk of cancer recurrence (less than 2% at 3 years) with a regimen in which the rate of serious toxic effects was low (with an incidence of heart failure that was only 0.5%). At the ASCO 2017 annual meeting, an updated analysis with 7-year DFS was provided [27]. The 7-year DFS was 93.3% (95% CI: 90.4–96.2); 7-year DFS was 94.6% for ER+ pts (95% CI: 91.8–97.5) and 90.7% for ER− pts (95% CI: 84.6–97.2). Moreover, 7-year recurrence-free interval (RFI) was 97.5% (95% CI: 95.9–99.1); 7-year breast cancer-specific survival (BCSS) was 98.6% (95% CI: 97.0–100); and 7-year OS was 95.0% (95% CI: 92.4–97.7). These data suggest that TH as adjuvant therapy for node-negative HER2+ breast cancer was associated with few recurrences and only 4 distant recurrences with longer follow-up . In the absence of randomized data, this regimen might become an option for patients with small node-negative HER2-positive disease in clinical scenarios where there is concern about potential toxicity from established regimens.

Ongoing Adjuvant Trials

Several drugs are under intensive study for use in the adjuvant therapy of HER2-positive breast cancer: trastuzumab, pertuzumab (Perjeta), ado-trastuzumab emtansine (formerly known as T-DM1 [Kadcyla]), and the investigational tyrosine kinase inhibitor neratinib (Table 16.2).

Table 16.2 Ongoing adjuvant phase III trials
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The BETH trial is evaluating the blockade of both the HER2 and vascular endothelial growth factor (VEGF) pathways by combining trastuzumab with the anti-VEGF monoclonal antibody bevacizumab, based on preclinical data showing a correlation between HER2 and VEGF expression [28, 29]. In the BETH trial [30], more than 3000 patients were treated with docetaxel plus carboplatin (TC) with trastuzumab versus TC with trastuzumab and bevacizumab, and targeted therapy was given for one year in both arms. The researchers found that after a median of 38 months of follow-up, DFS was 92% for both arms of the TCH cohort. In addition, the results of the trial were negative for any benefit of adding bevacizumab to adjuvant therapy for HER2-positive breast cancer. This lack of benefit may have occurred because 92% of the patients in the TCH control arm remained disease-free after a median follow-up of 38 months. This trial also demonstrated that it is not necessary to include an anthracycline as part of the treatment regimen, even for large tumors or node-positive disease.

Data from metastatic trials of pertuzumab [31] and ado-trastuzumab emtansine [32] have now led to ongoing adjuvant trials, one of which is the APHINITY trial (NCT01358877), which compares standard chemotherapy (non-anthracycline or anthracycline-based) plus trastuzumab with or without pertuzumab. The results of the APHINITY trial were presented at the ASCO 2017 Annual meeting [33]. In this phase III clinical trial of 4805 women with HER2-positive breast cancer, the addition of pertuzumab to trastuzumab reduced the chance of developing invasive breast cancer by 19% compared to trastuzumab alone. At a median follow-up of almost 4 years, 171 patients (7.1%) in the pertuzumab group had developed invasive breast cancer, compared to 210 patients (8.7%) in the placebo group. At 3 years, an estimated 94.1% of patients in the pertuzumab group were free of invasive breast cancer, compared to 93.2% of patients in the placebo group. The rates of serious side effects were low and similar in both groups—heart failure or heart-related death occurred in 0.7% of patients in the pertuzumab group and 0.3% of patients in the placebo group. Severe diarrhea was more common with pertuzumab, occurring in 9.8% of patients compared to 3.7% of those who received placebo. The results of APHINITY trial led to full FDA approval. Based on the phase III APHINITY data, ASCO updated their recommendations in 2018 stating that 1 year of pertuzumab may be offered in addition to trastuzumab and combination chemotherapy for patients with high-risk, early-stage breast cancer, such as those with node-positive disease. 2018 ASCO updated guidelines stressed that APHINITY data showed no clinically meaningful benefit among patients with node-negative breast cancer and the first planned interim analysis did not show an OS benefit. Importantly, there are no data to guide the duration of pertuzumab treatment in patients who received neoadjuvant pertuzumab and achieved a pathologic complete response.

The KATHERINE trial (NCT01772472) [34] is comparing 14 cycles of ado-trastuzumab emtansine versus 14 cycles of trastuzumab in patients with HER2-positive disease and less than a pathologic complete response (pCR) after preoperative therapy with a trastuzumab-based regimen. Fifty-percent of planned enrollment is completed. The primary endpoint of the study is DFS.

Neratinib is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab pre-treated HER2-positive (HER2+) metastatic breast cancer. The ExteNET study examined sequential therapy with 1 year of trastuzumab followed by 1 year of neratinib in stage 2–3c Her2+ breast cancer patients who had received the last dose of trastuzumab within the last 1 year before enrollment in the clinical trial [35]. In this study, eligible women with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry were randomly assigned according to hormone receptor status (ER-positive vs ER-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), followed by 1 year of oral neratinib 240 mg/day or matching placebo. After a median follow-up of 5.2 years (IQR 2.1–5.3), patients in the neratinib group had significantly fewer invasive DFS events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0.73, 95% CI: 0.57–0.92, P = 0.0083). Five-year invasive disease-free survival was 90.2% (95% CI: 88.3–91.8) in the neratinib group and 87.7% (85.7–89.4) in the placebo group. Without diarrhea prophylaxis, the most common grade 3–4 adverse events in the neratinib group compared with the placebo group were diarrhea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhea were identified with neratinib compared with placebo. This study led to FDA approval of 1 year of extended adjuvant therapy with neratinib on July 17, 2017, to follow adjuvant trastuzumab-based therapy. ASCO 2018 guidelines reported their recommendations about neratinib use in patients with HER2-positive early breast cancer. The expert panel emphasized that the observed benefit from neratinib was higher in hormone receptor-positive and node-positive patients, and no OS advantage has been observed thus far. Patients who began neratinib within 1 year of trastuzumab completion appeared to derive the greatest benefit. Currently there are no reported data on the incremental benefit offered by neratinib in patients who completed up to a year of pertuzumab in the neoadjuvant or adjuvant setting.

Neoadjuvant Setting

In the last decade, researchers have modernized trial design by using pCR as an endpoint, since pCR correlates with long-term outcome and is quicker than waiting, possibly for years, for data on recurrence or death. Consequently, researchers have examined the impact of HER2-targeted agents on pCR in the neoadjuvant setting (Table 16.3).

Table 16.3 Selected clinical trials in the neoadjuvant setting for HER-2-positive breast cancer
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The results of the NOAH trial , a randomized phase III study, increased enthusiasm for this approach [36]. The study was originally designed to compare neoadjuvant chemotherapy plus trastuzumab followed by 1-year trastuzumab to neoadjuvant chemotherapy alone in patients with locally advanced or inflammatory HER-2 positive tumors. Among the 238 patients who were originally randomized to neoadjuvant treatment with or without trastuzumab, the addition of anti-HER-2 therapy improved pCR from 22% to 43% (P < 0.001). Trastuzumab also resulted in a 40% reduction of the risk of recurrence, progression or death compared to chemotherapy alone.

The value of overlapping anthracycline with trastuzumab in the neoadjuvant setting was explored in the American Z1041 trial [37], which randomized 282 women with HER-2-positive and ≥2-cm tumors to receive trastuzumab and paclitaxel concurrently with of after FEC-75. There was no difference in pCR for sequential versus overlapping anthracycline and trastuzumab (54% and 56%), but the concurrent use of anthracyclines and trastuzumab resulted in a greater drop in the cardiac ejection fraction (2.9% vs 0.8% at 12 weeks, respectively). Finally, similar rates of pCR were described in patients treated with chemotherapy and trastuzumab in the HannaH trial (41% and 45% for intravenous vs subcutaneous trastuzumab, respectively) [38]. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with subcutaneous treatment; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of DFS showed rates of 95% in both groups 1 year post-randomization.

In an attempt to improve pCR, some researchers have begun exploring the use of other anti-HER2 blockers alone or in combination with trastuzumab in the neoadjuvant setting. In the German GeparQuinto study [39], 620 patients received four cycles of epirubicin and cyclophosphamide (EC) followed by docetaxel and were randomized to either trastuzumab or lapatinib. All patients received standard-of-care trastuzumab for 1 year after surgical resection. The primary outcome was pCR, and trastuzumab yielded approximately 7% more complete responses than lapatinib (30.3% vs 22.7%; P = 0.04). Given these results and the significant number of adverse events described in this study, it is unlikely that lapatinib could replace trastuzumab in the neoadjuvant setting; dual HER-2 inhibition appears to be a better option.

In four trials examining combinations of trastuzumab with lapatinib or pertuzumab—including NeoALTTO (NCT00553358) and Neo-Sphere (NCT00545688)—dual blockade resulted in a higher pCR rate. NeoALTTO, an international, randomized, phase III study, compared the use of single-agent lapatinib, trastuzumab or the combination of both in addition to paclitaxel for neoadjuvant treatment [40]. Interestingly, the combination arm showed a remarkable improvement in pCR that nearly duplicated that in the two single-agent anti-HER2 arms (51% vs 29.5% trastuzumab vs 24.7% lapatinib; P < 0.001). As expected, the addition of lapatinib resulted in worse side effects, mainly related to diarrhea and rash. However, in contrast to NeoALTTO, the NSABP B-41 study showed no significant difference between the combination of trastuzumab and lapatinib and either drug used as a single agent [41]. Two issues warrant further discussion. First, even though the populations included in both trials were similar, the chemotherapy regimens were not. In the NSABP study, all patients received four cycles of AC and then were randomized to paclitaxel plus trastuzumab, lapatinib or both. Second, the rates of pCR in all three arms were unusually high (62% for the combination, 53% for trastuzumab and 52.5% for lapatinib).

The FDA has recently granted accelerated approval to pertuzumab for use before surgery when combined with trastuzumab and chemotherapy. This controversial decision was based on the results of two phase II clinical trials. The NeoSphere trial [42] was a multicenter, open-label, randomized phase II study in which 417 patients were randomized to one of four possible arms: pertuzumab (P) + trastuzumab (T) + docetaxel (Do); T + Do; P + Do or P + T alone. All eligible patients then underwent surgical resection followed by adjuvant FEC and 1 year of trastuzumab. The three-drug arm (P + T + Do) yielded the maximal rate of pCR (46%) and was significantly different from T + Do (29%; P = 0.014). Pertuzumab + docetaxel resulted in a 24% pCR, and the chemotherapy-free arm had a 17% pCR. In the T + Do and P + T + D0 arms, respectively, the 3-year survival rates were 85% and 92% for DFS (HR: 0.60, 95% CI: 0.28–1.27) and 86% and 90% for PFS (HR: 0.69, 95% CI: 0.34–1.40). Importantly, the addition of pertuzumab did not produce any significant drop in cardiac function (4–5% EF drop across all groups). An additional neoadjuvant phase II trial (TRYPHAENA) [43] was conducted in 225 patients with HER2-positive, locally advanced, operable, or inflammatory breast cancer and was designed primarily to assess the cardiac safety of pertuzumab in different neoadjuvant regimens. Patients were randomly allocated to receive one of three neoadjuvant regimens prior to surgery: three cycles of FEC followed by three cycles of docetaxel, all in combination with pertuzumab and trastuzumab (A); three cycles of FEC alone followed by three cycles of docetaxel and trastuzumab in combination with pertuzumab (B); or six cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with pertuzumab (C). Following surgery, all patients received trastuzumab intravenously every 3 weeks to complete 1 year of therapy. The results suggest that all three arms achieved >55% pCR. During post-treatment follow-up, 2.8%, 4.0% and 5.4% patients in groups A-C had any-grade left ventricular systolic dysfunction; 11.1%, 16.0% and 11.8% patients experienced left ventricular ejection fraction declines ≥10% from baseline to <50. Currently, there are insufficient cardiac safety data to recommend concomitant administration of an anthracycline with pertuzumab and trastuzumab.

The I-SPY 2 trial (NCT01042379) is an ongoing multidrug, multicenter neoadjuvant phase II breast cancer trial to determine whether adding experimental agents to standard neoadjuvant medications increases the probability of pCR compared to standard neoadjuvant chemotherapy for each biomarker signature established at trial entry. A variety of agents are being investigated, both in combination with trastuzumab and alone, including T-DM1 , pertuzumab, neratinib, pembrolizumab as well as AKT inhibitors. The findings reported at the San Antonio Breast Cancer Symposium included positive results for the PARP inhibitor veliparib, the first drug to complete testing in the trial. Although the estimated pCR rate for patients with triple-negative breast cancer was 52% after receipt of chemotherapy plus veliparib/carboplatin and standard paclitaxel followed by anthracycline-based chemotherapy vs 26% with control chemotherapy alone, in “signatures” other than triple-negative breast cancer, the combination was predicted to be far less successful. For the hormone receptor-positive/HER2-negative group, the estimated pathologic complete response rate was 14% for the combination and 19% for controls. The pCR rates for HER2+ group have not been reported yet.

The GeparSixto [44] study evaluated the benefit of adding carboplatin to paclitaxel plus pegylated liposomal doxorubicin given as a weekly regimen for 18 weeks to 595 patients. Added to this backbone were three targeted agents corresponding to tumor subtype: trastuzumab and lapatinib for HER2-positive patients and bevacizumab (Avastin) for triple-negative patients. Investigators compared the rates of pCR between paclitaxel/doxorubicin and paclitaxel/doxorubicin/carboplatin. The addition of carboplatin significantly increased the pathologic complete response rate, which was 37.2% in the control arm and 46.7% in the carboplatin arm (P < 0.2) for patients with triple-negative breast cancer. However, the HER2-positive subgroup did not benefit. Among HER2-positive patients, pathologic complete responses were achieved by 36.8% and 32.8% in the control arm and the carboplatin arm, respectively (P = 0.581; test for interaction P = 0.015).

Optimizing Therapy for Hormone Receptor–Coexpressing Disease

At least half of HER2-positive breast cancer coexpresses one or both hormone receptors, and this coexpression may serve as a pathway for resistance to HER2-targeted therapy. However, HER2-targeted therapy is not necessarily inactive in hormone receptor-positive breast cancer. In fact, analyses from the AC/trastuzumab and AC/T arms of the BCIRG-00651 and B-3153 trials have shown that the HRs for DFS are very similar for hormone receptor-positive (HR, 0.65 and 0.61 for BCIRG-006 and B-31, respectively) and hormone receptor-negative (HR, 0.64 and 0.62 for BCIRG-006 and B-31, respectively) disease. This also holds true for OS. Subset analysis of the HERA study at 11 years of follow-up also demonstrated long-term trastuzumab benefit for all patients, regardless of HR status [45]. Although trastuzumab imparts DFS and OS benefit, regardless of hormone receptor status, the presence of ER may indicate more indolent, luminal-like tumor behavior. For example, Kaplan–Meier curves from HERA indicate that although the long-term risk of recurrence is similar in hormone receptor-positive and hormone receptor-negative subtypes, patients with hormone receptor-negative disease have earlier recurrences, which is consistent with a more aggressive disease biology. Further evidence supporting the notion that disease behavior differs based on hormone receptor expression comes from neoadjuvant clinical trials, which have consistently shown that pCR rates are lower for hormone receptor-positive, HER2-positive breast cancer than for hormone receptor-negative disease [40, 41, 46, 47]. However, the longer follow-up of the NeoSphere trial indicates that patients with hormone receptor coexpression have numerically higher PFS than those with tumors lacking hormone receptors (5-year PFS for patients who achieved pCR: 90% if hormone receptor positive, 84% if hormone receptor negative ; 5-year PFS for patients who did not achieve pCR: 80% if hormone receptor positive, 72% if hormone receptor negative). Thus, patients with hormone receptor-positive tumors may do better in the long run. Intriguing biomarker analyses from HERA suggest that although ER-positive tumors with a high level of HER2 amplification (by FISH ratio) derive clear benefit from trastuzumab, those with a low level of HER2 amplification may not receive benefit from trastuzumab-based therapy [48].

Several clinical trials aiming to evaluate co-targeting of hormone receptor and HER2 have been conducted. The first of these, TBCRC-006, evaluated 12 weeks of neoadjuvant lapatinib plus trastuzumab (with letrozole for ER-positive tumors) [49]. pCR (breast) for HER2-positive/hormone receptor-positive tumors was 21% in this proof-of-concept study, indicating that a relatively well-tolerated chemotherapy-free regimen might be highly effective for patients if accurate biomarkers for selection can be identified.

Trastuzumab emtansine has also been evaluated in the neoadjuvant and adjuvant settings. The WGS-ADAPT study compared four cycles of T-DM1, either alone or in combination with endocrine therapy, to trastuzumab plus endocrine therapy for hormone receptor-positive, HER2-positive patients [50]. This relatively short course of T-DM1 was associated with an impressive pCR rate (breast and lymph nodes) of 41%, which was considerably higher than that achieved with trastuzumab plus endocrine therapy.

Although neither of these relatively small studies has changed the standard of care, the intriguing results should encourage the investigation of whether similar, less-toxic regimens might be beneficial for selected patient populations.

In December 2016, the results of the NSABP B-52 trial were presented. This study was designed to evaluate whether the addition of an aromatase inhibitor to standard chemotherapy plus HER2-targeted therapy (TCHP) would improve pCR rates for hormone receptor-positive/HER2-positive breast cancer and to test whether endocrine therapy is antagonistic in combination with chemotherapy [51]. Although the addition of endocrine therapy to TCHP did not lead to a statistically notable improvement in pCR (41% for TCHP vs. 46% for TCHP plus endocrine therapy), it did not appear to be antagonistic, leaving room for future studies to test less toxic chemotherapy regimens concurrently with hormone therapy approaches.

In summary, in just over a decade, the management of early-stage HER2-positive breast cancer has changed drastically because of the development of highly effective biologically targeted therapies . The therapeutic options available to the patient in both the neoadjuvant and adjuvant settings are now nearly countless, making the choice of optimal therapy somewhat difficult at times. Our pursuit to provide patients with the safest and most effective therapies for their particular disease requires us to design carefully selected clinical trials with attention toward the discovery of molecular drivers of disease biology and markers of response to therapy.

Resistance to Trastuzumab and Lapatinib

Although HER2-targeted therapies have had a significant impact on patient outcomes, resistance to these agents is common. In clinical trials, 74% of patients with HER2+ metastatic breast cancer did not have a tumor response to first-line trastuzumab monotherapy [52], and 50% did not respond to trastuzumab in combination with chemotherapy [6]. These examples illustrate the problem that inherent (de novo) resistance to HER2-targeted agents poses for the effective treatment of HER2+ BC. Moreover, only approximately one quarter of patients with HER2+ metastatic breast cancer who were previously treated with trastuzumab achieved a response with lapatinib plus capecitabine [8]. These limitations have led to efforts to better understand the molecular determinants of resistance to these agents to improve the selection of patients who are most likely to benefit from specific therapies and to develop new agents that can overcome resistance. Here, we discuss new strategies that are mostly being investigated in metastatic breast cancer, although some are being studied in adjuvant and neoadjuvant settings.

Afatinib

Afatinib is an oral small molecule that irreversibly inhibits HER-1, 2 and 4 [53]. In a phase II study, 4 of 35 patients with trastuzumab-resistant metastatic breast cancer showed partial responses [53]. Adverse events included diarrhea and rash. However, the recently published LUX-Breast 1 [54] trial was a negative trial for afatinib. This was a phase III study comparing vinorelbine plus trastuzumab or afatinib plus vinorelbine for metastatic patients who progressed to one chemotherapy regimen containing trastuzumab. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavorable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine.

Neratinib

Neratinib is also an oral, irreversible inhibitor of HER-1,-2 and -4 [55]. A phase II trial evaluated neratinib in 136 HER-2-positive patients [55]. The median PFS was 22.3 and 39.6 weeks and the overall response rate (ORR) was 24% and 56% in pretreated and trastuzumab-naïve patients, respectively. Diarrhea was the most common grade 3/4 adverse effect. Another phase I–II trial combined neratinib plus trastuzumab in 45 metastatic, and trastuzumab-resistant patients showed an encouraging 27% ORR [56]. Finally, a phase I–II trial evaluated neratinib plus vinorelbine in trastuzumab- or lapatinib-pretreated patients (n = 77) [57]. ORR was 41% (no prior lapatinib) and 8% (prior lapatinib). A phase III trial (ExteNET) in the adjuvant setting is ongoing (NCT00878709) (Table 16.2).

MM-111

MM-11 is a bi-specific monoclonal antibody that reversibly targets the HER-2 and -3 heterodimer. A phase I–II study is currently evaluating its efficacy as a single agent in HER-2-positive advanced breast cancer patients who have received prior trastuzumab or lapatinib therapy (clinicaltrials.gov, NCT00911898). Another phase I trial is studying MM-111 plus trastuzumab in HER2-positive, heregulin-positive, advanced and refractory breast cancer (clinicaltrials.gov, NCT01097460).

Trastuzumab Deruxtecan

Trastuzumab deruxtecan (ds-8201a), a HER2-targeting antibody-drug conjugate, demonstrated significant clinical activity in heavily pretreated patients with HER2-expressing metastatic breast cancers who previously received ado-trastuzumab emtansine (T-DM1; Kadcyla). Whereas T-DM1 is a tubulin-targeting chemotherapy, trastuzumab deruxtecan is a topoisomerase 1 inhibitor. It is highly potent, with a drug-to-antibody ratio of 7.8, compared with 3.5 for T-DM1 .

In an ongoing 2-part phase I study, the ORR to trastuzumab deruxtecan in 57 evaluable patients with HER2-positive tumors was 61.4%. In the HER2-positive cohort, the ORR was 56.4% (22 of 39) among those with ER-positive disease and 75.0% (12 of 16) among those with ER-negative disease. Notably, the ORR was 62.5% among the 50 patients in this cohort who had received prior pertuzumab treatment. The disease control rate (DCR) was 94.7% overall in the HER2-positive subset: 92.3% in the ER-positive group, 100.0% in the ER-negative group, and 94.0% among those who had received prior pertuzumab. Median PFS was not reached in the ER-positive group and was 10.3 months in the ER-negative group. Median PFS was 10.3 months in the HER2-positive cohort who had received prior pertuzumab, as reported by Shanu Modi, MD, at the 2017 San Antonio Breast Cancer Symposium. The main toxicity was grade 1/2 gastrointestinal toxicity. Grade 1/2 nausea was reported by 67.9%. Grade 3 and 4 events were hematological in nature. The rates of grade 3/4 anemia were 8.7% in the HER2-positive group and 0.9% in the HER2-low group. The rates of grade 3 decreases in neutrophil count and white blood cell count were each 10.4%. Across the study, 5 patients (4.3%) had a grade 4 decrease in neutrophil count.

In August 2017, trastuzumab deruxtecan received FDA breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after T-DM1. An ongoing pivotal phase II trial called DESTINY-Breast01 is examining the efficacy and safety of trastuzumab deruxtecan in patients with HER2-positive unresectable and/or metastatic breast cancer who are resistant or refractory to T-DM1 .

HER2-Targeted Vaccines

Cancer vaccines designed to induce specific anti-HER-2 immunity are being investigated. Different strategies include protein-based vaccines, plasmid DNA-based vaccines, and vaccines that deliver HER-2 in a viral vector. HER-2 peptide-based vaccines have been tested in patients with metastatic HER-2-positive breast cancer [58]. Immunized patients developed delayed-type hypersensitivity reactions and strong CD8+ cell responses specific for HER-2 [59]. A dendritic cell-based vaccine was also tested in a small group of patients with stage IV breast cancer [60]. One patient showed a partial response, and three had stable disease for ≥12 months. Using a different strategy, cell-based GM-CSF secreting vaccines were tested in combination with trastuzumab [61].

Other Exploratory Anti-HER-2 Blocking Strategies

Ongoing trials combining anti-HER-2 agents with drugs blocking other signaling pathways hold the promise of further improvement. An auspicious approach is the combination of anti-HER-2 therapy with insulin growth factor receptor (IGFR-1)-blocking agents. IGFR-1 inhibition has been shown to restore sensitivity to trastuzumab in animal models [62]. Another potential combination is dual blockade of HER-2 and SRC, which was recently shown to work at a central node downstream of multiple trastuzumab-resistance mechanisms [63]. Finally, HER-3 is another strong activator of PI3K/Akt signaling pathway that has been demonstrated to be up-regulated after HER-2 blockade [64]. Although still in early phases of development, Rb disruption strategies and the use of CDK-4/6 inhibitors may be clinically useful [65]. Future studies of HER2-positive patients will be challenging because of the small window to improve outcome beyond what is achievable today.

Conclusion

The current available evidence supports the use of anti-HER2 drugs as a neoadjuvant treatment, and in terms of selecting the appropriate chemotherapy regimen, a couple of important points should be emphasized. First, dual blockade of the HER-2 receptor, even without chemotherapy, results in an at least 15% pCR (NeoSphere Trial), which suggests that 1 in 6 patients may not need chemotherapy. This certainly represents an attractive option for patients who cannot tolerate more than targeted agents. Second, the addition of chemotherapy leads to a more robust effect, with values of 40–50% when trastuzumab alone is used and >50% when dual blockade is applied. Moreover, anthracyclines appear to play a significant role in HER2-positive tumors; however, the results from the NeoALTTO and TRYPHAENA trials suggest that when dual blockade is used, anthracycline toxicity might be spared. Third, in all clinical trials available, pCR is markedly diminished in tumors expressing hormone receptors in addition to HER2. Finally, there is a need for predictors of which patients will most benefit from trastuzumab-containing therapies. Few markers are known, and confusion about some markers has emerged. For instance, p95, a truncated HER2 protein that had been associated with resistance to trastuzumab, was unexpectedly linked to a stronger response to the drug when tested in the GeparQuattro study [66].

Most likely, the most important question is how reliable is pCR as a valid surrogate for DFS and OS. A meta-analysis with 12900 patients enrolled in randomized neoadjuvant trials showed the strongest correlation between pCR and event-free survival (EFS) in patients with triple-negative breast cancer (TNBC) (EFS: HR 0.24, 95% CI: 0.18–0.33; OS: 0.16, 0.11–0.25) and in those with HER2-positive, hormone-receptor-negative tumors who received trastuzumab (EFS: 0.15, 0.09–0.27; OS: 0.08, 0.03, 0.22) [47]. Based on the phase III APHINITYdata, ASCO updated their recommendations in 2018 stating that 1 year of pertuzumab may be offered in addition to trastuzumab and combination chemotherapy for patients with high-risk, early-stage breast cancer, such as those with node-positive disease. Importantly, there are no data to guide the duration of pertuzumab treatment in patients who received neoadjuvant pertuzumab and achieved a pathologic complete response [67]. Neoadjuvant treatment with anti-HER-2 agents remains a valid and approved option, especially in those patients with locally advanced, unresectable tumors. Its use in small resectable cancer is probably appropriate but must be balanced with practical considerations and the patient’s own preferences.

Adjuvant/Neoadjuvant Regimens in HER2-Positive Breast Cancer

  • AC followed by paclitaxel + trastuzumab

  • Doxorubicin 60 mg/m2 IV day 1,

  • Cyclophosphamide 600 mg/m2 IV day 1,

  • Cycled every 21 days for 4 cycles.

  • Followed by:

  • Paclitaxel 80 mg/m2 day 1, 1 h IV infusion weekly for 12 weeks.

  • With*:

  • Trastuzumab 8 mg/kg IV with first dose of paclitaxel

  • Followed by:

  • Trastuzumab 6 mg/kg IV every 21 days to complete 1 year of treatment.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • Dose dense AC (doxorubicin/cyclophosphamide) followed by paclitaxel trastuzumab

  • Doxorubicin 60 mg/m2 IV day 1,

  • Cyclophosphamide 600 mg/m2 IV day 1,

  • Cycled every 14 days for 4 cycles, all cycles are with GCSF support.

  • Followed by:

  • Paclitaxel 175 mg/m2 day 1, 3 h IV infusion,

  • Cycled every 14 days for 4 cycles, all cycles are with GCSF support.

  • With*:

  • Trastuzumab 4 mg/kg IV with first dose of paclitaxel

  • Followed by:

  • Trastuzumab 2 mg/kg IV weekly to complete 1 year of treatment.

  • As an alternative, trastuzumab 6 mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • AC (doxorubicin/cyclophosphamide) followed by weekly paclitaxel + trastuzumab + pertuzumab

  • Doxorubicin 60 mg/m2 IV day 1,

  • Cyclophosphamide 600 mg/m2 IV day 1,

  • Cycled every 21 days for 4 cycles.

  • Followed by*:

  • Pertuzumab 840 mg IV day 1 followed by 420 mg IV, every 21 days to complete 1 year of treatment,

  • Trastuzumab 8 mg/kg day 1 followed by 6 mg/kg IV, every 21 days to complete 1 year of treatment,

  • Paclitaxel 80 mg /m2 day 1, 1 h IV infusion weekly for 12 weeks.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • TCH (Docetaxel + carboplatin + trastuzumab)

  • Docetaxel 75 mg/m2 IV day 1,

  • Carboplatin AUC 6 IV day 1,

  • Cycled every 21 days for 6 cycles.

  • Trastuzumab 4 mg/kg IV week 1

  • Followed by*:

  • Trastuzumab 2 mg/kg IV weekly for 17 weeks.

  • Followed by:

  • Trastuzumab 6 mg/kg IV cycled every 21 days to complete 1 year of trastuzumab treatment.

  • OR

  • Trastuzumab 8 mg/kg IV week 1

  • Followed by:

  • Trastuzumab 6 mg/kg IV cycled every 21 days to complete 1 year of trastuzumab treatment.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • TCH (Docetaxel + carboplatin + trastuzumab) + pertuzumab

  • Docetaxel 75 mg/m2 IV day 1,

  • Carboplatin AUC 6 IV day 1,

  • Cycled every 21 days for 6 cycles.

  • AND*

  • Pertuzumab 840 mg IV day 1

  • Trastuzumab 8 mg/kg IV day 1

  • Followed by:

  • Trastuzumab 6 mg/kg IV day 1

  • Pertuzumab 420 mg IV day 1

  • Cycled every 21 days to complete 1 year of therapy.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • AC followed by docetaxel + trastuzumab

  • Cyclophosphamide 600 mg/m2 IV day 1,

  • Doxorubicin 60 mg/m2 IV day 1,

  • Cycled every 21 days for 4 cycles.

  • Followed by:

  • Docetaxel 100 mg/m2 IV day 1, all cycles are with GCSF support.

  • Cycled every 21 days for 4 cycles.

  • With*:

  • Trastuzumab 8 mg/kg IV week 1

  • Followed by:

  • Trastuzumab 6 mg/kg IV cycled every 21 days to complete 1 year of trastuzumab therapy.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • AC followed by docetaxel + trastuzumab + pertuzumab

  • Cyclophosphamide 600 mg/m2 IV day 1,

  • Doxorubicin 60 mg/m2 IV day 1,

  • Cycled every 21 days for 4 cycles.

  • Followed by*:

  • Pertuzumab 840 mg IV day 1 follewed by 420 mg IV

  • Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV

  • Docetaxel 75–100 mg/m2 IV day 1, with GCSF support.

  • Cycled every 21 days for 4 cycles.

  • Followed by:

  • Trastuzumab 6 mg/kg IV

  • Pertuzumab 420 mg IV day 1

  • Cycled every 21 days to complete 1 year of trastuzumab therapy.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • Docetaxel + cyclophosphamid + trastuzumab

  • Docetaxel 75 mg/m2 IV day 1,

  • Cyclophosphamide 600 mg/m2 IV day 1

  • Cycled every 21 days for 4 cycles, all cycles are with GCSF support.

  • With*:

  • Trastuzumab 8 mg/kg IV week 1

  • Followed by:

  • Trastuzumab 6 mg/kg IV cycled every 21 days to complete 1 year of trastuzumab therapy.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.

  • Paclitaxel + trastuzumab

  • Paclitaxel 80 mg/m2 day 1, 1 h IV infusion weekly for 12 weeks.

  • With:

  • Trastuzumab 4 mg/kg IV with first dose of paclitaxel

  • Followed by:

  • Trastuzumab 2 mg/kg IV weekly to complete 1 year of treatment.

  • As an alternative trastuzumab 6 mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.

  • *Evaluate left ventricular ejection fraction prior to and every 3 months during treatment.