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REVIEW ARTICLE: ONCOLOGY UPDATES
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 99-109

Recent updates in systemic therapy of breast cancer: A brief narrative review


Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Date of Submission22-Oct-2020
Date of Decision24-Nov-2020
Date of Acceptance05-Mar-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Ajay Gogia
Associate Professor, Department Of Medical Oncology, AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_335_20

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  Abstract 


Breast cancer is the most common malignancy and the leading cause of cancer-related deaths in women globally. Systemic therapy of breast cancer has evolved rapidly in the past few years. In this brief review, we aim to summarize the potentially practice-changing recent updates in the management of breast cancer. We searched the PubMed database for randomized clinical trials for breast cancer treatment conducted over the past 2 years. In addition, abstracts and results of studies reported at major oncology meetings were evaluated. A total of 95 randomized clinical trials were included to prepare this review. Multiple new therapeutic options for almost all subsets of breast cancer have emerged in the past 2 years. Most importantly, for hormone-receptor-positive breast cancer, addition of abemaciclib to endocrine therapy in the adjuvant setting and alpelisib for PIK3CA-mutant refractory advanced disease have been shown to improve the survival outcomes. Addition of pembrolizumab or atezolizumab to neoadjuvant chemotherapy has significantly increased the pathological complete response rate for early triple-negative breast cancer, while adjuvant metronomic capecitabine for 1 year has led to improved disease-free survival. Moreover, adjuvant adotrastuzumab emtansine fared better than trastuzumab in the management of residual disease after neoadjuvant treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, while tucatinib and neratinib have shown meaningfully improved progression-free survival in HER2-positive advanced disease, including patients with cranial nervous system involvement. Expanding access to these advances is soon expected to transform the way we treat breast cancers.

Keywords: Breast cancer, human epidermal growth factor receptor 2-positive breast cancer, hormone receptor, immunotherapy, triple-negative breast cancer


How to cite this article:
Arora S, Gogia A. Recent updates in systemic therapy of breast cancer: A brief narrative review. Cancer Res Stat Treat 2021;4:99-109

How to cite this URL:
Arora S, Gogia A. Recent updates in systemic therapy of breast cancer: A brief narrative review. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Apr 23];4:99-109. Available from: https://www.crstonline.com/text.asp?2021/4/1/99/312084




  Introduction Top


Breast cancer is the most common malignancy and the leading cause of cancer-related deaths in women across the world, with an estimated 2.1 million new cases and 626,679 deaths reported in 2018.[1] In India, it is the most common cancer in both sexes combined, with 162,468 new cases and 87,090 deaths reported in 2018.[1],[2]

Breast cancer is now known to comprise multiple distinct molecular subtypes, with each subtype having a distinct molecular signature, disease biology, and response to therapeutic agents. The management of breast cancer has undergone multiple changes in the past few years, including the incorporation of agents from the new drug classes (e.g., immunotherapy), expansion of indications for already existing therapies, a general trend toward de-escalation of treatment in good-risk patients, and personalized treatment algorithms using molecularly targeted agents. In this review article, we aim to summarize the recent updates in the systemic therapy of breast cancer. Considering the extensive preclinical and clinical research output in this area, the current review primarily encompasses clinical trials that can have potentially practice-changing implications.


  Methods Top


We performed a comprehensive literature search for randomized clinical trials on breast cancer treatment published from January 1, 2019, to September 30, 2020, in the PubMed database. In addition, we searched the abstracts and presentations of studies reported at major oncology meetings, like the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and San Antonio Breast Cancer Symposium (SABCS) for the years 2019 and 2020. Two authors (SA and AG) independently reviewed trial results, thus identifying those that were novel and relevant to clinical practice, including the results of trials with negative findings. Only prospective randomized trials exploring new treatment paradigms or trials with pertinent implications in clinical practice were included in the review by the consensus of all authors. [Figure 1] depicts the method used for the selection of studies for the preparation of this review.
Figure 1: The selection of studies for the review on the recent updates in systemic therapy of patients with breast cancer

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  Results and Discussion Top


Hormone-receptor-positive breast cancer

Early breast cancer [Table 1]
Table 1: Summary of the recent updates in breast cancer

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Treatment of early breast cancer (EBC) includes surgery followed by adjuvant chemotherapy, radiation, and/or endocrine therapy (ET). Given the acute and long-term toxicities associated with these cytotoxic agents, there have been persistent efforts to identify the subset of patients at a high risk of recurrence that may benefit from adjuvant chemotherapy, while obviating the adverse effects in those at low risk. However, clinicopathological risk stratification has often failed to make this distinction with precision, and the 70-gene signature test, MammaPrint, has been shown to more accurately predict the clinical outcomes, thus helping spare the low-risk patients the toxicity of unnecessary adjuvant chemotherapy.[3] Longer-term results of the MINDACT trial were reported at the ASCO meeting 2020. This trial randomized 1497 patients with a high clinical risk of recurrence, but a low risk per the MammaPrint assay to either adjuvant chemotherapy or no chemotherapy.[4] With a median follow-up of 8.7 years, the distant metastasis-free survival was found to be 2.6% higher (92% vs. 89.4%), and the overall survival (OS) was found to be 1.4% higher (95.7% vs. 94.3%) in the chemotherapy group, providing good evidence that a modest gain in survival may not justify the use of adjuvant chemotherapy in these patients.

In hormone receptor (HR)-positive EBC treated with neoadjuvant ET, a preoperative endocrine prognostic index (PEPI) score (comprising pathological tumor size, nodal status, Ki-67 level, and the estrogen receptor Allred score) of zero on the resected surgical specimen predicts a very low risk of recurrence.[5] Furthermore, Ki-67 assessment after 14 days of neoadjuvant ET can predict for disease relapse.[6] As the addition of the cyclin-dependent kinase (CDK4/6) inhibitor, ribociclib, has been shown to significantly improve the OS in HR-positive advanced breast cancer (ABC), it was reasonable to assess its role in the neoadjuvant treatment of EBC.[7] The FELINE trial randomized 120 patients with HR-positive EBC to receive 6 cycles of 28 days each of neoadjuvant letrozole with either placebo or one of the two different (continuous or intermittent) dosing schedules of ribociclib.[8] The primary endpoint of the study, which was the preoperative endocrine prognostic index (PEPI) score of 0 at surgery, was not significantly improved with the addition of ribociclib to letrozole. Clinical or radiological response rates were also not significantly different between the groups; however, there was almost a doubling of complete cell cycle arrest (Ki-67 ≤ 2.7%) on day 14 of therapy with ribociclib (92% vs. 52%; P < 0.0001) which was not sustained at surgery, indicating on-therapy resistance. Thus, ribociclib added to ET in the neoadjuvant setting did not meaningfully improve the tumor control.

For many years, adjuvant endocrine therapy alone has been the standard of care for early-stage node-negative, HR-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, while adjuvant chemotherapy has been employed selectively for patients at a high risk of relapse. Despite the long duration of adjuvant endocrine treatment, approximately 20% of the patients will develop disease relapse.[9] Various efforts have been made to explore therapeutic options that might meaningfully reduce the recurrence rate. Abemaciclib, an oral CDK4/6 inhibitor, is approved in combination with fulvestrant and aromatase inhibitors (AIs) in ER-positive ABC based on the significant improvements in OS and progression-free survival (PFS), respectively. The monarchE, a phase III, multinational, open-label, randomized-controlled trial, assessed the efficacy of abemaciclib in the adjuvant setting.[10] In this trial, 5637 patients with HR-positive and HER2-negative EBC with 4 or more involved lymph nodes, or 1-3 lymph nodes with high-risk features (tumor size ≥5 cm, histologic grade 3, or Ki-67 ≥20%) after surgery were randomized 1:1 to receive adjuvant ET alone or in combination with abemaciclib 150 mg twice daily for 2 years. Radiation therapy and neoadjuvant chemotherapy were allowed as indicated. At a median follow-up of 15 months, invasive disease-free survival (IDFS), which was the primary endpoint of the study, was significantly better in the combination arm (2-year IDFS 92.2% vs. 88.7%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60–0.93; P = 0.01). Most events were distant recurrences, with distant recurrence-free survival also being significantly better in the combination arm. Although grade 3 or worse adverse events (chiefly diarrhea and neutropenia) were more common and two-thirds of the patients required dose modification in the experimental arm, serious adverse events were comparable. Most recurrences in the initial 2 years of receiving ET are due to endocrine resistance, and targeting CDK4/6 represents an important method to overcome this resistance and improve the outcomes in this subset of patients.[11] The monarchE trial has established a potential new role for CDK4/6 inhibitors in the adjuvant setting for patients with high-risk EBC. However, longer-term follow-up of these patients is needed to verify if the IDFS benefit is sustained and translates into a commensurate OS benefit. Interim results from the PALLAS trial, which randomized 5,760 patients with stage-II/III, HR-positive, HER2-negative breast cancer to receive adjuvant ET in combination with palbociclib or placebo, were reported at the ESMO congress 2020 after a median follow-up of 2 years.[12] In contrast to the monarchE trial results, there was no difference in the IDFS rate between the two arms of the PALLAS trial (88.2% vs. 88.5%; HR 0.93; 95% CI 0.76–1.15). To confirm if CDK4/6 inhibitors could be a game changer in the adjuvant setting, final results of the trials evaluating palbociclib (PALLAS) and ribociclib (NATALEE) are eagerly awaited.[13],[14]

Advanced breast cancer

CDK4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib, administered in combination with AIs have become the standard of care for postmenopausal women with HR-positive metastatic breast cancer (MBC) with bone-only metastases and not in visceral crisis. Each of these inhibitors resulted in a significant improvement in the PFS compared to AIs alone in the PALOMA-2, MONARCH-3, and MONALEESA-2 trials.[15],[16],[17] Ribociclib has additionally shown benefit in both pre- and peri-menopausal women, as well as an OS benefit.[7] However, the selective estrogen receptor down-regulator, fulvestrant, was compared with anastrozole in the FALCON trial and demonstrated superior PFS.[18] It was, hence, logical to assess the efficacy of CDK4/6 inhibitors with fulvestrant in HR-positive MBC. The PARSIFAL trial randomized 486 patients with previously untreated HR-positive, HER2-negative MBC to receive palbociclib in combination with either fulvestrant or letrozole.[19] At a median follow-up of 32 months, there was no difference between the investigator-assessed PFS for the palbociclib + fulvestrant arm and palbociclib + letrozole arm (27.9 vs. 32.8 months; HR 1.1; 95% CI 0.9-1.5; P = 0.321). The 4-year OS (67.6% vs. 67.5%; HR 1; 95% CI 0.7–1.5; P = 0.986) and grade 3 or worse toxicities were also comparable between the two groups. Hence, given their ease of administration and long clinical experience, AIs remain the agents of choice to combine with palbociclib in the first-line treatment of HR-positive MBC, while fulvestrant + palbociclib may be considered a reasonable alternative. In patients who have progressed on ET, the combination of fulvestrant and palbociclib remains the standard of care, based on the efficacy demonstrated in the PALOMA3 trial.[20] Phosphoinositide 3-kinases (PI3K)/AKT/mammalian target of the rapamycin (mTOR) and CDK4/6 activity are the two principle mechanisms of endocrine resistance in HR-positive and HER2-negative ABC. After having successfully targeted the CDK4/6 pathway, there are now positive data from the inhibition of the PIK3CA in this subset of patients. Alpelisib is an oral, small molecule, a-specific PI3K inhibitor that showed meaningful activity in a phase-Ib study. The SOLAR-1 trial randomized 572 patients with chemotherapy-naïve, HR-positive, HER2-negative ABC after the failure of AIs to receive alpelisib or placebo in combination with fulvestrant.[21] Patients with and without a PIK3CA mutation were enrolled; the median PFS was significantly longer in the combination arm as compared to the fulvestrant-only arm (11 vs. 5.7 months; HR, 0.65; 95% CI, 0.5–0.85; P < 0.001) in patients harboring a PIK3CA mutation, but not in those with wild-type PIK3CA. Hyperglycemia, rash, and diarrhea were significantly more common with alpelisib, but were manageable. The data for OS from this trial were presented at ESMO 2020, and the OS was numerically but not statistically better in the alpelisib group (39.3 vs. 31.4 months; HR, 0.86; 95% CI, 0.64–1.15; P = 0.15).[22] Thus, alpelisib represents a new therapeutic avenue for patients with PIK3CA-mutated HR-positive, HER2-negative ABC.

Triple-negative breast cancer

Triple-negative breast cancers (TNBCs) account for approximately 12–17% of all breast cancer cases in the Western countries and up to 31% of all breast cancer cases in India.[23],[24] Unlike HER2-positive or HR-positive breast cancers, there are no molecular targets or actionable driver mutations in this subset. Given the largely unmet need to exploit molecular pathways for improving the otherwise poor outcomes of these patients, TNBC is an area of active research for finding new agents.

In a phase I/II single-arm study involving 108 patients with refractory metastatic TNBC, Bardia et al. demonstrated meaningful activity of the antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (SG) that combines the anti-human trophoblast cell surface antigen-2 (Trop2) antibody with SN-38 (the active metabolite of irinotecan, a topoisomerase-1 inhibitor).[25] In this pretreated TNBC population with a median of three lines of prior therapy, sacituzumab led to an objective response rate of 33.3%, with a median duration of response of 7.7 months (95% CI, 4.9–10.8 months), median PFS of 5.5 months (95% CI, 4.1–6.3 months), and median OS of 13 months (95% CI, 11.2–13.7 months). The drug was reasonably well tolerated, with nausea, diarrhea, and neutropenia being the most common toxicities. To confirm the findings of this study, the phase III ASCENT trial was designed, which randomized 468 patients with metastatic TNBC without brain metastases and previously treated with two or more lines of chemotherapy to receive SG or single-agent physician's choice chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine). The trial was stopped early in April 2020 based on the recommendations of the data safety monitoring committee due to the clear superiority of the experimental drug. The results of this study, presented at the ESMO congress 2020, showed significantly better median PFS (5.6 vs. 1.7 months; HR, 0.41; P < 0.0001) and OS (12.1 vs. 6.7 months; HR, 0.48; P < 0.0001) in the SG arm,[26] with a manageable safety profile. Thus, ADC represents a new treatment option in this heavily pretreated TNBC population.

Immunotherapy is emerging as an effective treatment option for TNBC, since it is the most immunogenic among the various breast cancer subtypes. Two recent trials have demonstrated the efficacy of the programmed death ligand-1 (PD-L1) inhibitors, atezolizumab and pembrolizumab, in advanced TNBC. Atezolizumab, when added to nab-paclitaxel in advanced TNBC in the IMpassion130 trial, showed significantly improved PFS and OS in patients whose tumors were positive for PD-L1.[27] The KEYNOTE-355 trial compared pembrolizumab with placebo in combination with chemotherapy in patients with previously untreated advanced TNBC.[28] At a median follow-up of 17.5 months, the results (reported at the ASCO meeting, 2020) showed that pembrolizumab significantly improved the PFS in patients with a PD-L1 combined positive score (CPS) of more than 10%. The follow-up for OS was ongoing at the time of reporting.

Building upon the encouraging results from the addition of immuno-oncology agents in the advanced setting, both pembrolizumab and atezolizumab showed an improvement in the pathological complete response (pCR) rates in early TNBC when added to the standard neoadjuvant chemotherapy backbone. The KEYNOTE-522 trial randomized 1174 patients with early TNBC undergoing neoadjuvant chemotherapy to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy with paclitaxel/carboplatin followed by anthracycline/cyclophosphamide.[29] The pCR rate, which was the primary endpoint of the trial, was significantly better (64.8% vs. 51.2%; P < 0.001) in the pembrolizumab arm. Although the trial recruited patients irrespective of their PD-L1 status, 83% of the patients were positive for PD-L1 (CPS >1%). The incidence of serious treatment-related adverse events was higher in the pembrolizumab-chemotherapy arm as compared to the placebo-chemotherapy arm, but the adverse events were consistent with the previously known toxicity profile of pembrolizumab. At a median follow-up of 15.5 months, an event-free survival benefit was also demonstrated with the use of pembrolizumab, with a HR of 0.63 (95% CI, 0.43-0.93). However, this trial did not allow for the use of adjuvant capecitabine in patients who failed to achieve a pCR after neoadjuvant therapy. With the caveat of a cross-trial comparison being that it is only hypothesis-generating, one may speculate that adjuvant capecitabine in patients not achieving pCR may offer a DFS benefit of similar magnitude (HR, 0.58; 95% CI, 0.39–0.87) as that seen in the triple-negative subset of the CREATE-X trial.[30]

Analogous to the KEYNOTE-522 trial, the placebo-controlled IMpassion031 trial examined the benefit of adding atezolizumab to neoadjuvant chemotherapy comprising nab-paclitaxel, doxorubicin, and cyclophosphamide.[31] An important difference was that this trial allowed the use of adjuvant capecitabine in patients not achieving pCR per the standard of care. This study enrolled 333 patients, of which approximately half had PD-L1 positivity (CPS >1%) and showed that atezolizumab improved the pCR rate from 41% to 58% (P = 0.0044). An exploratory analysis showed that atezolizumab benefited almost all patient subgroups, including those that were negative for PD-L1 expression.

Exploiting the anti-tumor efficacy of capecitabine through the inhibition of angiogenesis and stimulation of immune response when administered as metronomic therapy, the SYSUCC-001 trial randomized 434 women with stage Ib-IIIc TNBC after the completion of standard curative treatment (surgery, chemotherapy, and/or radiation) to receive 1 year of adjuvant capecitabine 650 mg/m2 twice daily or observation.[32] The 5-year DFS in the capecitabine arm (83% vs. 73%) was significantly better than that in the observation arm (HR, 0.63; 95% CI, 0.42-0.96; P = 0.027), but there was no significant difference in the OS. However, given the natural history of TNBC, which is usually characterized by early relapse, this may lead to an OS benefit with longer follow-up.[33] The results of this study are contrary to those of the GEICAM trial that randomized 876 patients with similar inclusion criteria to receive 8 cycles of capecitabine at a higher dose (2000 mg/m2/day for 14 days in 21 days cycles) or observation and found no difference in the DFS. This indicates that capecitabine may be more efficacious when administered in a metronomic dose schedule.[34] Improvement of DFS when capecitabine is administered as metronomic therapy for a prolonged period of time has valuable implications for clinical practice, as TNBC has an aggressive disease biology with high rates of relapse and lack of targeted agents; hence, reduction in the relapse risk is essential to better the outcomes.

Another recent addition to the therapeutic armamentarium for advanced TNBC is the AKT kinase inhibitor, capivasertib. Activation of the PI3K/AKT gene or inactivation/deletion of the PTEN gene frequently leads to the activation of the PI3K/AKT signaling pathway, which in turn is associated with treatment resistance and poor prognosis. In the phase-II PAKT trial, previously untreated patients (or neoadjuvant taxane-exposed if concluded at least 12 months before randomization) with advanced TNBC were randomly assigned to receive weekly paclitaxel with either capivasertib or placebo until disease progression or unacceptable toxicity. The trial met its primary endpoint with a median PFS of 5.9 months in the capivasertib combination arm and 4.2 months in the placebo combination arm (HR, 0.74; 95% CI, 0.5–1.08; 1-sided P = 0.06; predefined significance level 1-sided P = 0.1). The improvement in PFS from the addition of capivasertib was primarily seen in patients with PIK3CA/AKT1/PTEN-altered tumors (9.3 vs. 3.7 months; HR, 0.3; 95% CI, 0.11–0.79; P = 0.01). There was also a significant improvement in the median OS (19.1 vs. 12.6 months; HR, 0.61; 95% CI, 0.37–0.99; P = 0.04). These findings are being further validated in the phase III randomized trial, CAPItello290 study (NCT03997123).


  Chemotherapy-Free Approach in Triple-Negative Breast Cancer Top


In pursuit of a chemotherapy-free approach for patients with advanced TNBC, Cortes et al. evaluated pembrolizumab monotherapy in patients with advanced TNBC previously treated with one to two lines of chemotherapy.[35] In the KEYNOTE-119 trial, 622 patients were randomized to receive pembrolizumab monotherapy 200 mg every 3 weeks or palliative chemotherapy of physician's choice. The primary endpoint of the trial, OS, was not significantly superior in the pembrolizumab arm compared to the chemotherapy arm, neither in the entire cohort of enrolled patients, nor in those with CPS ≥10% or 1%. Treatment-related grade 3–5 adverse events were less common in the pembrolizumab arm (14% vs. 36%). However, in an exploratory analysis of patients with CPS ≥20%, pembrolizumab significantly prolonged the OS (14.9 vs. 12.5 months; HR, 0.58; 95% CI, 0.38–0.88), suggesting that this warrants further evaluation and a chemotherapy-free approach, analogous to poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA-mutated ABC, may be successful in a subset of patients.

Human epidermal growth factor receptor 2-positive breast cancer

Amplification of HER2 results in the persistent activation of the downstream PI3K/AKT/mTOR pathway, which in turn leads to a more aggressive disease biology and enhanced sensitivity to chemotherapeutic agents. Neoadjuvant chemotherapy is often the preferred approach for patients with HER2-positive breast cancers measuring more than 0.5 cm. Incorporation of the newer anti-HER2 agents approved over the past decade has consistently improved the pCR rates, which is associated with significantly better DFS and OS.[36]

Human epidermal growth factor receptor 2-positive early breast cancer

The phase III TRAIN-2 trial randomized 438 patients with stage II/III HER2-positive breast cancer to receive 3 cycles of 5-fluorouracil (5-FU) (500 mg/m2) + epirubicin (90 mg/m2) + cyclophosphamide (500 mg/m2) followed by 6 cycles of weekly paclitaxel (80 mg/m2 day 1,8) + carboplatin (area under the curve 6 mg/ml/min) (FEC-PC arm) or 9 cycles of paclitaxel + carboplatin (PC arm). Patients in both arms received dual HER2 blockade with trastuzumab (6 mg/kg after a loading dose of 8 mg/kg) and pertuzumab (420 mg after a loading dose of 840 mg.[37] The updated results of this trial, with a median follow-up of 49 months reported no significant difference in the pCR rate (67% vs. 68%), 3-year DFS (93% vs. 94%), or OS (98% in both arms) between the 2 arms.[38] Anthracycline-based therapy was not beneficial in any of the subgroups analyzed, but was associated with a significantly higher incidence of febrile neutropenia (10% vs. 1%), decline in the left ventricle ejection fraction (36% vs. 22%), and 2 cases of acute leukemia. Thus, carboplatin/taxane combination without anthracycline is the preferable regimen for neoadjuvant treatment in this subset of patients.

The KATHERINE trial investigated the role of the ADC trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer in the adjuvant setting.[39] In this trial, 1486 women with residual disease in the surgical specimen after neoadjuvant taxane-containing chemotherapy (+/-anthracycline) and trastuzumab were randomized to receive trastuzumab or T-DM1 for 1 year. The IDFS at 3 years was significantly better in the T-DM1 group as compared to the trastuzumab group (88.3% vs. 77%; HR, 0.5; 95% CI, 0.39–0.64; P < 0.001), as was freedom from distant recurrence (89.7% vs. 83%; HR, 0.6; 95% CI, 0.45–0.79). This benefit was seen across all subgroups, and there was also a trend toward better OS with T-DM1 (HR, 0.7; 95% CI, 0.47–1.05; P = 0.08). Grade 3 or worse adverse events (25.7% vs. 15.4%) and treatment discontinuation rate due to adverse events (18% vs. 2.1%) were higher in the T-DM1 group.

In order to minimize the toxicity from anti-cancer treatment, multiple de-escalation studies in HER2-positive breast cancer have been reported recently. The first of these, PERSEPHONE, was a non-inferiority trial that randomized 4089 patients with HER2-positive EBC who were candidates for chemotherapy, to receive 6 or 12 months of adjuvant trastuzumab.[40] The 4-year DFS, which was the primary endpoint of this study, was 89.4% in the 6-month group versus 89.8% in the 12-month group, with a hazard ratio 1.07 (95% CI, 0.93–1.24; P = 0.011). The 4-year OS in the 6-month group was also non-inferior to that of the 12-month group (93.8% vs. 94.8%; HR, 1.14; 95% CI, 0.95–1.37; P = 0.001); however, grade 3 or worse adverse effects were significantly less common in the 6-month group (19% vs. 24%; P = 0.0002). The findings of this study, along with an individual participant data and trial level meta-analysis by Gulia et al., strengthens the conviction that a shorter duration of adjuvant trastuzumab result in outcomes comparable to those with one year of therapy.[41] The next in this series was the Japanese non-inferiority trial, RESPECT, that randomized 275 older women aged 70–80 years (mean age 73.5 years) with stage I-IIIa HER2-positive breast cancer to receive 1 year of trastuzumab alone or in combination with adjuvant chemotherapy.[42] The 3-year DFS with trastuzumab monotherapy did not meet the non-inferiority criteria compared to the chemotherapy combination (89.5% vs. 93.8%; HR, 1.36; 95% CI, 0.72–2.58; P = 0.51). However, trastuzumab monotherapy was associated with a restricted mean survival time that was inferior by only 0.39 months, with significantly less toxicity and maintained quality of life. Thus, in older patients, trastuzumab alone may be considered in select patients who are not eligible for aggressive chemotherapy. On a similar note, the PHERGain trial attempted a fluorodeoxyglucose-positron emission tomography (PET)/computed tomography- and pathological response-adapted de-escalation strategy in HER2-positive EBC.[43] In this study, 356 patients with stage I-IIIA HER2-positive EBC were randomized to receive the standard docetaxel + carboplatin+ pertuzumab + trastuzumab (TCHP, arm A) or trastuzumab + pertuzumab ± ET (PH, arm B). After 2 cycles of neoadjuvant therapy, PET responders in the PH arm continued the same for an additional 6 cycles before surgery, while the non-responders switched to 6 cycles of TCHP followed by surgery and then 10 cycles of PH. Among those who continued on the PH arm, the ones who achieved pCR completed 10 more cycles of PH, and those who had residual disease on the surgical specimen were given 6 cycles of TCHP followed by 4 cycles of PH. The co-primary endpoints in this study were the pCR rate in the PET responders and 3-year IDFS in arm B; the results of the first primary endpoint were reported at ASCO 2020. Approximately 40% of the patients in arm B who were PET responders achieved a pCR, suggesting that a PET scan may identify patients with HER2-positive EBC who are likely to achieve pCR with dual HER2 blockade and may safely forego chemotherapy with its attendant toxicities. Another important study was the KRISTINE trial, which randomized 444 patients with stage-II-III HER2-positive EBC to receive six cycles of neoadjuvant treatment with ado-trastuzumab emtansine (T-DM1) plus pertuzumab (T-DM1/P) or TCHP and found that pCR rate with the former was inferior to that of the TCHP arm (44.4% vs. 55.7%; P = 0.016).[44] The 3-year follow-up results of KRISTINE showed that patients in the T-DM1/P arm had more locoregional progression events before surgery, but the risk of a DFS event was similar after resection (7% vs. 8%; HR, 1.11; 95% CI, 0.52–2.40).[45] The KAITLIN trial was a de-escalation study for HER2-positive EBC, which aimed to increase the efficacy and reduce the toxicity by replacing taxanes and trastuzumab with T-DM1 in the adjuvant setting.[46] In this trial, 1846 patients with high-risk HER2-positive EBC were randomized after resection to receive 3–4 cycles of anthracyclines + cyclophosphamide followed by either taxane + PH or T-DM1/P. The 3-year IDFS rate in the T-DM1/P arm was not better than that in the taxane/PH arm, in both the node-positive (92.8% vs. 94.1%; HR, 0.97; 95% CI, 0.71–1.32; P = 0.8270) and intention-to-treat populations (93.1% vs. 94.2%; HR, 0.98; 95% CI, 0.72–1.32; P = 0.8270). The T-DM1/P arm also had a higher incidence of serious adverse events and treatment discontinuation, asserting that taxane/PH still remains the standard of care for this patient subset.

Building upon the findings of the HannaH study, that established the feasibility of subcutaneous trastuzumab, the FeDeriCa trial tested the feasibility and efficacy of a fixed-dose combination of trastuzumab and pertuzumab with recombinant human hyaluronidase, and the primary results were reported at the SABCS 2019.[47],[48] In this non-inferiority trial, 500 patients with stage-II-IIIC HER2-positive breast cancer undergoing dose-dense neoadjuvant chemotherapy with doxorubicin, cyclophosphamide, and taxane were randomized to receive either intravenous or subcutaneous trastuzumab and pertuzumab. The primary endpoint of the trial (pre-dose cycle 8 pertuzumab serum trough levels, geometric mean ratio) was 1.22 (90% CI, 1.14–1.31), which was above the prespecified non-inferiority margin of 0.8. The pCR rate (59.5% vs. 59.7%) and toxicity profile (including cardiac toxicity) were comparable between the treatment arms. Now more than ever, this faster and quicker method of trastuzumab/pertuzumab administration is of relevance in the COVID-19 scenario to minimize time spent in the hospital.

Human epidermal growth factor receptor 2-positive advanced breast cancer

Two tyrosine kinase inhibitors (TKIs) have recently been approved by the Food and Drug Administration (FDA) in patients with relapsed HER2-positive MBC, including those with brain metastases. First of these, tucatinib, is highly selective for the HER2 kinase domain. The HER2CLIMB trial compared tucatinib (300 mg twice daily continuously) with placebo in combination with capecitabine (1000 mg/m2 twice daily on days 1–14 every 21 days) and trastuzumab (6 mg/kg after a loading dose of 8 mg/kg on day 1, every 21 days) in metastatic HER2-positive disease previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine.[49] The trial enrolled 480 patients from 15 countries; the primary end point was PFS. In this heavily pretreated population (patients had received a median of 4 prior lines of therapy), the 1-year PFS was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group, with a median PFS of 7.8 months and 5.6 months, respectively. At 2 years, the OS in the tucatinib arm was 44.9% compared to 26.6% in the placebo arm (HR for death 0.66; 95% CI, 0.50–0.88; P = 0.005). In the subgroup analysis, PFS was found to be significantly better in all the subgroups, except in patients aged 65 years or more. Diarrhea, palmar-plantar erythrodysesthesia, nausea, stomatitis, and liver enzyme elevation were more common in the tucatinib-combination group. Notably, 291 patients included in the HER2CLIMB trial had brain metastases at enrollment. Of these, 174 had active brain metastases. Tucatinib significantly improved the median central nervous system (CNS) PFS (9.9 vs. 4.2 months; HR, 0.32; 95% CI, 0.22–0.48; P < 0.0001) and OS (18.1 vs. 12.0 months; HR, 0.58; 95% CI, 0.40–0.85; P = 0.005) in patients with brain metastases.[50] The estimated 1-year OS was 70.1% in the tucatinib arm compared to 46.7% in the placebo arm. An interesting question is whether tucatinib would have led to any incremental benefit, had the control arm also included another HER2 inhibitor such as lapatinib.

The second TKI, neratinib is an irreversible pan-HER (HER1, HER2, and HER4) inhibitor that was evaluated in the NALA trial in HER2-positive MBC patients previously treated with two or more anti-HER2 agents.[51] This trial randomized 621 patients, including 101 (16%) patients with asymptomatic CNS metastases, to receive neratinib (240 mg once daily) plus capecitabine (1000 mg/m2 twice daily on days 1–14 every 21 days) (N + C), or lapatinib (1250 mg once daily) plus capecitabine (750 mg/m2 twice daily on days 1–14 every 21 days) (L + C). The mean PFS (8.8 vs. 6.6 months) was significantly better in the N + C arm (HR, 0.76; 95% CI, 0.63–0.93; P = 0.0059), although the mean OS (24 vs. 22.2 months) was not significantly improved (HR, 0.88; 95% CI, 0.72–1.07; P = 0.2098). Neratinib also significantly delayed the time to intervention for symptomatic CNS disease, suggesting some efficacy in brain metastases. Although neratinib was associated with a higher incidence of diarrhea, nausea, and vomiting, treatment discontinuation rate and quality of life were comparable between the two arms.

Pyrotinib is a small molecule, irreversible, pan-ErbB inhibitor that is the third new TKI in the arena of HER2-positive MBC. The Chinese phase III PHOEBE trial randomized 267 patients with HER2-positive MBC previously treated with trastuzumab and taxanes +/-anthracyclines to receive capecitabine (1000 mg/m2 twice daily for 14 out of 21 days in each cycle) in combination with either pyrotinib (400 mg once daily) or lapatinib (1250 mg once daily). The primary endpoint, PFS, was significantly better in the pyrotinib arm compared to the lapatinib arm (12.5 vs. 6.8 months; HR, 0.39; 95% CI, 0.27–0.56; P < 0.0001), as was the 12-month OS (91.3% vs. 77.4%; HR, 0.46; 95% CI, 0.22–0.99). Although the incidence of grade 3 or worse adverse effects (primarily diarrhea of short duration) was higher in the pyrotinib group, serious adverse events and discontinuation rates were comparable. Following this trial, pyrotinib was approved in combination with capecitabine as the second-line therapy in HER2-positive MBC, but it has not yet been approved by the FDA.

Opening up new therapeutic avenues for HER2-positive ABC patients, trastuzumab deruxtecan (DS-8201), an ADC combining anti-HER2 monoclonal antibody with a topoisomerase-I inhibitor, was evaluated in the phase II single-group trial, DESTINY.[52] In a total of 184 patients who had progressed on a median of 6 anti-HER2 therapies previously, including T-DM1, DS-8201 led to an impressive objective response rate of 61%, disease control rate of 97.3%, median response duration of 14.8 months, and median PFS of 16.4 months. The most common serious adverse events observed were neutropenia, anemia, and nausea, with a particularly high incidence (13.6%) of interstitial lung disease, including fatal events. This substantial and durable anti-tumor activity of trastuzumab deruxtecan exceeds that of all the currently available options for this heavily pretreated patient cohort and warrants further evaluation in a phase III trial. Marking another significant progress at the SABCS 2019, Rugo et al. reported the interim analysis results of the SOPHIA trial, which investigated margetuximab (an Fc-engineered anti-HER2 monoclonal antibody that enhances CD16A-mediated innate and adaptive immunity against the tumor cells) in 536 patients with HER2-positive ABC who had received at least 2 prior lines of anti-HER2 therapy.[53] Patients were randomized to receive chemotherapy with either margetuximab or trastuzumab; the median PFS was significantly better in the margetuximab arm (5.8 vs. 4.9 months; HR, 0.76; 95% CI, 0.59–0.98; P = 0.033).

Loco-regional control in metastatic breast cancer

A long-standing debate in the management of MBC has been the role of locoregional surgery in patients who present with stage-IV disease. While few retrospective studies have favored addressing the primary tumor, which was also indicated in a meta-analysis of 67,682 patients in 19 retrospective studies, prospective randomized controlled trials failed to show any OS benefit of surgery.[54],[55],[56],[57] The phase III ECOG-ACRIN E2108 study randomized 256 patients with stage-IV breast cancer and no progression after 4–8 months of optimal systemic therapy to continue systemic therapy alone or to undergo additional locoregional therapy (surgery and/or radiation).[57] There was no difference in the OS (68% in both arms, P = 0.63) and PFS (P = 0.40). As expected, the 3-year locoregional recurrence/progression was higher in the systemic-therapy alone arm (25.6% vs. 10.2%; P = 0.003), but there was no difference in the long-term health-related quality of life scores between the two arms. Pooled with the study from the Tata Memorial Hospital, this trial confirms the lack of survival benefit from locoregional therapy in MBC.[56] We may infer that though not a standard of care, selected patients with oligometastatic breast cancer may be considered for locoregional treatment of the primary and metastatic sites.

Adjuvant bone-modifying agents

Bone-modifying agents (bisphosphonates and denosumab) are standard in ABC to reduce skeletal-related events, but studies evaluating these agents in EBC have produced inconsistent results thus far. The positive impact of bisphosphonates on breast cancer recurrence (including bone and distant recurrence) and mortality in postmenopausal women with EBC was established by a meta-analysis reported in 2015.[58] Recently reported results from the HOBOE trial confirm the merits of adjuvant zoledronate in premenopausal women.[59] Coleman et al. evaluated the efficacy of denosumab, a fully human monoclonal antibody that binds RANKL, in reducing bone-metastases-free survival (BMFS).[60] In this international phase III trial, 4509 women with stage-II-III breast cancer undergoing neoadjuvant or adjuvant chemotherapy were randomly assigned to receive denosumab every 4 weeks for 6 months, and then every 12 weeks till 5 years, or a matching placebo. After a follow-up of 5 years, denosumab was not found to reduce the BMFS (HR, 0.97; 95% CI, 0.82–1.14; P = 0.70) and was associated with a higher incidence of osteonecrosis of the jaw (5% vs. <1%) and hypocalcemia (7% vs. 4%). Based on these findings, denosumab is not routinely recommended for patients with EBC undergoing neoadjuvant therapy.


  Conclusion Top


Major strides have been made over the past couple of years in the treatment of almost all subsets of breast cancer, and yet many more therapeutic options are at various stages of development and are likely to enter the clinic in the foreseeable future. The therapeutic landscape of breast cancer is rapidly evolving and access to these drugs is soon expected to transform the way we treat it.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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