Evolution of Targeted Therapy in Breast Cancer: Where Precision Medicine Began

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Date: 02.04.2019

During the past decade, a large amount of the research effort within the field of oncology has been devoted to the development and use of targeted therapy. Great strides have been made in our understanding of which patients are appropriate candidates for certain types of treatments (immunotherapy and PARP inhibitors are good examples), and many national and international trials are under way to identify useful targeted therapies for patients with chemotherapy-resistant and/or advanced-stage disease. We have made a lot of progress, but we still have a long way to go in terms of optimizing our ability to identify targeted therapy candidates.

Understanding the past can help us shape the future, and, as we look to improve our approaches to targeted therapy across the spectrum of malignancies, the history of targeted therapy in breast cancer therapy can serve as an extremely relevant case study. Breast cancer is one of the first malignancies for which targeted therapies have been used successfully. Endocrine therapies that target the estrogen (ER) and progesterone receptor have long been the cornerstone of systemic therapy approaches for hormone receptor–positive breast cancer, and the discovery of HER2 overexpression has led to the development of multiple HER2-targeted agents that have revolutionized the way HER2-positive breast cancer is treated. Both of these targeted approaches have drastically improved outcomes for these patients. Now, with decades of successful anti-estrogen and now anti-HER2–directed therapy to build upon, our understanding of resistance to targeted therapy is becoming more nuanced. Current clinical trials in breast cancer focus on combating and preventing resistance to targeted therapy, both in the advanced stage as well as in the curative setting.

Here, we offer some insights into the history of endocrine therapy and HER2-directed therapy for breast cancer, as well as a discussion of some of the more current developments in this field. It is our hope that this perspective is helpful not only to those with a focus on breast cancer and breast disease but also for those with a broader interest in precision medicine.

Aiming at hormone receptors that are present on some breast cancer cells has been, essentially, the starting point of targeted anticancer therapy. In recent years, enormous research efforts have been directed at understanding and inhibiting the growth signals of cancer cells, but, in truth, the association between estrogen and breast cancer has been known since the late 19th century.1,2 The first critical observation, made by George Thomas Beatson, was that changing the hormonal environment within the patient could lead to beneficial modifications in breast tumor growth and even to regression of metastatic disease.3

Dr. Beatson, then a surgeon at Edinburgh University, developed an interest in the interaction between ovaries and breast with respect to milk formation. Driven by research even then, he observed that rabbit breasts stopped producing milk after he removed the animals’ ovaries. He reflected: “This fact seemed to me of great interest, for it pointed to one organ holding control over the secretion of another and separate organ.” This observation was the breakthrough cognition of hormones as messengers in organisms, and Beatson took this pivotal principle to the clinic: He started to surgically remove the ovaries of patients with advanced breast cancer, and, in some of his patients, clinical improvement was seen.4 Without knowing about estrogen, he had discovered that its presence was crucial to the growth of some breast cancers and that removing the ovaries—the main source of estrogen—was a successful anticancer treatment.

Basically, this also is what we do today as standard of care, either by blocking estrogen on breast cancer cells (achieved by selective estrogen receptor modulators, such as tamoxifen) or by deprivation/elimination of circulating estrogen (achieved by aromatase inhibitors and ovarian suppression therapy or oophorectomy). These approaches have been the mainstay of therapy for ER-positive and progesterone receptor–positive cancers for decades and remain so today.

The first modern trials of adjuvant ovarian ablation were carried out in Manchester and Norway more than half a century after Beatson’s discovery,5,6 and their results were not accepted everywhere. Rather quickly, some cultural differences between Europe and the United States became apparent7: in Europe, there was continuing interest in the exploitation of antihormonal approaches, whereas American researchers were more interested in the development of cytotoxic agents that could serve as the mainstay of breast cancer therapy. A bit of this trend is still present in today’s clinical practice pattern; however, globalization of research networks and information sharing has largely alleviated these historical differences.

Other interventions that indicated that hormones are important came from observations after adrenalectomy8 and hypophysectomy9 in the early 1950s; however, it took more than another decade to finally pinpoint the reason why hormonal ablation worked in some patients with breast cancer and not in others. Finally, the detection of estrogen receptors on the surface of breast cancer cells by Jensen et al10 in the 1960s explained why estrogen deprivation and/or receptor blockade works as therapeutic principle in many breast cancers.

Tamoxifen

It was not until the late 1960s that the first clinically usable anti-estrogen was discovered: Tamoxifen,11 a selective estrogen receptor modulator, now became an alternative to surgical removal or radiotherapeutic ablation of endocrine glands. Tamoxifen was approved in 1977 by the U.S. Food and Drug Administration (FDA) for the management of metastatic breast cancer.12 Interestingly, the initial studies included unselected patients because of a lack of estrogen receptor essays, but results still showed a response rate of 40% to 50% in women with advanced breast cancer.13 During the next decade, several clinical trials reported improvement in disease-free survival with the use of tamoxifen in both pre- and postmenopausal women with early breast cancer14-16 By binding to the estrogen receptor on cell surfaces in a competitive manner, tamoxifen became the mainstay of endocrine intervention in all breast cancer settings and is still used today as part of the standard of care. This best-studied anticancer drug in history, with hundreds of millions of patient-treatment years, essentially marked the beginning of the era of tailored or targeted oncology. Most important, its use has led to clear-cut prolongations of patients’ lives in the advanced breast cancer setting17 and to important long-term benefit for patients with early-stage breast cancer.18,19

Aromatase Inhibitors and Ovarian Suppression

The development of aromatase inhibitors, which, by inhibiting aromatase—the enzyme that catalyzes the conversion of androgens to estrogens—can decrease circulating estrogen to nearly zero in postmenopausal women who already lack ovarian estrogen production, was a second targeted approach that pushed the field forward. This approach became the standard of care in postmenopausal women when several pivotal studies proved it to be more effective than tamoxifen alone.20 More recently, it has been found that, for premenopausal women with more aggressive early-stage ER-positive breast cancer, inducing menopause either biochemically (with luteinizing hormone releasing hormone analogs such as goserelin21) or surgically (with oophorectomy) followed by an aromatase inhibitor is a more effective way than use of tamoxifen alone to prevent recurrence and death as a result of breast cancer.22

Combining targeted therapies, such as ovarian suppression and aromatase inhibition, can be more effective but also more toxic than using one drug alone; although the combination generally is better tolerated than cytotoxic drugs, endocrine therapies are not without adverse effects.23 The importance of balance between benefit and toxicity is something that we have seen with the addition of anti–CTLA-4 and anti–PD-1 therapy in melanoma24 and is something that we certainly will see more of as we combine targeted therapies in other diseases. Some of the ongoing conversations about the pros and cons of more aggressive endocrine therapy in early-stage breast cancer25 will become important in other disease types as well, particularly as the options for combining targeted therapy move from the advanced stage to the upfront setting. Identification of patients for whom more is really more and those who can get away with less will be critically important. Patient and societal perspectives are important as we consider the substantial cost of many new medications and the lingering effects of ongoing financial toxicity on individuals and communities.26

Fulvestrant

In the metastatic setting, fulvestrant27 is a selective estrogen receptor downregulator that not only blocks the estrogen receptor on tumor cells but also permanently degrades it, which downregulates cellular levels of ER and progesterone receptor and therefore leads to decreased cell growth in estrogen-dependent cells. It can be used alone in the metastatic setting, as can aromatase inhibitors; both can be used as part of novel combination approaches with other agents, such as mTOR or cyclin-dependent kinase (CDK) 4/6 inhibitors28,29; these therapies will be discussed following later sections of this paper.

Endocrine treatments are important in all settings of luminal breast cancer therapy. One crucial feature for the optimal use of these agents is the identification of endocrine responsiveness, which means that proper analytic quality of receptor expression assays is critical to the successful use of endocrine therapy in the clinic. It is likely that sequential or concurrent combinations of endocrine agents with newer biologic agents will be tested and used in the future with much more detailed identification of responsiveness to specific therapies. As in other areas of oncology, improved biomarkers to better identify and eventually be able to individually select patients for given treatments on the basis of accurate prediction of response and resistance are important subjects of current and future research efforts.30

The first paper to identify HER2 as a proto-oncogene in human breast cancer was published in 1989.31 As we now know, HER2-overexpressing tumors constitute 15% to 20% of all tumors in patients with breast cancer. Since that time, there has been an explosion in our understanding of the prognostic and therapeutic implications of this oncogene, and no fewer than five drugs that target HER2 have been approved for use in the metastatic and/or (neo)adjuvant setting (Fig. 1).

Overexpression of HER2, which occurs in approximately 20% of breast cancers and largely is because of a specific gene copy number amplification, results in a hyperproliferative cancer cell and poor prognosis.32 This, plus emerging evidence that cancer cells can become oncogenically addicted33—which means that a single aberrant oncogene becomes such a driving force for growth and proliferation that other usually relevant pathways atrophy—makes HER2 a highly attractive therapeutic target. This principle of oncogene addiction as it pertains to HER2 was supported by the finding that ongoing treatment with the anti-HER2 antibody trastuzumab added to capecitabine after disease progression on trastuzumab improved overall survival compared with change to capecitabine alone.34 This oncogene addiction is the basis for the practice of ongoing HER2 targeting after disease progression.

Trastuzumab

The first anti-HER2 drug, trastuzumab, is a humanized monoclonal antibody directed at the extracellular domain of the transmembrane receptor HER2. This engineered murine-derived antibody was, at the time, a highly innovative approach to therapy. Early-phase studies in advanced “HER2-positive” breast cancer (quotation marks reflect the limitation that early assays for HER2 were less accurate than they are now) revealed long-term progression-free survivors. This became known among patient advocacy groups and resulted in a blessedly short-lived controversy about compassionate-use trastuzumab as the drug underwent regulatory approval. Recent advances include validation of subcutaneously injected and biosimilar drugs that expand accessibility and availability of the drug.

Metastatic setting.

On the basis of a seminal phase III trial of trastuzumab added to different chemotherapy backbones that revealed great improvement in progression-fee survival (PFS) and overall survival despite considerable crossover,35 trastuzumab was approved by the FDA in 1998 for use in combination with a taxane. The other arm of this trial that combined trastuzumab with doxorubicin/cyclophosphamide experienced an unacceptably high (27%) risk of clinical cardiotoxicity. This cardiotoxicity risk has not been replicated in several (neo)adjuvant trials that allowed concurrent use of trastuzumab with anthracycline and may have reflected the pretreated nature of the patients; however, this risk remains a consideration in combination therapy. Subsequent trials established that trastuzumab could be safely and effectively combined with a number of chemotherapy partners, including vinca alkaloids, platinums, and alkylators. Among the subset of dual hormone receptor–positive and HER2-positive cancers, a phase III trial of aromatase inhibition with or without trastuzumab found that these patients did very poorly on antiestrogen alone: PFS was approximately 2 months and was doubled by the addition of trastuzumab.36 Today, trastuzumab is incorporated with chemotherapy or antiestrogens in the first-line setting and, generally, is re-incorporated later with other backbones, after ado-trastuzumab emtansine (T-DM1) or lapatinib-containing regimens.

(Neo)adjuvant setting.

The first adjuvant trials of trastuzumab in HER2-positive breast cancer were reported simultaneously at a special session during the 2005 ASCO Annual Meeting and demonstrated a relapse-free survival advantage when combined in an anthracycline/taxane-based regimen (called AC-TH) in the joint analysis of NCCTG N9831 and NSABP B-31 results37 and when added after chemotherapy in results from the European study HERA.38 These reports, which were met with a standing ovation (perhaps a first in ASCO Annual Meeting history), set the standard for incorporation of trastuzumab into treatment of early HER2-positive breast cancer, and they were confirmed and extended by the BCIRG006 trial, which also found improved outcomes when trastuzumab was added to docetaxel plus carboplatin (called TCH).39 Recent updates suggest that trastuzumab added to polychemotherapy results in a 40% proportional and nearly 10% absolute overall survival advantage.40 Because of the aggressiveness of all of these regimens, a simpler regimen of single-agent taxane for 12 weeks with trastuzumab for 1 year (called TH) was tested in a single-arm trial in patients with low clinical risk and HER2-positive disease; results demonstrated a 98% distant disease–free survival at 3 to 4 years and established TH as an acceptable regimen for stage I disease, especially if tumors were HR positive.41 In all of these trials, trastuzumab was given for 1 year; trials of shorter durations have had mixed results. As a result of these studies, trastuzumab now is incorporated into all neoadjuvant and adjuvant regimens for HER2-positive disease and is given for 1 year.

Lapatinib

Lapatinib is a small-molecule HER1/HER2 dual inhibitor. Studies suggest that the clinical effect is driven primarily by its HER2 effect.

Metastatic setting.

Lapatinib was approved after a phase III trial in which was added to capecitabine (as a regimen called XL) in metastatic trastuzumab-pretreated HER2-positive breast cancer; results revealed a 50% improvement in PFS.42 Later studies of lapatinib added to taxanes in the earlier-line setting also suggested improvement in outcome; however gastrointestinal toxicity, particularly diarrhea, and pharmacokinetic interaction with paclitaxel required dose reduction43 and made lapatinib a less compelling option in the first-line metastatic setting. In heavily pretreated patients, lapatinib added to trastuzumab demonstrated improved survival compared with trastuzumab alone.44Added to aromatase inhibitor in dual HR–positive, HER2-positive breast cancer, lapatinib, like trastuzumab, doubled the baseline, poor, PFS seen with aromatase inhibitors alone.45 With the development of T-DM1 (discussed later in the paper), XL and lapatinib plus trastuzumab have become third-line or later regimens but remain reasonable to use.

(Neo)adjuvant setting.

Lapatinib in the adjuvant setting looked promising on the basis of a neoadjuvant study that demonstrated greatly augmented pathologic complete response compared with chemotherapy plus trastuzumab alone.46 However, other studies found a more modest impact on pathologic complete response,47,48 and a large adjuvant trial, ALTTO, failed to meet its prespecified statistical endpoint, although a numeric hazard ratio advantage of 0.84 in favor of lapatinib-containing arms was seen.49 Therefore, lapatinib is not included in neoadjuvant or adjuvant regimens today.

Pertuzumab

Pertuzumab is another anti-HER2 monoclonal antibody, but, unlike trastuzumab, it binds to the heterodimerization domain. Interestingly, pertuzumab adverse effects include diarrhea and rash, neither of which typically are associated with trastuzumab.

Metastatic setting.

Added to trastuzumab plus a taxane in the first-line setting in the CLEOPATRA trial, pertuzumab improved both PFS and overall survival, the latter by an astounding duration: 16 months.50 This established a new standard for first-line therapy. The benefit of pertuzumab added to trastuzumab with antiestrogens (called THP) also was demonstrated in the PERTAIN study, in which pertuzumab added 3 months of PFS (HR 0.65) to that of an aromatase inhibitor plus trastuzumab alone.51 Therefore, on the basis of its large survival benefit, THP is an accepted standard of care for first-line therapy, Although it is reasonable to consider pertuzumab added to an aromatase inhibitor plus trastuzumab for first-line treatment, it lacks an overall survival advantage, so most clinicians reserve pertuzumab use for THP; unlike trastuzumab, there are no data for pertuzumab use after progression.

(Neo)adjuvant setting.

Results of a single large neoadjuvant trial, NeoSPHERE demonstrated that pertuzumab added to chemotherapy plus trastuzumab significantly increased pathologic complete response52; as a result, the FDA for the first time in 2013 approved a drug on the basis of the pathologic complete response intermediate endpoint. This approach was validated by the results of the APHINITY adjuvant trial, in which event-free survival as an endpoint was improved by the addition of pertuzumab to AC-TH (AC-THP) or to the nonanthracycline TCH regimen (called TCHP),53 which resulted in approval by the FDA for this indication in 2017. However, it should be noted that the absolute benefit was small (HR 0.81; numerically similar to ALTTO but statistically significant), translated to a 1.6% absolute benefit in recurrence, and is without a known impact on overall survival; however, those analyses are premature. Many clinicians have interpreted the results as supportive of added pertuzumab in high-risk settings (i.e., hormone receptor–negative, node-positive disease). Therefore, pertuzumab may be incorporated into neoadjuvant or adjuvant high-risk settings and given for 1 year concurrent with trastuzumab. The benefit is far less clear in stage I/II disease. Many investigators who consider de-escalation trials are favoring trastuzumab plus pertuzumab regimens with minimizing chemotherapy; however, these regimens remain unproven.

The antibody-drug conjugate T-DM1 links the tubulin inhibitor emtansine to trastuzumab, which functionally creates a Trojan horse anti-HER2 that spares the toxicity of the free cytotoxic, which is delivered intracellularly to HER2-overexpressing cells. It can produce diarrhea and thrombocytopenia, among other adverse effects, but generally is well tolerated.

Metastatic Setting

In the EMILIA trial in pretreated patients with HER2-positive metastatic breast cancer, T-DM1 alone was compared with capecitabine plus lapatinib, the accepted second-line regimen at the time, and proved superior from an efficacy standpoint; results showed a nearly 6-month improvement in overall survival as well as better tolerability: 16% fewer patients suffered from severe adverse events.54 In the first-line setting, the MARIANNE trial found that T-DM1 and T-DM1 plus pertuzumab were no better than a taxane plus trastuzumab55; by inference, T-DM1 is inferior to the standard first-line metastatic regimen THP but remains a favored second-line regimen. T-DM1 is now standard second-line therapy in countries where it is affordable and available, and it is given alone.

(Neo)adjuvant Setting

In the neoadjuvant setting, the KRISTINE trial found an inferior pathologic complete response rate to T-DM1 plus pertuzumab compared with TCHP, which suggests that, in this setting also, T-DM1 is inferior to a free cytotoxic plus trastuzumab.56 No results with T-DM1 in the adjuvant setting are available yet, although several trials, such as KATHERINE (NCT01772472), KAITLIN (NCT01966471), and ATEMPT (NCT01853748), have been completed but not yet reported. As of now, there is no known role for T-DM1 in the early breast cancer setting.

Neratinib.

This is one of a class of irreversible HER1/HER2 small molecule inhibitors that has been in development for several years; in this case, the drug was developed over time by multiple drug companies. Although toxicity is an important issue—diarrhea predominates—central nervous system penetrance is one of the areas of interest for this class.

Metastatic setting.

In the NEFERT-T first-line trial, neratinib plus paclitaxel showed efficacy similar to that of trastuzumab plus paclitaxel,57 which suggests inferiority to the standard THP first-line regimen. Central nervous system progression appeared less frequent and occurred later in the neratinib arm of NEFERT-T; however, a Translational Breast Cancer Research Consortium (TBCRC) phase II trial of single-agent neratinib in progressive central nervous system metastases in HER2-positive disease found an only 8% response rate.58 The role of neratinib at this time in the metastatic setting is unclear; additional studies are needed.

(Neo)adjuvant setting.

In the ISPY2 adaptive randomization neoadjuvant series, neratinib was compared with trastuzumab combined with a taxane and then followed by AC, and there was a suggestion of superiority in the HER2-positive cohort, especially those patients whose disease was hormone receptor negative59; by ISPY2 design, this is suggestive but not definitive. More compelling evidence comes from the adjuvant ExteNET trial, in which women were randomly assigned to receive neratinib versus placebo after completion of the year of trastuzumab. This trial at 5 years revealed 27% fewer invasive disease-free survival events (absolute difference, 2.5%); however, without aggressive prophylaxis, approximately 40% of patients suffered grade 3 diarrhea.60 It should be noted that the adjuvant HERA trial of trastuzumab versus nothing61 examined 2 years versus 1 year of treatment without finding a difference in outcome.

In ExteNET, this benefit somewhat surprisingly appeared to be driven largely by the HR-positive and node-positive (especially ≥ four nodes) subsets. On the basis of these findings, the FDA neratinib for adjuvant use in 2017. Many clinicians are still struggling to interpret and apply these findings in clinical care; most consider neratinib in high-risk node-positive settings, especially if the cancer also is HR positive.

Future Directions

Despite these advances in the management of HR-positive and HER2-overexpressing tumors, relapse and thedevelopment of metastatic disease are still very real problems, and the final common pathway for patients with HR-positive and HER2- positive metastatic breast cancer is the development of resistance to targeted treatments and continued progression of disease. The resistance to endocrine therapy or anti-HER2 therapy can be either intrinsic (de novo) resistance, wherein the tumor never responds to endocrine/anti-HER2 therapy, or—more often—acquired resistance, in which the response wanes over time and the cancer eventually progresses.62

An endocrine-sensitive cell depends on the ER to internalize estrogen and transport it to the nucleus to allow for cellular proliferation. In the setting of endocrine resistance, other pathways are activated, which allows the cell to proliferate despite appropriate ER blockade (tamoxifen) or lack of estrogen (aromatase inhibitors). Several biologic mechanisms of resistance have been postulated, including ER pathway alterations (loss of ER expression, ESR1 mutation), cell cycle machinery (loss of Rb gene, p16 and p18 alteration), upregulation of alternate pathways (EGFR, HER2, PI3K, and mitogen-activated protein kinase overexpression), and changes in the apoptosis mechanisms and tumor microenvironment.63 Dual targeting may be important to prevent cancer cell proliferation in this setting.

CDK 4/6 inhibitors

The CDK inhibitor story is perhaps one of the most important targeted therapy stories of the past few years. Scientists discovered that Rb phosphorylation by CDK 4/6 promotes the G1-to-S phase transition and that this pathway may be upregulated in endocrine-resistant cells.64 If CDK 4/6 could be blocked and control over the cell cycle could be regained, perhaps cancer cells would remain sensitive to endocrine therapy. PALOMA-1 (NCT02614794), the first randomized trial of CDK 4/6 inhibition in breast cancer, was a phase II study to evaluate letrozole plus palbociclib, a CDK 4/6 inhibitor, versus letrozole alone as first-line therapy for metastatic ER-positive breast cancer.65Extraordinarily, the PFS was 20.2 months for the palbociclib arm, which resulted in the accelerated approval of palbociclib in this setting in February 2015. Subsequent phase III data (PALOMA-2)66 confirmed this doubling of PFS with the use of palbociclib in the frontline setting, and two additional CDK 4/6 inhibitors, ribociclib and abemaciclib, are now on the market. These three agents have extended countless lives when used with aromatase inhibitors as part of first-line therapy for metastatic disease,67 or with fulvestrant68,69 in second-line therapy. Several clinical trials are either ongoing (NCT02513394, NCT03155997) or planned (NCT03285412) to look at the use of CDK 4/6 inhibitors in stage II/III high-risk ER-positive breast cancer to see if incorporation of this class of drugs into adjuvant therapy reduces the risk of developing metastatic disease.

mTOR Inhibitors

Inhibitors of mTOR comprise another important chapter in the story of endocrine resistance. mTOR activates ER in a ligand-independent fashion, and hyperactivation of this pathway has been observed in endocrine-resistant breast cancer cells.70 Therefore, mTOR has become a rational target to enhance the efficacy of hormonal therapy. The BOLERO 2 trial showed that, in patients with ER-positive metastatic breast cancer resistant to letrozole or anastrozole who were given exemestane as the next line of therapy, the mTOR inhibitor everolimus, when given with exemestane, could extend PFS from 4.1 months to 10.6 months.71 Everolimus is used regularly now in the treatment of patients with metastatic breast cancer, and, like CDK 4/6 inhibitors, is being evaluated in clinical trials in the upfront setting (NCT01674140, NCT01805271). Several other studies (NCT 02732119, NCT02871791) looking at triplet combinations—endocrine therapy with CDK 4/6 inhibition and mTOR inhibition—as a way to improve outcomes for patients with stage IV disease.

Investigational Agents

A number of ongoing clinical trials are exploring the optimal combination and sequencing of the above-mentioned therapies in ER-positive metastatic disease and at other possible therapeutic targets. Entinostat is a small molecule of class I histone deacetylases that is thought to prevent the emergence of drug-tolerant clones and to sensitize cells to anticancer therapies.72 A phase II trial showed that entinostat added to exemestane prolonged PFS compared with exemestane alone (4.3 vs. 2.3 months) and, even more interestingly, extended overall survival even longer (26.9 months vs. 19.8 months).73 E2112 (NCT02115282) is a phase III randomized controlled trial, the results of which will likely dictate whether entinostat becomes part of the arsenal of therapies available for management of ER-positive metastatic disease.

Mutations in ESR1, which are found rarely in untreated ER-positive breast cancer, are present in 20% to 50% of those patients who experience progression during treatment with an aromatase inhibitor. These mutations have been shown to predict resistance to additional aromatase inhibitor–based therapy and to suggest better responsiveness to fulvestrant-containing regimens.74 As a result, a number of companies have developed an interest in designing more potent selective estrogen receptor downregulators that may have potential uses in this population. Bardia et al75 presented data from a phase I trial of the oral selective estrogen receptor downregulator RAD1901 at the 2017 ASCO Annual Meeting; the study demonstrated a 23% objective response rate among 40 heavily pretreated women with ER-positive, HER2-negative breast cancer.

Ongoing Research in HER2-Positive Breast Cancer

With so many excellent drugs at our disposal to treat HER2-positive disease, the future lies in improved tailoring of therapy. We now have multiple targeted agents for use in the metastatic setting, as described. Others include tucatinib, a potent and selective oral HER2 inhibitor that recently has been granted orphan drug designation for patients with HER2-positive brain metastases and that represents an exciting new option for this group of patients. The HER2CLIMB trial (NCT02614794) is actively enrolling.

Recent studies suggest that HER2-positive disease is highly heterogeneous; the disease incorporates all of the subtypes, especially the HER2-enriched and luminal subtypes. Studies of CDK 4/6 inhibition are ongoing in patients with ER+ and HER2+ breast cancers, which typically have lower pCR rates as a result of neoadjuvant HER2-based chemotherapy in the upfront setting; it is believed that crosstalk between HER2 and ER signaling may play a role in tumor resistance and that inhibition of CDK 4/6 may prevent progression of disease in this situation. MonarcHER (NCT02675231) has just closed to accrual, looking at CDK 4/6 inhibition in the third-line setting for metastatic disease, and PATINA (NCT02947685), which started recruiting more recently, brings palbociclib to the first-line metastatic setting.

Targeted therapy has been an area of much focus in all malignancies, and this time in our history has been referred to regularly as the era of precision medicine.76 As our understanding of genomics, driver pathways, and mutational evolution deepens, we will continue to move the field forward. Those in the field of breast cancer have already had to ask some of the questions that will shape the future of oncology therapeutics more broadly: Once we understand how to approach a target, how do we change or modify the approach when resistance develops? If we identify targeted treatments that work well in advanced-stage disease, can and should we move them forward into the upfront setting? Can we combine multiple targeted therapies, and at what cost—to the patient and to society? When is doing more too much, and when it is necessary? These are all questions that we will continue to ask ourselves, in the field of breast cancer and beyond, as we refine our definitions of and our approach to precision medicine.

Source: ascopubs.org

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