*3.1.2. Ribociclib*

survival compared with those who had no change in ER status (HR of relapse = 2.4, p = 0.03) [24]. Another study of paired sample analysis of primary cancer and liver metastases posttreatment showed ER status and HER2 status change in 30% and 10% of patients [25]. How these changes in receptor status affect management and outcome is not well understood.

Molecular changes in the target receptors after treatment causing treatment failure is a wellknown phenomenon in many malignancies. For HR-positive breast cancer, the target of interest is *ESR1*, which encodes for ERα. *ESR1* mutation has not been detected in sequencing analysis of 390 treatment-naïve primary breast cancer tissues in the Cancer Genome Atlas project [11]. In another study, tissue of patients with hormone-resistance breast cancer were sequenced, and showed 14 or 80 these cases showed *ESR1* mutations affecting the ligand-binding domain [26]. The mutations were the highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. p.Tyr537Ser and p.Asp538Gly play a role in hydrogen bonding of the mutant amino acid with Asp351 and favors the agonist conformation of the ER receptor. As a result the mutant ER becomes active in the absence of hormonal stimulation, and renders ER antagonists ineffective. The clinical significance of

Palbociclib is a first-in-class CDK4/6 inhibitor [27]. Based on the impressive PFS found in the phase 2 study PALOMA-1 [28], palbociclib was granted accelerated approval in 2015 by the Food and Drug Administration (FDA) for treatment of HR+ve/HER2−ve MBC in the first line

PALOMA-2, is a double-blind, placebo-controlled, randomized phase 3 study of palbociclib plus letrozole in women with HR+ve/HER2−ve MBC patients who had no prior treatment for advanced disease [29]. Patients were randomized to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was PFS. Secondary end points included OS, objective response rate (ORR), clinical benefit response (CBR) and safety. The study recruited 666 women within 17 months. The primary endpoint was met – the addition of palbociclib to letrozole, as compared with placebo-letrozole, increased the median PFS from 14.5 months (95% confidence interval [CI], 12.9–17.1) to 24.8 months (95% CI, 22.1 to not estimable) (hazard ratio [HR] 0.58, 95% CI, 0.46–0.72; p < 0.001). Subgroup analyses of PFS confirmed a consistent benefit across all subgroups evaluated including different race, prior disease-free survival, visceral involvement, prior

**2.4. Molecular changes secondary to the use of aromatase inhibitor**

*ESR1* mutation will be further discussed in Section 3.4.

**3. New clinical therapy and emerging treatment**

**3.1. CDK4/6 inhibitor is now a new standard treatment**

*3.1.1.1. Key results of phase 3 PALOMA studies*

*3.1.1. Palbociclib*

164 Breast Cancer and Surgery

setting.

Ribociclib is the second CDK 4/6 inhibitor received the U.S. FDA approval in March 2017. The first approval study was MONOLEESA-2 for first line setting. MONOLEESA-7, which is also a first line trial, had special interest in pre- and peri-menopausal women. The data also became available recently.

## *3.1.2.1. Key results of phase 3 MONOLEESA studies*

MONOLEESA-2 is a double-blind, placebo-controlled, phase 3 study of ribociclib plus letrozole [31]. It mirrors PALOMA-2 for the target patient population. Patients were randomized 1:1 to ribociclib-letrozole or placebo-letrozole. The study demonstrated that the addition of ribociclib to letrozole significantly improved PFS from 14.5 months to over 25 months giving a HR of 0.56 for disease progression or death (95% CI, 0.43–0.72; p < 0.001). The ORR was 40.7% in the ribociclib group and 27.5% in the placebo group in the intention-to-treat population. The CBR was 79.6% in the ribociclib group and 72.8% in the placebo group (p = 0.02) respectively in the intention-to-treat population. The most common grade 3 and 4 AEs were neutropenia (60%), elevated alanine aminotransferase (9%), elevated aspartate aminotransferase (6%), infection (4%) and vomiting (4%). Other common AEs were minor and mild.

The results of MONOLEESA-7 was first released in the San Antonio Breast Cancer Symposium (SABCS) 2017 [32]. Unlike other studies of CDK4/6 inhibitors, this study recruited pre- or perimenopausal HR+ve/HER2−ve MBC patients who had received no prior endocrine therapy for advanced disease, but allowed up to 1 line of chemotherapy. Patients were randomized to receive standard treatment of goserelin, plus either tamoxifen or AI, together with ribociclib or placebo. The median age of recruited patients were 44 years old, and 40% had *de novo* metastatic disease. For those who developed metastasis after primary resection, more than 50% had disease-free interval for more than 12 months. Median PFS turned out to be 13.0 months for the placebo group and 23.8 months for the ribociclib group (HR 0.553; 95% CI, 0.441–0.694; p < 0.001). About ¼ of the patients received tamoxifen, and there was no difference from those who received AI in term of PFS benefit gained with addition of ribociclib. Goserelin was an effective method for ovarian suppression for treatment of pre/peri-menopausal HR+ve/HER2−ve MBC, and tamoxifen was as good as AI partnering with ribociclib.

intention-to-treat population was 48.2% and 34.5% for abemaciclib and placebo arms respectively (p = 0.002). Diarrhea was reported in 81.3% but most was grade 1. The most common

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While most clinical trials of palbociclib and ribociclib focused on first or early line treatment for metastatic disease, abemaciclib is the only CDK4/6 inhibitor that has proven to have meaningful activity in refractory disease. MONARCH-1 is a phase II single-arm open-label study for HR+ve/HER2−ve MBC patients who had progressed on or after endocrine therapy, and had 1 or 2 chemotherapy regimens [35]. Abemaciclib was given at 200 mg BD continuously as monotherapy. The primary objective was ORR. Other endpoints included CBR, PFS, and OS. This study recruited 132 patients. Median line of treatment was 3. ORR was 19.7%, CBR was 42.4%, median PFS was 6.0 months, and median OS was 17.7 months. Major treatmentrelated AEs were diarrhea (all grade 90.2%, grade 3 & 4 19.7%), fatigue (all grade 65.2%, grade 3 12.9%), and nausea (all grade 64.4%, grade 3 4.5%). Neutropenia was reported in 87.5% of

At the age of precision medicine, we aim to understand the potential biomarker of response that can guide us on treatment. For palbociclib, investigated biomarkers include cyclin D1 amplification and p16 loss, ER expression, Rb level, and Ki67 index [28, 36], as well as hormone-receptor expression level, *PIK3CA* mutation status, and plasma circulating tumor DNA *ESR1* mutation status [37, 38]. No biomarker of response has been identified for palbociclib. As to ribociclib, ctDNA was collected for MONALEESA-2 study at baseline. Although patient with *PIK3CA* variants had shorted PFS compared with those with wild-type *PIK3CA*, they derived similar PFS benefit to the addition of ribociclib (Altered *PIK3CA* HR 0.53, wild-type *PIK3CA* HR 0.44) [31]. Similarly, altered *TP53* was a poor prognostic factor, yet both wild-type *TP53* and altered *TP53* had similar response to added benefit of ribociclib. There was a week trend toward limited PFS benefit with ribociclib was observed in patients with alteration in CDH1 and FGFR1/ZNF7–3. The incidence of these genetic events was found in only 5–11% of patients, thus the results still inconclusive. A better understanding in biology of endocrine resistance and obtaining study biopsy at the time of starting treatment or upon disease recur-

PALOMA-2 showed superior efficacy of adding palbociclib to letrozole in first line treatment of HR+ve/HER2−ve MBC with an unprecedented PFS of over 2 years. This benefit extended to all subgroups, including those with prior exposure to hormonal therapy or chemotherapy. This

The most concerning toxicity of palbociclib and ribociclib was neutropenia. It happened in 80–90% of patients of which grade 3 or 4 neutropenia was reported in 60%. Patients who developed neutropenic fever, grade 4 neutropenia, or prolonged neutropenia would require dose reduction. The significance of dose reduction is not clear. PALOMA-3 is a

grade 3 or 4 toxicity was neutropenia (21.1%) and diarrhea (9.5%).

rence or progression might provide valuable insight in this field.

study confirms the new standard of adding CDK4/6 inhibitor in this disease.

*3.1.5. Discussion for CDK4/6 inhibitor*

patients of which 26.9% were grade 3 or 4.

*3.1.4. Biomarker of response*

#### *3.1.3. Abemaciclib*

In September 2017, abemaciclib was approved by the U.S. FDA to be used in combination with fulvestrant for HR-positive MBC progressed following endocrine therapy. It was also approved as monotherapy for HR-positive MBC with disease progression following endocrine therapy and chemotherapy in the metastatic setting.

#### *3.1.3.1. Important clinical trials of abemaciclib*

MONARCH-2 is a randomized placebo-controlled trial to study the combination of abemaciclib with fulvestrant in patients with HR+ve/HER2−ve MBC who have progressed on or had less than 12 months from end of adjuvant endocrine therapy [33]. Patient received abemaciclib daily without resting period. The original study dose was 200 mg BD, but the protocol amended to reduce the dose to 150 mg BD as there were many clinically significant diarrheas. Abemaciclib plus fulvestrant significantly prolonged median PFS versus fulvestrant alone (16.4 versus 9.3 months; HR 0.553; 95% CI, 0.449–0.681; p < 0.001). In the intention-to-treat population, abemaciclib plus fulvestrant achieved an ORR of 35.2% compared with 16.1% in the control arm (p < 0.001), and it included 14 patients with complete response (3.1%). The treatment gave durable response with 12-month duration of response rate of 67.8 and 66.9% in the abemaciclib and the placebo arm respectively. After 12 cycles of treatment, the mean change in tumor size for the abemaciclib arm and placebo arm were − 62.5% and − 32.8% respectively. The most common adverse events in the abemaciclib arm were diarrhea (all grade 86.4%, grade 3 & 4 13.4%), neutropenia (all grade 46.0%, grade 3 & 4 26.5%), nausea (all grade 45.1%, grade 3 2.7%), and fatigue (all grade 39.9%, grade 3 2.7%).

The results of MONARCH-3 came after MONARCH-2. MONARCH-3 is a double-blind randomized phase 3 study of abemaciclib or placebo plus a non-steroid AI in HR+ve/HER2−ve MBC patients who had no prior systemic therapy in the advanced setting [34]. Patients were randomized to receive either abemaciclib 150 mg BD continuously or placebo with anastrozole 1 mg or letrozole 2.5 mg daily. Median PFS was significantly longer in the abemaciclib arm compared with placebo arm (HR 0.54; 95% CI, 0.41–0.72; p < 0.001). The ORR in the intention-to-treat population was 48.2% and 34.5% for abemaciclib and placebo arms respectively (p = 0.002). Diarrhea was reported in 81.3% but most was grade 1. The most common grade 3 or 4 toxicity was neutropenia (21.1%) and diarrhea (9.5%).

While most clinical trials of palbociclib and ribociclib focused on first or early line treatment for metastatic disease, abemaciclib is the only CDK4/6 inhibitor that has proven to have meaningful activity in refractory disease. MONARCH-1 is a phase II single-arm open-label study for HR+ve/HER2−ve MBC patients who had progressed on or after endocrine therapy, and had 1 or 2 chemotherapy regimens [35]. Abemaciclib was given at 200 mg BD continuously as monotherapy. The primary objective was ORR. Other endpoints included CBR, PFS, and OS. This study recruited 132 patients. Median line of treatment was 3. ORR was 19.7%, CBR was 42.4%, median PFS was 6.0 months, and median OS was 17.7 months. Major treatmentrelated AEs were diarrhea (all grade 90.2%, grade 3 & 4 19.7%), fatigue (all grade 65.2%, grade 3 12.9%), and nausea (all grade 64.4%, grade 3 4.5%). Neutropenia was reported in 87.5% of patients of which 26.9% were grade 3 or 4.

#### *3.1.4. Biomarker of response*

The results of MONOLEESA-7 was first released in the San Antonio Breast Cancer Symposium (SABCS) 2017 [32]. Unlike other studies of CDK4/6 inhibitors, this study recruited pre- or perimenopausal HR+ve/HER2−ve MBC patients who had received no prior endocrine therapy for advanced disease, but allowed up to 1 line of chemotherapy. Patients were randomized to receive standard treatment of goserelin, plus either tamoxifen or AI, together with ribociclib or placebo. The median age of recruited patients were 44 years old, and 40% had *de novo* metastatic disease. For those who developed metastasis after primary resection, more than 50% had disease-free interval for more than 12 months. Median PFS turned out to be 13.0 months for the placebo group and 23.8 months for the ribociclib group (HR 0.553; 95% CI, 0.441–0.694; p < 0.001). About ¼ of the patients received tamoxifen, and there was no difference from those who received AI in term of PFS benefit gained with addition of ribociclib. Goserelin was an effective method for ovarian suppression for treatment of pre/peri-menopausal HR+ve/HER2−ve

In September 2017, abemaciclib was approved by the U.S. FDA to be used in combination with fulvestrant for HR-positive MBC progressed following endocrine therapy. It was also approved as monotherapy for HR-positive MBC with disease progression following endo-

MONARCH-2 is a randomized placebo-controlled trial to study the combination of abemaciclib with fulvestrant in patients with HR+ve/HER2−ve MBC who have progressed on or had less than 12 months from end of adjuvant endocrine therapy [33]. Patient received abemaciclib daily without resting period. The original study dose was 200 mg BD, but the protocol amended to reduce the dose to 150 mg BD as there were many clinically significant diarrheas. Abemaciclib plus fulvestrant significantly prolonged median PFS versus fulvestrant alone (16.4 versus 9.3 months; HR 0.553; 95% CI, 0.449–0.681; p < 0.001). In the intention-to-treat population, abemaciclib plus fulvestrant achieved an ORR of 35.2% compared with 16.1% in the control arm (p < 0.001), and it included 14 patients with complete response (3.1%). The treatment gave durable response with 12-month duration of response rate of 67.8 and 66.9% in the abemaciclib and the placebo arm respectively. After 12 cycles of treatment, the mean change in tumor size for the abemaciclib arm and placebo arm were − 62.5% and − 32.8% respectively. The most common adverse events in the abemaciclib arm were diarrhea (all grade 86.4%, grade 3 & 4 13.4%), neutropenia (all grade 46.0%, grade 3 & 4 26.5%), nausea (all

The results of MONARCH-3 came after MONARCH-2. MONARCH-3 is a double-blind randomized phase 3 study of abemaciclib or placebo plus a non-steroid AI in HR+ve/HER2−ve MBC patients who had no prior systemic therapy in the advanced setting [34]. Patients were randomized to receive either abemaciclib 150 mg BD continuously or placebo with anastrozole 1 mg or letrozole 2.5 mg daily. Median PFS was significantly longer in the abemaciclib arm compared with placebo arm (HR 0.54; 95% CI, 0.41–0.72; p < 0.001). The ORR in the

MBC, and tamoxifen was as good as AI partnering with ribociclib.

grade 45.1%, grade 3 2.7%), and fatigue (all grade 39.9%, grade 3 2.7%).

crine therapy and chemotherapy in the metastatic setting.

*3.1.3.1. Important clinical trials of abemaciclib*

*3.1.3. Abemaciclib*

166 Breast Cancer and Surgery

At the age of precision medicine, we aim to understand the potential biomarker of response that can guide us on treatment. For palbociclib, investigated biomarkers include cyclin D1 amplification and p16 loss, ER expression, Rb level, and Ki67 index [28, 36], as well as hormone-receptor expression level, *PIK3CA* mutation status, and plasma circulating tumor DNA *ESR1* mutation status [37, 38]. No biomarker of response has been identified for palbociclib.

As to ribociclib, ctDNA was collected for MONALEESA-2 study at baseline. Although patient with *PIK3CA* variants had shorted PFS compared with those with wild-type *PIK3CA*, they derived similar PFS benefit to the addition of ribociclib (Altered *PIK3CA* HR 0.53, wild-type *PIK3CA* HR 0.44) [31]. Similarly, altered *TP53* was a poor prognostic factor, yet both wild-type *TP53* and altered *TP53* had similar response to added benefit of ribociclib. There was a week trend toward limited PFS benefit with ribociclib was observed in patients with alteration in CDH1 and FGFR1/ZNF7–3. The incidence of these genetic events was found in only 5–11% of patients, thus the results still inconclusive. A better understanding in biology of endocrine resistance and obtaining study biopsy at the time of starting treatment or upon disease recurrence or progression might provide valuable insight in this field.

#### *3.1.5. Discussion for CDK4/6 inhibitor*

PALOMA-2 showed superior efficacy of adding palbociclib to letrozole in first line treatment of HR+ve/HER2−ve MBC with an unprecedented PFS of over 2 years. This benefit extended to all subgroups, including those with prior exposure to hormonal therapy or chemotherapy. This study confirms the new standard of adding CDK4/6 inhibitor in this disease.

The most concerning toxicity of palbociclib and ribociclib was neutropenia. It happened in 80–90% of patients of which grade 3 or 4 neutropenia was reported in 60%. Patients who developed neutropenic fever, grade 4 neutropenia, or prolonged neutropenia would require dose reduction. The significance of dose reduction is not clear. PALOMA-3 is a study of palbociclib in combination with fulvestrant in patients who progressed on first line hormonal therapy [30]. Detailed analysis showed that dose modification of palbociclib for grade 3 and 4 neutropenia had no adverse effect on PFS [39]. Together with improved quality of life (QoL), and low incidence of neutropenic fever of less than 2%, palbociclib and ribociclib are drugs very well tolerated.

palbociclib to standard endocrine therapy in patients with high risk of relapse after neoadjuvant chemotherapy [NCT01864746]. MonarchE [NCT03155997] is also recruiting. It studied the effect of adding 2 years of abemaciclib to standard adjuvant endocrine therapy in high-

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CDK4/6 inhibitors revolutionized how HR+ve/HER2−ve MBC should be treated. There is an unmet need for biomarker of response to guide management decision. Further studies on the benefit of continuing CDK 4/6 inhibitors beyond progression or the optimal time to add these

mTOR is a downstream effector of the PI3K/AKT pathway. Targeting mTOR is a rational strategy to reverse endocrine resistance. TAMRAD is a phase 2 study that explored the combination of oral mTOR inhibitor everolimus with tamoxifen versus tamoxifen in patients with HR+ve/ HER2−ve MBC who have progressed on AI [46]. The dosage of everolimus was 10 mg daily. This primary end point was CBR. Everolimus significantly improved the CBR from 42–61%. Time to progression increased from 4.5 months with tamoxifen alone to 8.6 months with addition of everolimus (HR 0.54; 95% CI, 0.36–0.81). Significant adverse reaction included fatigue (72%), stomatitis (56%), rash (44%), anorexia (43%), and diarrhea (39%). Second line AI is a common strategy upon progression on first line AI. BOLERO-2 is a phase 3 trial which randomized patients who have receive exemestane plus everolimus or everolimus alone [47]. Patients had recurrence or progression while on previous endocrine therapy with a nonsteroidal AI in the adjuvant setting or to treat advance disease. The primary end point was PFS. The study stopped early after the interim analysis, as median PFS was 6.9 months with everolimus plus exemestane, versus 2.8 months with exemestane alone (HR 0.43; 95% CI, 0.35–0.54; p < 0.001) based on assessments by local investigators. These patients were heavily pretreated – besides nonsteroidal AI, 57% had received an antiestrogen, 26% had chemotherapy in the advance setting, and 54% had 3 or more lines of therapies. Stomatitis was the most frequent and debilitating adverse events (all grades 56%, grade 3 8%), followed by rash (add grades 36%, grade 3 1%), fatigue (all grades 33%, grade 3 3%), and diarrhea (all grades 30%, grade 3 2%). As everolimus is an immunosuppressant, the incidence of infection cannot be under-estimated and there were 2 cases of deaths from sepsis. Other class-specific severe toxicities included anemia (grade 3 5%), hyperglycemia (grade 3 4%), pneumonitis (grade 3 3%), and elevated AST (grade 3 3%) and elevated ALT (grade 3 3%). The study was not powered to detect a difference in OS, and the analysis of OS was negative [48]. Subsequent molecular analysis of archival tissue showed that the mutational status of *PIK3A*, amplification of *FGFR1*, or P3K/AKT/ mTOR pathway alteration did not affect treatment response to everolimus [49]. This analysis reviewed some potential quantitative differences in the efficacy of everolimus among tumors of specific *PIK3CA* exons, *FGFR2*, *mTOR*, and chromosomal instabilities. These remains to be further investigated. BOLERO-2 also included analysis of plasma cell-free DNA (cfDNA) for 2 *ESR1* mutations [50]. *ESR1* D538G mutation was detected in 21% and *ESR1* Y537S mutation was found in 13%. Interestingly, patients with D538G mutation had PFS benefit with addition

of everolimus (HR 0.34; 95 CI, 0.02–0.57), while those carrying Y537S mutation did not.

risk node-positive early stage patients post-resection.

**3.2. Traditional mTOR inhibitor remains a standard treatment**

targeted agents would also be needed.

While PALOMA-1, PALOMA-2, and MONALEESA-2 provided the evidence to the use of CDK4/6 inhibitor in the first line setting, all these trials were done in post-menopausal women. In fact the last randomized trial dedicated to premenopausal women with MBS was published almost 2 decades ago. It is estimated that around 1/5 of newly diagnosed breast cancer in the U.S. was found in women younger than 50 years old [40]. In Asia-Pacific region, 40% of breast cancer patients were of age less than 50 years [41]. Breast cancer in young patients is believe to be more aggressive and has distinct tumor biology. MONALEESA-7 is the first of the series to explore the activity of CDK 4/6 inhibitor in these patients. It extended the use of CDK4/6 inhibitor in pre/peri-menopausal women in combination with GHRH agonist as the mean of ovarian suppression. It also proved that tamoxifen was an as effective hormonal partner as AI with CDK4/6 inhibitor.

The hazard ratios for all first line trials of CDK4/6 inhibitor were similar, ranging between 0.49 and 0.58. It appeared that these drugs had comparable efficacy. The choice of drug would probably depend on their toxicity profile, dosing regimen, or dosage form. The 3 CDK4/6 inhibitors were not made equal. Palbociclib and ribociclib are structurally similar, basing off a pyrido [2,3-d]pyrimidin-7-one scaffold that was optimized for selectivity toward CDK4/6 [42, 43]. Abemaciclib, on the other hand, derived from a 2-anilino-2,4-pyrimidine-[5-benzimidazole] scaffold. This compound not only has potent activity against CDK4 and 6, it also inhibits multiple kinases *in vitro* a concentration less than 100 nM [44]. Neutropenia is the most common side effect of palbociclib and ribociclib. It appeared that anemia, thrombocytopenia and possibly stomatitis were more common in patients given palbociclib. For ribociclib, results from MONOSEESA-2 showed grade 3 or 4 elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in up to 9% of the patients. Prolonged QTcF was also a concern for a small proportion of patients in the study. Although palbociclib and ribociclib have comparable spectrum of CDK activity [45], the small disparities in their chemical structure might explain the differences in their toxicities. Abemaciclib, being structurally distinct from the other 2 CDK4/6 inhibitors, has diarrhea being the most reported adverse event. Grade 3 and 4 neutropenia was at around 21–25%, half of that reported in the PALOMA or MONALEESA trials. Due to the lower incidence of bone marrow toxicity, this drug is taken twice per day continuously without the need for a resting week. It is also the only CDK4/6 inhibitor with an indication in heavily pretreated patients as a monotherapy.

Although HR+ve/HER2−ve breast cancer is regarded as a less aggressive form of breast cancer, a significant proportion of patients after curative resection ultimately relapse. The impressive response in metastatic setting and decent QoL data of palbociclib suggest that this drug might have a role as adjuvant therapy and help prevent recurrence. A number of adjuvant trials are ongoing. For instance, PALLAS evaluates the outcome of adding 2 years of palbociclib to standard endocrine therapy [NCT02513394]. PENELOPE-B studies the role of adding palbociclib to standard endocrine therapy in patients with high risk of relapse after neoadjuvant chemotherapy [NCT01864746]. MonarchE [NCT03155997] is also recruiting. It studied the effect of adding 2 years of abemaciclib to standard adjuvant endocrine therapy in highrisk node-positive early stage patients post-resection.

CDK4/6 inhibitors revolutionized how HR+ve/HER2−ve MBC should be treated. There is an unmet need for biomarker of response to guide management decision. Further studies on the benefit of continuing CDK 4/6 inhibitors beyond progression or the optimal time to add these targeted agents would also be needed.

#### **3.2. Traditional mTOR inhibitor remains a standard treatment**

study of palbociclib in combination with fulvestrant in patients who progressed on first line hormonal therapy [30]. Detailed analysis showed that dose modification of palbociclib for grade 3 and 4 neutropenia had no adverse effect on PFS [39]. Together with improved quality of life (QoL), and low incidence of neutropenic fever of less than 2%, palbociclib and

While PALOMA-1, PALOMA-2, and MONALEESA-2 provided the evidence to the use of CDK4/6 inhibitor in the first line setting, all these trials were done in post-menopausal women. In fact the last randomized trial dedicated to premenopausal women with MBS was published almost 2 decades ago. It is estimated that around 1/5 of newly diagnosed breast cancer in the U.S. was found in women younger than 50 years old [40]. In Asia-Pacific region, 40% of breast cancer patients were of age less than 50 years [41]. Breast cancer in young patients is believe to be more aggressive and has distinct tumor biology. MONALEESA-7 is the first of the series to explore the activity of CDK 4/6 inhibitor in these patients. It extended the use of CDK4/6 inhibitor in pre/peri-menopausal women in combination with GHRH agonist as the mean of ovarian suppression. It also proved that tamoxifen was an as effective hormonal

The hazard ratios for all first line trials of CDK4/6 inhibitor were similar, ranging between 0.49 and 0.58. It appeared that these drugs had comparable efficacy. The choice of drug would probably depend on their toxicity profile, dosing regimen, or dosage form. The 3 CDK4/6 inhibitors were not made equal. Palbociclib and ribociclib are structurally similar, basing off a pyrido [2,3-d]pyrimidin-7-one scaffold that was optimized for selectivity toward CDK4/6 [42, 43]. Abemaciclib, on the other hand, derived from a 2-anilino-2,4-pyrimidine-[5-benzimidazole] scaffold. This compound not only has potent activity against CDK4 and 6, it also inhibits multiple kinases *in vitro* a concentration less than 100 nM [44]. Neutropenia is the most common side effect of palbociclib and ribociclib. It appeared that anemia, thrombocytopenia and possibly stomatitis were more common in patients given palbociclib. For ribociclib, results from MONOSEESA-2 showed grade 3 or 4 elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in up to 9% of the patients. Prolonged QTcF was also a concern for a small proportion of patients in the study. Although palbociclib and ribociclib have comparable spectrum of CDK activity [45], the small disparities in their chemical structure might explain the differences in their toxicities. Abemaciclib, being structurally distinct from the other 2 CDK4/6 inhibitors, has diarrhea being the most reported adverse event. Grade 3 and 4 neutropenia was at around 21–25%, half of that reported in the PALOMA or MONALEESA trials. Due to the lower incidence of bone marrow toxicity, this drug is taken twice per day continuously without the need for a resting week. It is also the only CDK4/6

inhibitor with an indication in heavily pretreated patients as a monotherapy.

Although HR+ve/HER2−ve breast cancer is regarded as a less aggressive form of breast cancer, a significant proportion of patients after curative resection ultimately relapse. The impressive response in metastatic setting and decent QoL data of palbociclib suggest that this drug might have a role as adjuvant therapy and help prevent recurrence. A number of adjuvant trials are ongoing. For instance, PALLAS evaluates the outcome of adding 2 years of palbociclib to standard endocrine therapy [NCT02513394]. PENELOPE-B studies the role of adding

ribociclib are drugs very well tolerated.

168 Breast Cancer and Surgery

partner as AI with CDK4/6 inhibitor.

mTOR is a downstream effector of the PI3K/AKT pathway. Targeting mTOR is a rational strategy to reverse endocrine resistance. TAMRAD is a phase 2 study that explored the combination of oral mTOR inhibitor everolimus with tamoxifen versus tamoxifen in patients with HR+ve/ HER2−ve MBC who have progressed on AI [46]. The dosage of everolimus was 10 mg daily. This primary end point was CBR. Everolimus significantly improved the CBR from 42–61%. Time to progression increased from 4.5 months with tamoxifen alone to 8.6 months with addition of everolimus (HR 0.54; 95% CI, 0.36–0.81). Significant adverse reaction included fatigue (72%), stomatitis (56%), rash (44%), anorexia (43%), and diarrhea (39%). Second line AI is a common strategy upon progression on first line AI. BOLERO-2 is a phase 3 trial which randomized patients who have receive exemestane plus everolimus or everolimus alone [47]. Patients had recurrence or progression while on previous endocrine therapy with a nonsteroidal AI in the adjuvant setting or to treat advance disease. The primary end point was PFS. The study stopped early after the interim analysis, as median PFS was 6.9 months with everolimus plus exemestane, versus 2.8 months with exemestane alone (HR 0.43; 95% CI, 0.35–0.54; p < 0.001) based on assessments by local investigators. These patients were heavily pretreated – besides nonsteroidal AI, 57% had received an antiestrogen, 26% had chemotherapy in the advance setting, and 54% had 3 or more lines of therapies. Stomatitis was the most frequent and debilitating adverse events (all grades 56%, grade 3 8%), followed by rash (add grades 36%, grade 3 1%), fatigue (all grades 33%, grade 3 3%), and diarrhea (all grades 30%, grade 3 2%). As everolimus is an immunosuppressant, the incidence of infection cannot be under-estimated and there were 2 cases of deaths from sepsis. Other class-specific severe toxicities included anemia (grade 3 5%), hyperglycemia (grade 3 4%), pneumonitis (grade 3 3%), and elevated AST (grade 3 3%) and elevated ALT (grade 3 3%). The study was not powered to detect a difference in OS, and the analysis of OS was negative [48]. Subsequent molecular analysis of archival tissue showed that the mutational status of *PIK3A*, amplification of *FGFR1*, or P3K/AKT/ mTOR pathway alteration did not affect treatment response to everolimus [49]. This analysis reviewed some potential quantitative differences in the efficacy of everolimus among tumors of specific *PIK3CA* exons, *FGFR2*, *mTOR*, and chromosomal instabilities. These remains to be further investigated. BOLERO-2 also included analysis of plasma cell-free DNA (cfDNA) for 2 *ESR1* mutations [50]. *ESR1* D538G mutation was detected in 21% and *ESR1* Y537S mutation was found in 13%. Interestingly, patients with D538G mutation had PFS benefit with addition of everolimus (HR 0.34; 95 CI, 0.02–0.57), while those carrying Y537S mutation did not.

Everolimus is an inhibitor of mTORC1. It is postulated that mTORC1 inhibition by everolimus set off negative feedback mechanism via AKT signaling, and leads to treatment resistance. Vistusertib is a small molecule ATP competitive dual inhibitor of mTORC1 and mTORC2. Preclinical model demonstrated that vistusertib had superior activity to everolimus in suppressing tumor growth [51]. MANTA is a randomized phase 2 study of fulvestrant in combination with vistusertib or everolimus or fulvestrant alone in HR-positive HER2-negative MBC patients who have disease resistance to AI [52]. No more than 1 line prior chemotherapy was allowed in advanced setting. Primary end point was PFS. At median follow up of 17 months, it showed that addition of vistusertib did not add PFS benefit compared with fulvestrant alone (7.6 versus 5.4 months; HR 0.88; 95% CI, 0.63–1.24, p = 0.46). In fact, the fulvestrant-everolimus arm had superior PFS compared with the fulvestrant-vistusertib arm (12.3 versus 7.6 months; HR 0.63; 95% CI, 0.45–0.9, p = 0.01). Stomatitis and rash were the most common adverse effects of this dual mTOR inhibitor, and the frequency was comparable to that of everolimus. In summary, dual inhibition of mTOR did not derive superior effect. Everolimus remains the only mTOR inhibitor approved by the U.S. FDA for HR+ve/HER2−ve MBC.

buparlisib in combination with fulvestrant can reverse resistance mTOR inhibitor (Novartis data), BELLE-3 studied the combination of fulvestrant with or without buparlisib in HR+ve/ HER2−ve MBC patients who have progressed on or after mTOR inhibition [56]. It demonstrated that addition of buparlisib to fulvestrant prolonged the median PFS 1.8 months to 3.9 months (HR 0.67; 95% CI, 0.53–0.84, one-sided p < 0001). Circulating tumor DNA (ctDNA) analysis of *PIK3CA* status was available. Of the 432 subjects, 34% carried PIK3CA mutation. Among these patients, the median PFS was 4.7 months for those in the buparlisib arm versus 1.6 months for those in the placebo arm, thus those who received the PI3K inhibitor were 50% less likely to have disease progression. Despite these encouraging findings, grade 3 or 4 adverse events related to buparlisib were alarming – they included elevated ALT (22%), elevated AST (18%), and hyperglycemia (12%). Other toxicities potentially related to the drug such as depression, anxiety, and rash were also concerning. The company decided not to pursue further develop-

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On the other hand, the company has turned its focus to a α-specific PI3K inhibitor alpelisib. Early phase study showed preliminary preferential antitumor activity in *PIK3CA*-altered tumor treated with alpelisib [57]. A presentation of the preliminary results for the combination of alpelisib and fulvestrant demonstrated encouraging early efficacy [58]. The study recruited 87 patients with HR+ve/HER2−ve MBC. Alpelisib was given at 300 mg on a continuous daily schedule. In the PIK3A-altered population, the CBR was 45%. Median PFS was 9 and 5 months in the *PIK3CA*-altered groups and *PIK3CA* wild-type group respectively. This drug appeared to be better tolerated than pan-PI3K inhibitors. At the moment, the phase III SOLAR-1 trial [NCT02437318] studying the same combination in patients who have progressed on or have

Fulvestrant is the only clinically available SERD. It targets the ER for proteasomal degradation and halts the action of estrogen. It is capable of binding to the ligand-binding domain of ERα, converting it to a form incapable with transcriptional activity [59, 60]. Fulvestrant is given by intramuscular injection on day 1, 15, 29, then every 28 days. The initial studied and market dose was 250 mg. At first line setting, as in the FACT study (SWOG S0226 trial), fulvestrant at 250 mg did not demonstrate survival advantage over AI [61]. As second line treatment, fulvestrant at 250 mg showed similar time to progression (TTP) to anastrozole. Yet the later CONFIRM study demonstrated that doubling the dose to 500 mg gave a superior PFS and OS compared with 250 mg [5, 62]. FALCON is a phase 3 study which further brings fulvestrant at 500 mg to first line setting in comparison with anastrozole. The PFS was 16.6 and 13.8 months

failed AI is ongoing. First PFS analysis is expected to be available later the year.

for the fulvestrant and anastrozole groups respectively with a p value of 0.0486 [6].

Given the special property of SERD on receptor degradation and conformation, it would be interesting to explore if patients with *ESR1* mutation respond differently from those with *ESR1* wild type. SoFEA is a study comparing exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI. Prospective-retrospective analysis of plasma ctDNA from SoFEA found *ESR1* mutation in 39% of patients, of which half were polyclonal [63]. Those with *ESR1* mutation had better PFS after giving fulvestrant compared

ment of the drug due to its safety profile.

**3.4. SERDS and its new role**

### **3.3. PI3K inhibitors as an emerging treatment**

Intracellular signaling pathways have complex interaction. Targeted inhibition of a particular component in the pathway might cause relief of upstream feedback inhibition. Inhibition of the effector mTOR in the PI3K/AKT/mTOR pathway, could result in adaptive hyperactivation of the upstream AKT activity and leads to treatment failure [53]. As *PIK3CA* mutation is the most common genetic changes in breast cancer and represents a more proximal target, targeting *PIK3CA* might exert upstream halt of growth signaling. A number of PI3K inhibitors have been developed. Pictilisib is an orally active pan-inhibitor of class 1 PIK3K. FERGI is a randomized phase 2 study which recruited HR+ve/HER2−ve MBC patients who have progressed on or after AI [54]. Patients were given either fulvestrant or fulvestrant with pictilisib. The primary end point was PFS. There was no difference between 2 groups, both in the intention-to-treat population or patients with *PIK3CA* mutation. Pictilisib-associated serious adverse events in the original study dose of 340 mg per day were reported in 16%, whereas those leading to discontinuation were rash, pneumonitis, diarrhea, abdominal pain, stomatitis or elevated AST or ALT. Close to half the patients required dose modification. Toxicities greatly limited drug exposure of the patients. Although in the second part of the study dosage has been reduced and toxicity profile improved, the drug was not further developed due to its lack of PFS benefit.

Another extensively studied PI3K inhibitor is buparlisib. It is also a pan-class I PI3K inhibitor. It showed encouraging results in early clinical studies and it was ultimately brought to a number of phase 3 trials. BELLL-2 combined fulvestrant with buparlisib or placebo in HR+ve/HER2−ve MBC patients who have progressed on or after AI, and had received up to 1 line of chemotherapy in the advanced setting [55]. The median PFS was 6.9 months in the buparlisib group versus 5.0 months in the placebo group (HR 0.78; 95% CI, 0.67–0.l89; one sided p < 0.001). In patients with PI3K pathway-activation, median PFS was 6.8 months in the buparlisib group versus 4.0 months in the placebo group (HR 0.76; one sided PFS p −0.014). The most common grade 3 or 4 toxicities in the buparlisib group was increased ALT (25%), increased AST (18%), hyperglycemia (15%), and rash (8%). As preclinical data showed that buparlisib in combination with fulvestrant can reverse resistance mTOR inhibitor (Novartis data), BELLE-3 studied the combination of fulvestrant with or without buparlisib in HR+ve/ HER2−ve MBC patients who have progressed on or after mTOR inhibition [56]. It demonstrated that addition of buparlisib to fulvestrant prolonged the median PFS 1.8 months to 3.9 months (HR 0.67; 95% CI, 0.53–0.84, one-sided p < 0001). Circulating tumor DNA (ctDNA) analysis of *PIK3CA* status was available. Of the 432 subjects, 34% carried PIK3CA mutation. Among these patients, the median PFS was 4.7 months for those in the buparlisib arm versus 1.6 months for those in the placebo arm, thus those who received the PI3K inhibitor were 50% less likely to have disease progression. Despite these encouraging findings, grade 3 or 4 adverse events related to buparlisib were alarming – they included elevated ALT (22%), elevated AST (18%), and hyperglycemia (12%). Other toxicities potentially related to the drug such as depression, anxiety, and rash were also concerning. The company decided not to pursue further development of the drug due to its safety profile.

On the other hand, the company has turned its focus to a α-specific PI3K inhibitor alpelisib. Early phase study showed preliminary preferential antitumor activity in *PIK3CA*-altered tumor treated with alpelisib [57]. A presentation of the preliminary results for the combination of alpelisib and fulvestrant demonstrated encouraging early efficacy [58]. The study recruited 87 patients with HR+ve/HER2−ve MBC. Alpelisib was given at 300 mg on a continuous daily schedule. In the PIK3A-altered population, the CBR was 45%. Median PFS was 9 and 5 months in the *PIK3CA*-altered groups and *PIK3CA* wild-type group respectively. This drug appeared to be better tolerated than pan-PI3K inhibitors. At the moment, the phase III SOLAR-1 trial [NCT02437318] studying the same combination in patients who have progressed on or have failed AI is ongoing. First PFS analysis is expected to be available later the year.

#### **3.4. SERDS and its new role**

Everolimus is an inhibitor of mTORC1. It is postulated that mTORC1 inhibition by everolimus set off negative feedback mechanism via AKT signaling, and leads to treatment resistance. Vistusertib is a small molecule ATP competitive dual inhibitor of mTORC1 and mTORC2. Preclinical model demonstrated that vistusertib had superior activity to everolimus in suppressing tumor growth [51]. MANTA is a randomized phase 2 study of fulvestrant in combination with vistusertib or everolimus or fulvestrant alone in HR-positive HER2-negative MBC patients who have disease resistance to AI [52]. No more than 1 line prior chemotherapy was allowed in advanced setting. Primary end point was PFS. At median follow up of 17 months, it showed that addition of vistusertib did not add PFS benefit compared with fulvestrant alone (7.6 versus 5.4 months; HR 0.88; 95% CI, 0.63–1.24, p = 0.46). In fact, the fulvestrant-everolimus arm had superior PFS compared with the fulvestrant-vistusertib arm (12.3 versus 7.6 months; HR 0.63; 95% CI, 0.45–0.9, p = 0.01). Stomatitis and rash were the most common adverse effects of this dual mTOR inhibitor, and the frequency was comparable to that of everolimus. In summary, dual inhibition of mTOR did not derive superior effect. Everolimus remains the only

Intracellular signaling pathways have complex interaction. Targeted inhibition of a particular component in the pathway might cause relief of upstream feedback inhibition. Inhibition of the effector mTOR in the PI3K/AKT/mTOR pathway, could result in adaptive hyperactivation of the upstream AKT activity and leads to treatment failure [53]. As *PIK3CA* mutation is the most common genetic changes in breast cancer and represents a more proximal target, targeting *PIK3CA* might exert upstream halt of growth signaling. A number of PI3K inhibitors have been developed. Pictilisib is an orally active pan-inhibitor of class 1 PIK3K. FERGI is a randomized phase 2 study which recruited HR+ve/HER2−ve MBC patients who have progressed on or after AI [54]. Patients were given either fulvestrant or fulvestrant with pictilisib. The primary end point was PFS. There was no difference between 2 groups, both in the intention-to-treat population or patients with *PIK3CA* mutation. Pictilisib-associated serious adverse events in the original study dose of 340 mg per day were reported in 16%, whereas those leading to discontinuation were rash, pneumonitis, diarrhea, abdominal pain, stomatitis or elevated AST or ALT. Close to half the patients required dose modification. Toxicities greatly limited drug exposure of the patients. Although in the second part of the study dosage has been reduced and toxicity profile

mTOR inhibitor approved by the U.S. FDA for HR+ve/HER2−ve MBC.

improved, the drug was not further developed due to its lack of PFS benefit.

Another extensively studied PI3K inhibitor is buparlisib. It is also a pan-class I PI3K inhibitor. It showed encouraging results in early clinical studies and it was ultimately brought to a number of phase 3 trials. BELLL-2 combined fulvestrant with buparlisib or placebo in HR+ve/HER2−ve MBC patients who have progressed on or after AI, and had received up to 1 line of chemotherapy in the advanced setting [55]. The median PFS was 6.9 months in the buparlisib group versus 5.0 months in the placebo group (HR 0.78; 95% CI, 0.67–0.l89; one sided p < 0.001). In patients with PI3K pathway-activation, median PFS was 6.8 months in the buparlisib group versus 4.0 months in the placebo group (HR 0.76; one sided PFS p −0.014). The most common grade 3 or 4 toxicities in the buparlisib group was increased ALT (25%), increased AST (18%), hyperglycemia (15%), and rash (8%). As preclinical data showed that

**3.3. PI3K inhibitors as an emerging treatment**

170 Breast Cancer and Surgery

Fulvestrant is the only clinically available SERD. It targets the ER for proteasomal degradation and halts the action of estrogen. It is capable of binding to the ligand-binding domain of ERα, converting it to a form incapable with transcriptional activity [59, 60]. Fulvestrant is given by intramuscular injection on day 1, 15, 29, then every 28 days. The initial studied and market dose was 250 mg. At first line setting, as in the FACT study (SWOG S0226 trial), fulvestrant at 250 mg did not demonstrate survival advantage over AI [61]. As second line treatment, fulvestrant at 250 mg showed similar time to progression (TTP) to anastrozole. Yet the later CONFIRM study demonstrated that doubling the dose to 500 mg gave a superior PFS and OS compared with 250 mg [5, 62]. FALCON is a phase 3 study which further brings fulvestrant at 500 mg to first line setting in comparison with anastrozole. The PFS was 16.6 and 13.8 months for the fulvestrant and anastrozole groups respectively with a p value of 0.0486 [6].

Given the special property of SERD on receptor degradation and conformation, it would be interesting to explore if patients with *ESR1* mutation respond differently from those with *ESR1* wild type. SoFEA is a study comparing exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI. Prospective-retrospective analysis of plasma ctDNA from SoFEA found *ESR1* mutation in 39% of patients, of which half were polyclonal [63]. Those with *ESR1* mutation had better PFS after giving fulvestrant compared with exemestane (HR 0.52, p = 0.02). Patients with *ESR1* wild type had similar benefit given either drug. PALOMA3 is a study that compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after prior endocrine therapy. Plasma ctDNA analysis showed *ESR1* mutation rate of 25%, of which 28% where polyclonal. Fulvestrant plus palbociclib gave rise to better PFS compared with fulvestrant alone in both *ESR1* mutant (HR 0.43, p = 0.002) and *ESR1* wild type patients (0.49, p < 0.001) [63]. Analysis of ctDNA from the BOLERO2 study also supported that *ESR1* mutation can be found in around 30% of patients who have failed prior endocrine therapy [50]. Patients with *ESR1* mutation had shorted OS compared with wild type. This study did not involve the use of fulvestrant.

enough data to suggest that CDK4/6 inhibitor should be part of standard treatment in patients with HR+ve/HER2−ve MBC, be it first line (PALOMA-2, MONALEESA-2, MONARCH-3, MONALEESA-7), second line (PALOMA-3, MONARCH-2), or later line in refractory cases (MONARCH-1). Since PI3K/AKT/mTOR plays an important role in hormonal resistance, mTOR inhibitor should also be considered in all patients. The only approved choice currently is everolimus. For the choice of hormonal partner in patients who have progressed on or failed prior AI, testing of *ESR1* mutation status might provide some guidance as to if switching to SERD would be helpful. It is still not clear if patients who progress on first line CDK4/6 inhibitors should be continued this targeted agent with a switch of hormonal partner. Chemotherapy should be reserved for patients who have exhausted the options for hormonal

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Although we are becoming increasingly equipped to overcome resistance to hormonal therapy, these treatment would fail nevertheless. The preliminary OS data for the phase II PALOMA-1 trial was presented in June 2017. It showed that the median OS was 37.5 months in patients who received palbociclib and AI versus 34.5 months in those who received AI (HR 0.897) [67], suggesting the impressive gain in median PFS after adding palbociclib might not translate into long term survival. Interestingly, analysis of OS for BELL2 appears to be trending toward similar observation. The median OS for patients who received buparlisib and fulvestrant versus those who received placebo and fulvestrant was 33.2 and 30.4 months respectively (HR 0.87; 95% CI, 0.74 to 1.02; p = 0.045) [68]. Even in patients who had PI3K pathway activated or PIK3CA mutation, the improvement in median PFS with addition of buparlisib did not translate into better median OS (HR 0.81, p > 0.05). These might be explained by two reasons. Firstly, post-progression survival can be affected by availability and effectiveness of subsequent therapy. Second, progression on CDK4/6 inhibitor might have selected out patients who then became refractory to other treatment especially chemotherapy. More understanding in the mechanism of resistance to hormonal therapy and targeted therapy is

HR+ve/HER2−ve MBC is the most common type of breast cancer. The main stay of treatment is hormonal therapy, and the choice of hormonal therapy includes SERM, AI, and SERD. SERD might play a more important role in selected patients, as development of *ESR1* mutation could render patients resistant to AI. Addition of targeted therapy such as CDK4/6 inhibitor or mTOR inhibitor can help prolong the use of hormonal therapy, and should be part of standard treatment for all patients in their treatment journey. Future research would focus on

therapy and these targeted therapies, or patients with impending visceral crisis.

**5. Conclusion**

needed to overcome these barriers.

**Conflict of interest**

strategies to overcome resistance to these therapies.

Dr. Chiu has no conflict of interest to declare.

While fulvestrant is non-inferior to AI in the first line setting, more data on OS is awaited. Yet emerging evidence suggest that testing of *ESR1* mutation could probably guide us in the choice of hormonal therapy in patients who have failed prior endocrine therapy. The approach is limited by the availability of ctDNA analysis, sensitivity of different ctDNA methodology, often difficult-to-obtain tissue biopsy upon the time of progression, and accessibility to *ESR1* test in local laboratory as it is still not a standard practice.
