Breast Cancer Treatment Protocols

SLNB is often not performed but may be done in some cases if an initial core biopsy showed DCIS, because more extensive sampling may show invasive carcinoma.

In the absence of risk factors for recurrence, women with DCIS who have small, low- or intermediate-grade tumors resected with widely negative margins can omit RT.

Consider risk-reduction therapy with tamoxifen 20 mg PO qDay (in pre- and postmenopausal women) or raloxifene 60 mg PO qDay (in postmenopausal women) for 5 years in patients with estrogen receptor (ER)–positive DCIS.

Tamoxifen can be given at a lower dose (5 mg daily) in patients with noninvasive breast cancer as shown by the babytam trial. [1]

Lobular carcinoma in situ (LCIS)

Management options include the following:

If LCIS is detected on stereotactic biopsy, wide excision is indicated. In 10-20% of cases, this may reveal invasive cancer or DCIS that requires additional local or systemic therapy. [4]

Surgical excision to negative margins is not indicated; however, patients with LCIS have about a 5% 5-y risk and a 20-30% lifetime risk of developing invasive breast cancer, which may be ipsilateral or contralateral and may be ductal or lobular in origin. [5]

Pleomorphic LCIS is a LCIS variant that warrants special consideration, in that treatment should include excision to negative margins. [6]

Neoadjuvant and/or Adjuvant Therapy for ER-Positive Early-Stage Breast Cancer

Consider the following:

Locally advanced (stage III) ER+ disease can be treated with neoadjuvant therapy. The goal of neoadjuvant treatment is to induce a tumor response before surgery and enable breast conservation.

For neoadjuvant treatment, chemotherapy is usually preferred. However, endocrine therapy may be considered in some cases (especially in postmenopausal patients who cannot receive chemotherapy and those with multiple comorbidities)

Patient who undergo upfront surgery can qualify for adjuvant chemotherapy based on gene expression profiling such as the Oncotype DX, MammaPrint, or Prosigna.

Almost all patients with ER+ (especially those with ER expression > 10%) breast cancer should be evaluated for adjuvant endocrine therapy

Patients at high risk for recurrence should be evaluated for adjuvant treatment with CDK4/6 inhibitors.

Postmenopausal women at high risk for recurrence can be evaluated for adjuvant treatment with a bisphosphonate.

Chemotherapy regimens

Dose-dense doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (AC-P):

Doxorubicin 60 mg/m 2 IV plus cyclophosphamide 600 mg/m 2 IV every 2 weeks for four cycles, with colony-stimulating factor (CSF) support, followed by

Alternative taxanes (ie, docetaxel, albumin-bound paclitaxel) may be used as substitutes in cases of medical necessity (eg, hypersensitivity reaction).

Change in administration sequence to paclitaxel followed by doxorubicin/cyclophosphamide is acceptable.

Docetaxel (Taxotere) plus cyclophosphamide (TC):

Docetaxel 75 mg/m 2 IV on Day 1 plus cyclophosphamide 600 mg/m 2 IV on Day 1 every 3 weeks for four cycles [9] ​

Neoadjuvant endocrine therapy

Usually reserved for postmenopausal women who are not candidates for chemotherapy but would benefit from neoadjuvant therapy:

Adjuvant endocrine therapy

Patients with invasive breast cancer that is ER+ or progesterone receptor positive (PR+) should be considered for adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (AIs). Selection considerations are as follows:

Selection of agents depends on menopausal status and concern about adverse effect profile (eg, thrombosis with tamoxifen, bone loss with AIs).

Tamoxifen has been shown to reduce the risk of recurrence by about 40% and the risk of death by about 30%, is effective in both premenopausal and postmenopausal women, and may be used either alone or after chemotherapy. [11]

AIs are effective for postmenopausal women, reducing the risk of recurrence by approximately 20% compared with tamoxifen. [12, 13, 14, 15]

Nonsteroidal AIs (anastrozole, letrozole) and steroidal AIs (exemestane) have comparable efficacy and adverse effects

Regimens for premenopausal patients:

Tamoxifen 20 mg PO daily for 2-5 y, followed by an AI for a total of up to 10 y of endocrine therapy; this regimen is typically used for patients who are premenopausal at diagnosis and become postmenopausal during therapy; it has been shown to be more effective than a 5y course of tamoxifen [17]

Ovarian function suppression (OFS) with a gonadotropin-releasing hormone (GnRH) agonist (eg, goserelin 3.6 mg SC depot every 28 days [every-3-months therapy not recommended due to ovarian function escape]) added to tamoxifen or an AI, is associated with increased benefit in patients at high risk for recurrence. [18]

Regimens for postmenopausal patients:

AIs for 5y, either alone or sequentially after 2-5 y of tamoxifen: anastrozole 1 mg PO daily or letrozole 2.5 mg PO daily or exemestane 25 mg PO daily

Adjuvant CDK4/6 inhibitor therapy

Adjuvant CDK4/6 inhibitors are recommended with patients a high risk for recurrence, as follows:

Ribociclib 600 mg PO on Days 1-21 of each 28-day cycle for 3 years, in combination with daily endocrine therapy; although 600 mg is the approved dose, the NATALEE trial reported that a 400-mg dose improves tolerability while maintaining efficacy [20]

Palbociclib 125 mg PO qDay for Days 1-21 of each 28-day cycle, in combination with aromatase inhibitor as initial endocrine-based therapy and in combination with fulvestrant in men or women with disease progression following endocrine therapy [21, 22]

Adjuvant poly (ADP-ribose) polymerase (PARP) inhibitor therapy

For patients with BRCA1- or BRCA2-mutated breast cancer at high risk for recurrence [23] :

Adjuvant bisphosphonate therapy

Consider in postmenopausal women at high risk for recurrence [24] :

Zoledronic acid 4 mg IV every 6 months for 3 years; q6mo dosing reduces osteonecrosis of the jaw [25]

Neoadjuvant and/or Adjuvant Therapy for Triple-Negative Early-Stage Breast Cancer

Any tumor that is T1c and above or node positive should be considered for neoadjuvant therapy. This approach offers several advantages, the most prominent being that the tumor's response to neoadjuvant therapy aids in predicting the likelihood of recurrence. This allows for the tailoring of adjuvant therapy.

Chemoimmunotherapy

Preoperative pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab [26] :

Pembrolizumab 200 mg IV on Day 1 plus paclitaxel 80 mg/m 2 IV on Days 1, 8, and 15 plus carboplatin area under the curve (AUC) 5 IV (see the Carboplatin AUC Dose Calculation [Calvert] calculator) on Day 1 every 3 weeks for cycles 1-4 followed by

Pembrolizumab 200 mg IV on Day 1 plus doxorubicin 60 mg/m 2 IV and cyclophosphamide 600 mg/m 2 every 3 weeks for cycles 5-8, then following surgery

Pembrolizumab 200 mg IV on Day 1 every 3 weeks for nine cycles​ or 400 mg IV every 6 weeks for four cycles

Chemotherapy

Dose-dense doxorubicin (Adriamycin) followed by paclitaxel (AC-P):

Doxorubicin 60 mg/m 2 IV plus cyclophosphamide 600 mg/m 2 every 2 weeks for four cycles with CSF support followed by

Alternative taxanes (eg, docetaxel, albumin-bound paclitaxel) may be used as substitutes in cases of medical necessity (eg, hypersensitivity reaction).

Change in administration sequence to paclitaxel followed by doxorubicin/cyclophosphamide is acceptable

Docetaxel (Taxotere) plus cyclophosphamide (TC):

Docetaxel 75 mg/m 2 IV on Day 1 plus cyclophosphamide 600 mg/m 2 IV on Day 1 every 3 weeks for four cycles [9] ​

Adjuvant capecitabine monotherapy (for TNBC only)

Can be considered in patients with TNBC who received neoadjuvant chemotherapy and had residual disease at the time of surgery [27] :

PARP inhibitors

Adjuvant olaparib monotherapy (for patients with BRCA1- or BRCA2-mutated breast cancer) [23] :

Neoadjuvant talazoparib (for patients with BRCA1- or BRCA2-mutated breast cancer) [28]

Can be considered as an alternative to neoadjuvant chemotherapy in these patients:

Neoadjuvant or Adjuvant Therapy for HER2-Positive Early-Stage Breast Cancer

Any tumor that is T2 and above or node positive should be considered for neoadjuvant therapy. This approach offers several advantages, the most prominent being that the tumor's response to neoadjuvant therapy aids in predicting the likelihood of recurrence. This allows for the tailoring of adjuvant therapy.

Trastuzumab-containing regimens

Paclitaxel plus trastuzumab:

Consider for low-risk HER2-positive patients who may not be eligible for other standard adjuvant treatments

Trastuzumab 4 mg/kg IV with first dose of paclitaxel, then 2 mg/kg IV weekly for 1 year or trastuzumab 6 mg/kg every 3 weeks following the completion of paclitaxel therapy, and given for a 1-year total duration of trastuzumab therapy [29]

Dose-dense doxorubicin (Adriamycin) followed by paclitaxel (AC-P):

Doxorubicin 60 mg/m 2 IV plus cyclophosphamide 600 mg/m 2 IV on Day 1 every 2 weeks for four cycles with colony-stimulating factor (CSF) support, followed by

Trastuzumab 4 mg/kg IV with first dose of paclitaxel then 2 mg/kg IV weekly for 1 year or trastuzumab 6 mg/kg every 3 weeks following the completion of paclitaxel, and given for a 1-year total duration of trastuzumab therapy [30]

AC-docetaxel plus trastuzumab:

Doxorubicin 60 mg/m 2 IV plus cyclophosphamide 600 mg/m 2 IV on Day 1 every 2 weeks for four cycles with CSF support, followed by

Trastuzumab 4 mg/kg IV with first dose of paclitaxel then 2 mg/kg IV weekly for 1 year or trastuzumab 6 mg/kg every 3 weeks following the completion of paclitaxel, and given for a 1-year total duration of trastuzumab therapy [31]

Docetaxel (Taxotere)/carboplatin/trastuzumab (Herceptin)(TCH):

Docetaxel 75 mg/m 2 IV plus carboplatin AUC 6 IV on Day 1 every 3 weeks for six cycles (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator) plus

Trastuzumab 4 mg/kg IV during week 1 and then 2 mg/kg IV weekly for 17 weeks; followed by trastuzumab 6 mg/kg every 3 weeks to complete 1 year of trastuzumab

Alternatively, trastuzumab 8 mg/kg IV week 1, then 6 mg/kg IV every 3 weeks to complete 1 year of therapy

This regimen may be more appropriate for patients with contraindications to anthracycline therapy [31]

TCH plus pertuzumab:

Trastuzumab 8 mg/kg IV on Day 1, then trastuzumab 6 mg/kg IV Day 1 every 3 weeks to complete 1 year of therapy plus

Docetaxel/cyclophosphamide plus trastuzumab:

Docetaxel 75 mg/m 2 IV on Day 1 plus cyclophosphamide 600 mg/m 2 IV Day 1 every 3 weeks for four cycles plus

Trastuzumab 4 mg/kg during week 1, then 2 mg/kg IV weekly for 11 weeks; followed by trastuzumab 6 mg/kg every 3 weeks to complete 1 year of trastuzumab

Alternatively, trastuzumab 8 mg/kg IV week 1, then 6 mg/kg IV every 3 weeks to complete 1 year of therapy [29]

Neratinib for adjuvant treatment following trastuzumab

Neratinib is indicated for the extended adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy [32] , as follows:

Neratinib 120 mg PO daily on Days 1-7, then 160 mg PO daily on Days 8-14, then by 240 mg PO daily on Days 15-28 in cycle 1 followed by

Ado-trastuzumab emtansine (T-DM1) for adjuvant setting only

Ado-trastuzumab emtansine is approved as an adjuvant treatment for HER2-positive early breast cancer when the patient has received neoadjuvant treatment including a taxane and trastuzumab and there is residual disease in the tissue removed during surgery. [34]

Considerations

See the list below:

The US Food and Drug Administration (FDA) has approved several biosimilars of trastuzumab (Herzuma, Kanjinti, Ogivri, Ontruzant, Trazimera) to treat HER2-overexpressed breast cancer. The availability of biosimilars provides additional treatment options for patients in the adjuvant setting.

The FDA granted accelerated approval to a fixed-dose pertuzumab/trastuzumab/hyaluronidase combination (Phesgo) for subcutaneous (SC) use in combination with IV chemotherapy, for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence. [35] Pertuzumab/trastuzumab/hyaluronidase may be substituted anywhere that the combination of IV pertuzumab and IV trastuzumab are given as part of systemic therapy.

Systemic Therapy for ER-Positive Metastatic Breast Cancer

First-line treatment of endocrine-sensitive disease

In postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, initial endocrine-based therapy for metastatic disease may include the following:

Ribociclib 600 mg PO once daily for Days 1-21 of a 28-day cycle plus endocrine therapy (aromatase inhibitor or fulvestrant) [36]

Palbociclib 125 mg PO once daily on Days 1-21 of each 28-day cycle with food plus endocrine therapy [37]

Abemaciclib 150 mg BID plus endocrine therapy; continue for 2 years, or until disease recurrence or unacceptable toxicity [38]

In premenopausal women with ER-positive, HER2-negative advanced breast cancer, the treatment of choice is as follows [39] :

Tamoxifen 20 mg PO daily or a nonsteroidal aromatase inhibitor ( letrozole 2.5 mg PO daily or anastrozole 1 mg PO daily) plus

Second-line treatment and beyond of endocrine-sensitive disease

See the list below:

Alpelisib 300 mg PO daily plus fulvestrant 500 mg IM on Days 1, 15, and 29, and once monthly thereafter, in tumors with confirmed PIK3CA mutation [40]

Everolimus 10 mg PO daily plus fulvestrant 500 mg IM on Days 1, 15, and 29, and once monthly thereafter

Treatment of endocrine-refractory disease

Antibody-drug conjugates (ADCs) are recommended for treatment of endocrine-refractory disease. However, ADCs are currently indicated for second-line use after at least one prior line of chemotherapy. Recommended single-agent regimens include any of the following:

Albumin-bound paclitaxel 260 mg/m 2 every 3 weeks or (off-label) 100 mg/m 2 IV on Days 1, 8, and 15 every 4 weeks [44]

Patients whose cancer progresses on first-line treatment should be offered an ADC. There is currently no consensus on which ADC to use first and whether these agents can be used sequentially. However, there is a growing consensus that in patients with HER2-low disease (defined as HER2 expression by immunohistochemistry 1+ or 2+ with non-amplification by in-situ hybridization), trastuzumab deruxtecan should be used first:

Trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks, in patients with HER2-low or HER2-positive disease [45]

Capivasertib plus fulvestrant is indicated for patients with hormone receptor–positive, HER2-negative (HR+/HER2-) locally advanced or metastatic breast cancer that has at least 1 PIK3CA/AKT1/PTEN-alteration, following progression on 1 or more endocrine-based regimens in the metastatic setting or recurrence on, or within 12 months of completing, adjuvant therapy. [46]

Capivasertib 400 mg PO BID for 4 consecutive days followed by 3 days off; repeat weekly schedule until disease progression or unacceptable toxicity, plus

In patients with triple-negative or HR+/HER2- disease [47] :

Patients whose cancer progresses on ADC therapy should be encouraged to seek clinical trial options. Otherwise, they can be treated with single-agent chemotherapy. Options include capecitabine and albumin-bound paclitaxe or any of the following:

Docetaxel 60-100 mg/m 2 IV every 3 weeks for at least 6 cycles or (off-label dose) 40 mg/m 2 IV weekly for 6 weeks followed by a 2-week rest and then repeat [48]

Gemcitabine 1,250 mg/m 2 IV on Days 1 and 8 in combination with paclitaxel of a 21-day cycle or (off-label) 800-1200 mg/m 2 IV on Days 1, 8, and 15 of a 28-day cycle [49]

Systemic Therapy for Triple-Negative Advanced Breast Cancer

First-line therapy for advanced triple-negative breast cancer (TNBC) that is programmed death–ligand 1(PD-L1) positive (combined positive score [CPS] ≥10 9 ), regardless of BRCA mutation status [52] :

First-line therapy for PD-L1–negative, BRCA1 or BRCA2 wild-type TNBC:

First-line therapy for PD-L1–negative, BRCA1- or BRCA2-mutated TNBC:

Second-line therapy for advanced TNBC:

Third-line therapy and beyond for advanced TNBC is with any of the following:

Docetaxel 60-100 mg/m 2 IV every 3 weeks for at least 6 cycles or (off-label) 40 mg/m 2 IV weekly for 6 weeks followed by a 2-week rest and then repeat [48]

Gemcitabine 1,250 mg/m 2 IV on Days 1 and 8 in combination with paclitaxel of a 21-day cycle or (off-label) 800-1200 mg/m 2 IV on Days 1, 8, and 15 of a 28-day cycle [49]

Systemic Therapy for HER2+ Metastatic Breast Cancer

First-line therapy for HER+ metastatic breast cancer [54] :

Second-line therapy for HER+ metastatic breast cancer:

Second-line therapy for HER+ metastatic breast cancer, including brain metastasis [56] :

Third-line therapy and beyond for HER+ metastatic breast cancer can be with any of the following:

Trastuzumab 4 mg/kg IV on Day 1, then 2 mg/kg IV weekly or 8 mg/kg IV on Day 1, followed by 6 mg/kg every 3 weeks, in combination with single-agent chemotherapy

Any of the following chemotherapy regimens may be used in combination with margetuximab or trastuzumab [59] :

Considerations

See the list below:

The FDA has approved several biosimilars of trastuzumab (Herzuma, Kanjinti, Ogivri, Ontruzant, Trazimera) to treat HER2-overexpressed breast cancer. The availability of biosimilars provides additional treatment options for patients in the adjuvant setting.

The FDA granted accelerated approval to a fixed-dose pertuzumab/trastuzumab/hyaluronidase combination (Phesgo) for subcutaneous (SC) use in combination with IV chemotherapy, for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence. [35] Pertuzumab/trastuzumab/hyaluronidase may be substituted anywhere that the combination of IV pertuzumab and IV trastuzumab are given as part of systemic therapy.

Breast Cancer Surgery

Surgical options include the following:

Axillary assessment is usually performed with sentinel lymph node biopsy (SLNB). Axillary dissection may be considered in cases of node-positive breast cancer.

Although axillary dissection had been the standard of care for patients with a positive SLNB, studies have indicated comparable local and systemic control rates without axillary dissection for patients who also receive radiation and systemic chemotherapy. [60, 61]

Breast Cancer Radiation Therapy

Radiation therapy (RT) is used in patients who undergo lumpectomy or, in selected cases, after mastectomy; treatment fields are determined by axillary node status. RT should follow chemotherapy if chemotherapy is indicated.

Patients undergoing lumpectomy with surgical axillary staging

RT recommendations are based on the patient's axillary node status. In patients with ≥4 positive axillary nodes, treatment is as follows:

Comprehensive regional nodal irradiation (RNI) including any portion of the undissected axilla at risk

In patients with 1-3 positive axillary nodes, treatment is as follows:

All of the following criteria met: cT1-T2 cN0, no preoperative chemotherapy, 1-2 positive sentinel lymph node (SLNs) – WBRT with or without boost to the tumor bed; comprehensive RNI with or without inclusion of axilla

Not all the above criteria met – WBRT with or without boost, including any portion of undissected axilla at risk; strongly consider RNI

In patients with negative axillary nodes, treatment is as follows:

Even without RT, risk of recurrence is extremely low in patients aged 55 and older with low-grade luminal A–type breast cancer (node-negative, grade 1 or 2 tumors < 2 cm) and a Ki67 tumor cell count of 13.25% or less, who receive breast-conserving surgery and endocrine therapy. [62]

Patients undergoing total mastectomy with surgical axillary staging, with or without reconstruction

RT recommendations are based on the patient's axillary node status, as follows (note that comprehensive RNI may include any portion of undissected axilla at risk):

Negative axillary nodes, tumor ≤5 cm, and negative margins < 1 mm – Consider RT to the chest wall; for high-risk patients, consider adding comprehensive RNI

Negative axillary nodes and tumor > 5 cm or positive margins – Consider RT to the chest wall, with or without comprehensive RNI

1-3 positive axillary nodes – Consider RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes

Margins positive – Re-excision to negative margins (preferred); if unable to excise, then strongly consider RT with or without comprehensive RNI

Special Considerations

Invasive Lobular Carcinoma

Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer after invasive ductal carcinoma (IDC), accounting for 10-15% of all breast cancer cases. [63]

The majority of ILCs are ER-positive and HER2-negative and exhibit distinct clinicopathologic and molecular characteristics compared with IDC. Those features impact the response of ILCs to systemic therapy:

Early-stage ILC tends to be less responsive than IDC to neoadjuvant chemotherapy. [64] However, ILC tends to respond well to neoadjuvant endocrine therapy. [65] In the adjuvant setting, ILC patients treated with a nonsteroidal aromatase inhibitors ( anastrozole or letrozole) had better long-term outcomes than those treated with tamoxifen. [66, 67] .

Metastatic endocrine-sensitive ILC tends to respond well to endocrine therapy in combination with targeted therapy (eg, a CDK4/6 inhibitor, everolimus, alpelisib). [68] Once ILC becomes endocrine refractory, capecitabine might be the preferred agent of choice. [69] Data are lacking on whether antibody-drug conjugates are effective in ILC.

Oligometastatic disease

See the list below:

Surgery and/or radiation therapy may be able to achieve prolonged disease control in selected patients with oligometastatic disease.

Contraindications to Treatment

Patient age and comorbidities must be taken into account when planning breast cancer treatment. In patients age ≥ 65 years with stage I-III breast cancer for whom neoadjuvant or adjuvant chemotherapy is planned, tools such as the Cancer and Aging Research Group (CARG) score should be used to determine the risk of grade 3-5 chemotherapy toxicity. [70]

Considerations regarding comorbidities include the following:

Certain comorbidities may pose relative or absolute contraindications to specific therapies, including cardiac disease (anthracyclines) and neuropathy (taxanes).

Adjustment of prognosis for comorbidity is more complex and is influenced by its severity and duration, patient age, and presence of other comorbidities.

For patients with significant comorbidities characterized by organ system dysfunction (eg, congestive heart failure, chronic obstructive pulmonary disease, cirrhosis, chronic kidney disease), the prognosis for the comorbidity must be considered in the context of the cancer; the Charlson index is commonly used for this purpose. [71]

Questions & Answers

References

1. Lazzeroni M, Puntoni M, Guerrieri-Gonzaga A, et al. Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study. J Clin Oncol. 2023 Jun 10. 41 (17):3116-3121. [QxMD MEDLINE Link].
2. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998 Sep 16. 90(18):1371-88. [QxMD MEDLINE Link].
3. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21. 295(23):2727-41. [QxMD MEDLINE Link].
4. Young OE, Renshaw L, Macaskill EJ, White S, Faratian D, Thomas JS, et al. Effects of fulvestrant 750mg in premenopausal women with oestrogen-receptor-positive primary breast cancer. Eur J Cancer. 2008 Feb. 44(3):391-9. [QxMD MEDLINE Link].
5. Fisher ER, Land SR, Fisher B, Mamounas E, Gilarski L, Wolmark N. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer. 2004 Jan 15. 100(2):238-44. [QxMD MEDLINE Link].
6. Masannat YA, Bains SK, Pinder SE, Purushotham AD. Challenges in the management of pleomorphic lobular carcinoma in situ of the breast. Breast. 2013 Apr. 22 (2):194-6. [QxMD MEDLINE Link].
7. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15. 21(8):1431-9. [QxMD MEDLINE Link].
8. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17. 358(16):1663-71. [QxMD MEDLINE Link].
9. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1. 24(34):5381-7. [QxMD MEDLINE Link].
10. Sella T, Weiss A, Mittendorf EA, King TA, Pilewskie M, Giuliano AE, et al. Neoadjuvant Endocrine Therapy in Clinical Practice: A Review. JAMA Oncol. 2021 Nov 1. 7 (11):1700-1708. [QxMD MEDLINE Link].
11. Early Breast Cancer Trialists’ Collaborative Group (EBCTG). Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998. 351:1451-67.
12. Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010 Jan 20. 28(3):509-18. [QxMD MEDLINE Link].
13. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec. 11(12):1135-41. [QxMD MEDLINE Link].
14. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005 Sep 7. 97(17):1262-71. [QxMD MEDLINE Link].
15. Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20. 26(12):1948-55. [QxMD MEDLINE Link].
16. Early Breast Cancer Trialists’ Collaborative Group (EBCTG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20. 365(9472):1687-717. [QxMD MEDLINE Link].
17. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11. 350(11):1081-92. [QxMD MEDLINE Link].
18. Pagani O, Walley BA, Fleming GF, et al. SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1. 41 (7):1376-1382. [QxMD MEDLINE Link].
19. Johnston SRD, Harbeck N, Hegg R, et al., monarchE Committee Members and Investigators. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020 Dec 1. 38 (34):3987-3998. [QxMD MEDLINE Link].
20. Dennis J. Slamon, Daniil Stroyakovskiy, et. al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. J Clin Oncol. 2023. 41:17 suppl:[Full Text].
21. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr. 17 (4):425-439. [QxMD MEDLINE Link].
22. Llombart-Cussac A, et al; PARSIFAL Steering Committee and Trial Investigators. Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Dec 1. 7 (12):1791-1799. [QxMD MEDLINE Link].
23. Tutt ANJ, Garber JE, Kaufman B, et al., OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun 24. 384 (25):2394-2405. [QxMD MEDLINE Link].
24. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015 Oct 3. 386 (10001):1353-1361. [QxMD MEDLINE Link].
25. Shapiro CL, Van Poznak C, Lacchetti C, Kirshner J, Eastell R, Gagel R, et al. Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline. J Clin Oncol. 2019 Nov 1. 37 (31):2916-2946. [QxMD MEDLINE Link]. [Full Text].
26. Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27. 382 (9):810-821. [QxMD MEDLINE Link].
27. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017 Jun 1. 376 (22):2147-2159. [QxMD MEDLINE Link].
28. Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, et al. Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline BRCA Pathogenic Variant. J Clin Oncol. 2020 Feb 10. 38 (5):388-394. [QxMD MEDLINE Link].
29. [Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Version 4.2023 — March 23, 2023; Accessed: August 8, 2023.
30. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20. 353(16):1673-84. [QxMD MEDLINE Link].
31. Slamon DJ, Mackey J, Robert N, et al. Role of anthracycline-based therapy in the adjuvant treatment of breast cancer: efficacy analysis determined by molecular subtypes of the disease, the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2007.
32. Chan A, Delaloge S, Holmes FA et al. ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar. 17 (3):367-377. [QxMD MEDLINE Link].
33. Barcenas CH, Hurvitz SA, et al, CONTROL Study Investigators. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann Oncol. 2020 Sep. 31 (9):1223-1230. [QxMD MEDLINE Link].
34. von Minckwitz G, Huang CS, Mano MS et al., KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14. 380 (7):617-628. [QxMD MEDLINE Link].
35. Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) [package insert]. South San Francisco, CA: South San Francisco, CA. June 2020. Available at [Full Text].
36. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022 Mar 10. 386 (10):942-950. [QxMD MEDLINE Link].
37. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17. 375 (20):1925-1936. [QxMD MEDLINE Link].
38. Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019. 5:5. [QxMD MEDLINE Link].
39. Tripathy D, Im SA, Colleoni M,. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul. 19 (7):904-915. [QxMD MEDLINE Link].
40. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16. 380 (20):1929-1940. [QxMD MEDLINE Link].
41. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9. 366(6):520-9. [QxMD MEDLINE Link].
42. Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1. 40 (28):3246-3256. [QxMD MEDLINE Link]. [Full Text].
43. Khan QJ, Bohnenkamp C, Monson T, Smith HE, Phadnis MA, Raja V, et al. Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial (abstract). Presented at the 2023 ASCO Annual meeting June 2-6, 2023. Chicago, IL. J Clin Oncol. 2023. 41(16 suppl):[Full Text].
44. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1. 27 (22):3611-9. [QxMD MEDLINE Link]. [Full Text].
45. Modi S, Jacot W, Yamashita T, Sohn J, DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7. 387 (1):9-20. [QxMD MEDLINE Link].
46. Turner NC, Oliveira M, Howell SJ, and the, CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1. 388 (22):2058-2070. [QxMD MEDLINE Link].
47. Rugo HS, Bardia A, Marmé F, Cortes J, Schmid P, Loirat D, et al. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10. 40 (29):3365-3376. [QxMD MEDLINE Link].
48. Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000 Mar. 18 (6):1212-9. [QxMD MEDLINE Link]. [Full Text].
49. Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov. 13 (11):2731-6. [QxMD MEDLINE Link]. [Full Text].
50. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1. 92 (9):2267-72. [QxMD MEDLINE Link]. [Full Text].
51. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, et al. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1. 22 (19):3893-901. [QxMD MEDLINE Link]. [Full Text].
52. Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul 21. 387 (3):217-226. [QxMD MEDLINE Link].
53. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019 Feb 21. 380 (8):741-751. [QxMD MEDLINE Link].
54. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19. 372 (8):724-34. [QxMD MEDLINE Link].
55. Cortés J, Kim SB, Chung WP, Im SA, et al. DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24. 386 (12):1143-1154. [QxMD MEDLINE Link].
56. Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13. 382 (7):597-609. [QxMD MEDLINE Link].
57. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8. 367(19):1783-91. [QxMD MEDLINE Link].
58. Saura C, Oliveira M, Feng YH, et al., NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20. 38 (27):3138-3149. [QxMD MEDLINE Link].
59. Rugo HS, Im SA, Cardoso F, Cortés J, et al. SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1. 7 (4):573-584. [QxMD MEDLINE Link].
60. Giuliano AE, McCall L, Beitsch PD, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology group Z0011 randomized trial. Ann Surg. 2010. 252:426-432; discussion 423-432.
61. Giuliano AE, McCall L, Beitsch PD, et al. ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node [abstract]. J Clin Oncol. 2010;28(Suppl 18):Abstract CRA506.
62. Biomarker Guidance May Allow Patients Aged 55 or Older With Low-Grade Luminal A–Type Breast Cancer to Avoid Radiation Therapy. The ASCO Post. Available at https://ascopost.com/news/june-2022/biomarker-guidance-may-allow-patients-aged-55-or-older-with-low-grade-luminal-a-type-breast-cancer-to-avoid-radiation-therapy/. June 7, 2022; Accessed: Auguts 8, 2023.
63. Mouabbi JA, Hassan A, Lim B, Hortobagyi GN, Tripathy D, Layman RM. Invasive lobular carcinoma: an understudied emergent subtype of breast cancer. Breast Cancer Res Treat. 2022 Jun. 193 (2):253-264. [QxMD MEDLINE Link].
64. Petrelli F, Barni S. Response to neoadjuvant chemotherapy in ductal compared to lobular carcinoma of the breast: a meta-analysis of published trials including 1,764 lobular breast cancer. Breast Cancer Res Treat. 2013 Nov. 142 (2):227-35. [QxMD MEDLINE Link].
65. Dixon JM, Renshaw L, Dixon J, Thomas J. Invasive lobular carcinoma: response to neoadjuvant letrozole therapy. Breast Cancer Res Treat. 2011 Dec. 130 (3):871-7. [QxMD MEDLINE Link].
66. Metzger Filho O, Giobbie-Hurder A, Mallon E, Gusterson B, Viale G, Winer EP, et al. Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial. J Clin Oncol. 2015 Sep 1. 33 (25):2772-9. [QxMD MEDLINE Link].
67. Michael Knauer; Christine Gruber; Otto Dietze, et al. Survival advantage of anastrozol compared to tamoxifen for lobular breast cancer in the ABCSG-8 study. Cancer Research. [Full Text].
68. Mouabbi JA, Raghavendra AS, Bassett RL Jr, Hassan A, Tripathy D, Layman RM. Histology-based survival outcomes in hormone receptor-positive metastatic breast cancer treated with targeted therapies. NPJ Breast Cancer. 2022 Dec 20. 8 (1):131. [QxMD MEDLINE Link].
69. J. Mouabbi W. Qiao A. Singareeka Raghavendra Y. Shen D. Tripathy R.M. Layman. Efficacy of single-agent chemotherapy in endocrine therapy-refractory metastatic invasive lobular carcinoma. ESMO Open. [Full Text].
70. Magnuson A, Sedrak MS, Gross CP, Tew WP, Klepin HD, Wildes TM, et al. Development and Validation of a Risk Tool for Predicting Severe Toxicity in Older Adults Receiving Chemotherapy for Early-Stage Breast Cancer. J Clin Oncol. 2021 Feb 20. 39 (6):608-618. [QxMD MEDLINE Link].
71. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987. 40(5):373-83. [QxMD MEDLINE Link].