Breast Cancer (Mammary Carcinoma): Drug Therapy

Prevention

Drug prevention in women at increased risk of breast cancer regarding [4; S3 guideline: see below]:

  • Invasive carcinomas
  • Preinvasive changes
    • Lobular carcinoma in situ (LCIS).
    • Ductal carcinoma in situ (DCIS) and
    • Intraductal atypical hyperplasia (ADH).

Therapy target

  • To improve prognosis in women at risk of developing a hormone-sensitive tumor (positivity of estrogen (ER) and progesterone receptors (PR)).

Prevention studies have been able to show the following effects:

  • SERM (selective estrogen receptor modulators).
    • Tamoxifen leads to a reduction in invasive breast carcinoma (MaCa), DCIS, LCIS, and ADH in women >35 years of age.
    • Raloxifene leads to a reduction in invasive MaCa in postmenopausal women.
  • Aromatase inhibitors
    • Anastrozole leads to a reduction in invasive MaCa in postmenopausal women
    • Exemestane leads to a reduction in invasive MaCa in postmenopausal women

Adjuvant drug prevention after breast carcinoma.

Endocrine therapy (adjuvant anti-hormonal therapy, adjuvant anti-endocrine therapy).

Therapeutic Objective

  • Improvement of prognosis and recurrence-free interval by antihormone therapy (approximately 75% of patients have a hormone-sensitive tumor: positivity of estrogen (ER) and progesterone receptors (PR)); duration of therapy: 5 to preferably 10 years.

In patients with estrogen and/or progesterone receptor positive tumors, endocrine treatment is always indicated regardless of the risk situation. This should be started – if chemotherapy was necessary – only after completion of chemotherapy. Therapy recommendations in premenopausal patients (as of 2013/2014).

  • Standard therapy/therapy of choice: tamoxifen.
    • Duration:
      • 5 years (= IAT, i.e. initial adjuvant therapy).
      • 10 years (= EAT, i.e., extended endocrine therapy) in terms of secondary prevention (particularly useful for young (premenopausal) patients)Note: Prolonged tamoxifen administration is not indicated for patients who become postmenopausal during the course of endocrine therapy.
    • Or until recurrence.
  • Exceptions < 40 years, no chemotherapy
    • Tamoxifen + LHRH agonist (2-5 years) (GnRH analogues) (ovarian suppression, OFS: ovarian function suppression).
    • LHRH agonist monotherapy in contraindication to tamoxifen e.g. thrombosis, embolism.
    • LHRH agonist + aromatase inhibitor
  • Overall survival is significantly prolonged according to the ATLAS study

Therapy in postmenopausal patients.

The following therapeutic regimens may be used:

  • 5 years of tamoxifen (IAT)
  • 5 years aromatase inhibitor so-called upfront therapy.
  • Switch therapy

In postmenopausal women, 3rd generation aromatase inhibitors are superior to tamoxifen in terms of disease-free survival. However, there is an increased risk of arthralgia, myalgia, osteoporosis, and osteoporotic fracture compared with tamoxifen. There are fewer hot flashes, thromboembolic events, and endometrial cancer. Aromatase inhibitors should be preferred for invasive lobular breast carcinomas. Note: Half of recurrences and two-thirds of breast cancer-related deaths occur within the first 15 years after diagnosis.

Therapeutic Target

  • Improvement of prognosis by hormone therapy (approximately 80% of patients have a hormone-sensitive tumor); duration: preferably over 10 years.

Further notes

  • Note: According to international study data within 5 years, 31 to 73% of patients discontinue adjuvant treatment with tamoxifen or an aromatase inhibitor! This is known to lead to an increased risk of recurrence and mortality.Based on the following figures, it appears that resumption of therapy also leads to improved disease progression: after eight years, 89.8% (95% confidence interval between 86.7 and 92.2%) were still alive without disease progression versus 82.0% (95% confidence interval between 76.6 and 86.3%) of patients who had not resumed therapy.
  • The Early Breast Cancer Trialists’ Collaborative Group examined the risk of recurrence for a 15-year period after the end of successful hormone therapy. The study showed that the risk of distant metastases increased steadily over the following 15 years-even in early carcinoma without lymph node involvement-and barely attenuated by the end of the 15-year follow-up period. Here are individual results 15 years after the end of hormone therapy:
    • Women with stage T1N0 (tumor size < 1 cm) 10% distant metastases.
    • Women in stage T2N0 (tumor size 3.1-5 cm) 20% distant metastases.

See also brief information below on dual Her2 blockade, triple-negative breast cancer (TNBC) therapy, adjuvant chemotherapy, and neoadjuvant chemotherapy (NACT).

Active ingredients (main indication)

3rd-generation aromatase inhibitors (antiestrogens; aromatase inhibitors, AIs).

Agents Special features
Anastrozole KI in severe renal/hepatic insufficiency.
Exemestane KI in severe renal/hepatic insufficiency.
Letrozole KI in severe renal/hepatic insufficiency.
  • Mode of action: Inhibition of the conversion of androgens to estrogen induced by aromatase.
  • The aromatase inhibitors anastrozole and letrozole have advantages over tamoxifen for early but not late stage disease (recurrences later; longer survival)
  • To counteract bone loss from adjuvant aromatase inhibitor therapy, biphosphates are used in breast cancer patients with ER-positive tumors. According to a meta-analysis, the benefit appears to extend beyond the vascular bone stabilizing effect: when therapy is initiated after the onset of menopause, cancer-specific survival is highly significantly improved; tumor stage was without influence. Here, the non-nitrogen aminobisphosphonate clodronate and the aminobisphosphonates zoledronic acid and ibandronate were equally effective. No benefit was shown by pamidronate. The other bisphosphonates could not be assessed for efficacy because too few women had been treated with them.
  • * The selective serotonin–norepinephrine inhibitor duloxetine improved joint pain and quality of life with aromatase inhibitor therapy (pain score was reduced by a mean of 0.82 points more than in the placebo group).

Further note

  • Ovarian suppression reduces long-term risk of recurrence in receptor-positive breast carcinoma in younger patients:
    • Disease-free survival 8 years after study initiation:
      • Tamoxifen treatment alone: 78.9%.
      • Combination of tamoxifen plus ovarian suppression: 83.2%.
      • Combination of exemestane plus ovarian suppression: 85.9 %.
    • Overall survival rates at 8 years:
      • Tamoxifen treatment alone: 91.5%.
      • Combination of tamoxifen plus ovarian suppression: 93.3 %.
      • Combination of exemestane plus ovarian suppression: 92.1 %.

Antiestrogens

Active ingredients Special features
Fulvestrant KI in severe hepatic insufficiency
  • Mode of action: Estrogen-antagonistic without estrogen-like residual effect (downregulation of estrogen receptors).
  • Use in hormone-sensitive metastatic or locally advanced breast carcinoma of postmenopausal women, or in recurrences or treatment failure under tamoxifen.
  • In patients with metastatic estrogen receptor-positive breast carcinoma, the combination of fulvestrant and the aromatase inhibitor anastrozole was shown to have long-term benefits in a randomized clinical trial. It prolonged overall survival: median survival was 49.8 months versus 42.0 months in the anastrozole group.
  • In a phase III trial, the PIK3 inhibitor alpelisib, in combination with fulvestrant, nearly doubled progression-free survival in patients with hormone receptor-positive and HER2-negative breast cancer.

Selective estrogen receptor modulators (SERMs).

Active ingredients
Tamoxifen
  • Mode of action: Estrogen-antagonistic: mammary; estrogen-agonistic: endometrial.
  • Tamoxifen is converted to the active metabolite endoxifen via cytochrome P450 (CYP) enzymes, among other pathways.
  • Note: A patient’s CYP2D6 genotype provides information on the endoxifen plasma concentration to be achieved; 20-33% of tamoxifen patients fail to achieve the desired therapeutic endoxifen plasma concentration target under standard dose!Conclusion: CYP2D6 genotyping for tamoxifen therapy is required!
  • Therapy of choice in hormone receptor-positive breast carcinoma.
  • Anti-hormone therapy with tamoxifen or an aromatase inhibitor (see above) reduces not only the risk of recurrence but also the risk of contralateral breast carcinoma (- 52 percent; relative risk 0.48; 0.22-0.97).
  • Young women (<35 years) with hormone receptor-positive breast carcinoma benefit more (reduction in risk of recurrence) from suppression of ovarian function in combination with tamoxifen or exemestane than from therapy with tamoxifen alone.

GnRH agonists (GnRH analogs) (ovarian suppression, OFS; ovarian function suppression).

Agents
Goserelin
  • Mode of action: suppress ovarian production of estrogen → estrogen serum levels ↓, down to levels in postmenopausal women.

Targeted therapy (targeted therapy, less commonly called molecular or molecular biology therapy).

Substances used in targeted therapy specifically block processes in cancer cells that are important for the growth of tumor tissue. Monoclonal antibodies

Active substances
Bevacizumab
Pertuzumab
Trastuzumab, emtasine
  • Mode of action Bevacizumab: recombinant monoclonal humanized IgG1 antibody against VEGF.
  • Mode of action Pertuzumab: recombinant humanized IgG class monoclonal antibody which binds to HER2 (but to a different epitope than the HER2 antibody trastuzumab).
  • Mode of action trastuzumab: antibody against the growth factor HER2/neu.
  • Red-hand letter: Herceptin (trastuzumab), 03/23/2017: monitoring cardiac function before, during, and after treatment with trastuzumab to reduce the incidence and severity of left ventricular dysfunction and congestive heart failure (CHI).
  • Mode of action Trastuzumab emtansine: The antibody trastuzumab is coupled with a cytotoxin (maytansine derivative DM1). The cytotoxin is transported in an inactive form into the tumor cells and only has a cytostatic effect there. Gentle towards healthy cells.
  • Patients with HER2-positive breast carcinoma, in which tumor cells are still detectable after neoadjuvant chemotherapy, the antibody-drug conjugate trastuzumab emtansine can protect against recurrences longer than the sole antibody trastuzumab.

Tyrosine kinase inhibitor

Active ingredient
Neratinib
  • Mode of action: irreversible binding to the intracellular TKI domains of HER1, HER2, and HER4 b
  • Indication: adjuvant therapy of adult patients with hormone receptor-positive HER2-overexpressed/amplified early-stage breast carcinoma who completed trastuzumab-based adjuvant therapy less than one year ago
  • Side effects: Diarrhea (93.6%), nausea (42.5%), fatigue (27.3%), vomiting (26.8%), abdominal pain (22.7%), exanthema (15.4%), loss of appetite (13.7%), upper abdominal pain (13.2%), stomatitis/mucositis (11.2%), and muscle spasms (10.0%)

EGFR tyrosine kinase inhibitor

Agents
Lapatinib
  • Mode of action: blocks the EGF receptor and the HER2 receptor.

CDK4/6 inhibitor (CDK4/6 inhibitor).

Active ingredients
Abemaciclib
Ribociclib
  • Mode of action: selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6; increases efficacy of antihormonal therapeutic partners through synergistic effects.
  • IQWiG (2/6/2020): Accordingly, for initial endocrine therapy with ribociclib in combination with the aromatase inhibitor letrozole and for follow-up endocrine therapy with ribociclib plus fulvestrant, additional benefit is not proven. For an initial endocrine therapy with ribociclib plus fulvestrant, on the other hand, there is an indication of a small additional benefit.
  • Note: In premenopausal or perimenopausal women, endocrine therapy should be combined with an LHRH agonist.
  • MONALEESA-7 trial (phase III study): ribociclib in combination with hormonal therapy in premenopausal women with advanced breast cancer highly significantly prolongs overall survival: of mostly untreated premenopausal women, 70.2% were still alive at 42 months.CONCLUSION: Women with HR+/HER2- advanced breast cancer should have access to CDK4/6 inhibitors such as ribociclib.

mTOR² inhibitor

Active ingredients
Everolimus
  • Mode of action: mTOR² (mammalian target of rapamycin) inhibitor, blocks a protein that plays a role in important metabolic processes in tumor cells → prolongs survival in metastatic breast carcinoma; counteracts bone resorption

Data from the BOLERO-2 trial demonstrate that the mTOR² inhibitor everolism, in combination with the aromatase inhibitor exemestane, significantly prolongs progression-free survival (PFS) in postmenopausal women with ER+/HER2-advanced breast cancer.

Dual Her2 Blockade

In HER2-positive metastatic breast carcinoma, dual Her2 blockade with the monoclonal antibodies trastuzumab and pertuzumab with taxane-containing chemotherapy is standard in first-line therapy. In the CLEOPATRA trial, the combination of docetaxel with trastuzumab and pertuzumab improved progression-free survival (PFS). Results of a subgroup analysis of the HER2CLIMB trial: Tucatinib (small molecule inhibitor of HER2 for the treatment of HER2-positive breast cancer; dosage; 300 mg orally, 2 x daily) in addition to trastuzumab and capecitabine (precursor of 5-fluorouracil) significantly prolongs survival in women with metastatic HER2-positive breast cancer with brain metastases (daughter tumors in the brain), After one year, 40.2% of patients on tucatinib combination therapy were still without CNS progression (progression of the disease in the central nervous system) (control arm: 0 patients).

Therapy of triple-negative breast cancer (TNBC)

The prognosis of metastatic triple-negative breast cancer promises to be improved by immunotherapy with checkpoint inhibitors.The IMpassion-130 trial demonstrated a significant and clinically relevant benefit of immunotherapy with a checkpoint inhibitor in metastatic TNBC. However, this only applies to patients in whom PD-L1-expressing tumor-infiltrating immune cells cover at least 1% of the tumor area ( PD-L1 IC+), which is the case in approximately 40% of untreated TNBC. The risk of progression or death in metastatic triple-negative breast cancer is reduced by 35% with first-line therapy with pembrolizumab in addition to chemotherapy compared with chemotherapy alone.

PARP inhibitors in therapy for advanced BRCA tumors

PARP inhibitors block an enzyme involved in DNA repair. Olaparib, from the class of drugs known as PARP (poly-ADP-ribose polymerase) inhibitors, is already used to treat BRCA-positive ovarian cancer. In a first randomized open-label phase III study with olaparib (dose of 300 mg/day), outcomes of patients with BRCA-positive (+ HER2-negative) breast cancer were improved compared to standard chemotherapy: with olaparib, the median time to progression was 7.0 months compared to 4.2 months with standard chemotherapy. The PARP inhibitor talazoparib, which prevents copy defect repair in tumor cells, also prolongs progression-free survival (19.5 to 22.3 months) in advanced BRCA1/2 breast cancer in a phase III trial.

Chemotherapy

Adjuvant Chemotherapy

According to the 2011 St Gallen Conference recommendations, indications for adjuvant chemotherapy include:

  • Luminal B-like
    • HER 2 negative
    • HER 2 positive
  • HER 2 positive (non- luminal)
  • Triple negative (ductal)
  • Luminal A in advanced disease, for example.
    • ≥ 4 lymph nodes
    • Grading 3
    • Ki-67 ≥ 14 %

Notice:

  • If adjuvant chemotherapy is not started within 120 days after diagnosis of operable breast carcinoma, this results in losses in survival of approximately 30%.
  • Therapy with the GnRH analog goserelin may prevent premature onset of menopause due to chemotherapy and preserve fertility in premenopausal women with hormone receptor-negative breast carcinoma.

The following chemotherapy regimens are currently in common use S3 guideline (7) p. 340.

Schema Cyclophosphamide (C) Anthracyclines: Doxorubicin(A) Epirubicin (E). 5-fluorouracil (F) Taxanes (T): paclitaxel (P) docetaxel (D) Methotrexate (MTX) Wdh. (cycle)
FEC 500-600 mg/m2 i.v. d 1 100 mg/m2 i.v. d 1 (E) 500-600 mg/m2 i.v. d 1 every 3 weeks
FAC/CAF 500-600 mg/m2 i.v. d 1 60 mg/m2 i.v. d 1 (A) 500-600 mg/m2 i.v. d 1 every 3 weeks
CEF 75 mg/m2 p.o. d 1- 14 60 mg/m2 i.v. d 1 +8 (E) 500 mg/m2 i.v. d 1 – – every 4 weeks
AC-T 600 mg/m2 i.v. d 1 cycle 1-4 60 mg/m2 i.v. d 1 (A) cycle 1 -4 1 75 mg/m2 d 1 (P) cycle 5-8 alternatively, 80 mg/m2 d 1, 1 2 times a week. every 3 weeks
AC-D 600 mg/m2 i.v. d 1 cycle 1-4 60 mg/m2 i.v. d 1 (A) cycle 1 -4 1 00 mg/m2 d 1 (D) cycle 5-8 every 3 weeks
TAC 500 mg/m2 i.v. d 1 50 mg/m2 i.v. d 1 (A) – 75 mg/m2 d 1(D) – every 3 weeks

Remarks/Recommendations

  • Adjuvant combination chemotherapy can reduce recurrence and mortality.
  • Dose intensity of anthracyclines: Doxorubicin 20 mg/m2/week, epirubicin at least 30 mg/m2/week. The planned dose intensity should be maintained because of efficacy.
  • Adjuvant endocrine therapy (subsequent to chemotherapy) in case of positive hormone receptor status (ER-pos. and/or PgR-pos.).
  • Because of higher cardiac risk, trastuzumab should not be given concomitantly with anthracyclines (doxorubicin, epirubicin). In this case, trastuzumab is given after completion of anthracycline administration or, in the case of staggered regimens, together with the taxane.
  • In HER-2 positive disease, pertuzumab and trastuzumab together with taxane-containing chemotherapy are now standard in first-line therapy (CLEOPATRA trial).
  • In breast cancer patients with locally advanced or metastatic breast carcinoma, chemotherapy with cyclophosphamide in combination with antiHER2 therapy may be the better route for very elderly patients instead of therapy with docetaxel (due toreduced toxicity with good efficacy).

Primary systemic chemotherapy (PST)

This is also known as neoadjuvant chemotherapy (NACT) and is now the standard treatment given to patients with:

  • Locally advanced breast cancer (LABC: locally advanced breast cancer).
    • Definition:
      • > 5 cm clinically, mammographically, or sonographically.
      • Secured skin involvement (redness, ulceration).
      • Thoracic wall infiltration (muscle or ribs),
      • Tumor-infiltrated axillary lymph nodes, fixed.
      • Metastatically affected lymph nodes in the axillary apex or infraclavicularly
  • Primary unresectable breast carcinoma
  • Inflammatory breast carcinoma

Sentinel lymph nodes must be extirpated before starting chemotherapy. Neoadjuvant therapy may result in a higher rate of breast-conserving therapy. The effect is greatest in hormone receptor-negative carcinomas. If neoadjuvant chemotherapy is indicated, it should include an anthracycline and a taxane (trastuzumab + pertuzumab if HER2 positive).6-8 cycles should be performed. The extent of postoperative radiation is based on the original tumor spread before chemotherapy, not on the findings after chemotherapy. Chemotherapy is usually combined with subsequent ablation followed by radiotherapy, rarely vice versa. Occasionally, breast-conserving surgery may be performed subsequently. Further notes

  • BrighTNess trial: in the highly aggressive form of stage 2 or 3 triple-negative breast carcinoma (TNBC) with and without germline BRCA mutations, the PARP inhibitor velaparib in combination with standard neoadjuvant chemotherapy did not increase the rate of pathohistologic complete remission (pCR). A secondary analysis of a randomized clinical trial of 604 women with stage II to III triple-negative breast cancer showed that neoadjuvant systemic therapy provided breast preservation in 53.2% of patients who would otherwise have required mastectomy, increasing the percentage of eligible patients for breast preservation from 76.5% at diagnosis to 83.8%.

Dietary recommendations during chemotherapy

In a phase II study, of 129 women with a nonmetastatic HER2-negative stage II/III breast tumor who planned neoadjuvant AC-T or FEC-T chemo, three days of fasting with soup, broth, and tea before chemotherapy appeared to increase response rates and improve tumor regression. Limitation: small number of participants; poor adherence (only one-third in the fasting-mimicking diet group maintained fasting for four cycles of chemotherapy, and only one-fifth for all cycles of chemotherapy); results of larger trials await. Legend